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1.	de Vries, Charlotte, et al. (author) Antibodies to Porphyromonas gingivalis Are Increased in Patients with Severe Periodontitis, and Associate with Presence of Specific Autoantibodies and Myocardial Infarction 2022 In: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 11:4 Journal article (peer-reviewed)abstract There is accumulating data suggesting that periodontitis is associated with increased risk of systemic and autoimmune diseases, including cardiovascular disease, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and there is an unmet need to identify these individuals early. With the periodontal bacteria Porphyromonas gingivalis (Pg) as one of the key drivers of periodontitis, we set out to investigate whether antibodies to Pg virulence factor arginine gingipain (Rgp) could serve as a biomarker for periodontitis patients at increased risk of autoimmunity and systemic disease. We measured serum anti-Rgp IgG in three study populations: PAROKRANK (779 individuals with myocardial infarction (MI); 719 controls), where 557 had periodontitis, and 312 were positive for autoantibodies associated with RA/SLE; the PerioGene North pilot (41 periodontitis; 39 controls); and an SLE case/control study (101 SLE; 100 controls). Anti-Rgp IgG levels were increased in severe periodontitis compared to controls (p < 0.0001), in individuals positive for anti-citrullinated protein antibodies (p = 0.04) and anti-dsDNA antibodies (p = 0.035), compared to autoantibody-negative individuals; and in MI patients versus matched controls (p = 0.035). Our data support longitudinal studies addressing the role of anti-Rgp antibodies as biomarkers for periodontitis patients at increased risk of developing autoimmunity linked to RA and SLE, and mechanisms underpinning these associations.
2.	Henning, Petra, 1974, et al. (author) Toll-like receptor-2 induced inflammation causes local bone formation and activates canonical Wnt signaling. 2024 In: Frontiers in immunology. - : Frontiers Media S.A.. - 1664-3224. ; 15:5 Journal article (peer-reviewed)abstract It is well established that inflammatory processes in the vicinity of bone often induce osteoclast formation and bone resorption. Effects of inflammatory processes on bone formation are less studied. Therefore, we investigated the effect of locally induced inflammation on bone formation. Toll-like receptor (TLR) 2 agonists LPS from Porphyromonas gingivalis and PAM2 were injected once subcutaneously above mouse calvarial bones. After five days, both agonists induced bone formation mainly at endocranial surfaces. The injection resulted in progressively increased calvarial thickness during 21 days. Excessive new bone formation was mainly observed separated from bone resorption cavities. Anti-RANKL did not affect the increase of bone formation. Inflammation caused increased bone formation rate due to increased mineralizing surfaces as assessed by dynamic histomorphometry. In areas close to new bone formation, an abundance of proliferating cells was observed as well as cells robustly stained for Runx2 and alkaline phosphatase. PAM2 increased the mRNA expression of Lrp5, Lrp6 and Wnt7b, and decreased the expression of Sost and Dkk1. In situ hybridization demonstrated decreased Sost mRNA expression in osteocytes present in old bone. An abundance of cells expressed Wnt7b in Runx2-positive osteoblasts and ß-catenin in areas with new bone formation. These data demonstrate that inflammation, not only induces osteoclastogenesis, but also locally activates canonical WNT signaling and stimulates new bone formation independent on bone resorption.
3.	Tengvall, Katarina, 1980-, et al. (author) Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk 2019 In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:34, s. 16955-16960 Journal article (peer-reviewed)abstract Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 x 10(-36)) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95% CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB115: 01 carriage, absence of HLA-A02: 01, and high anti-EBNA1 antibody levels (OR = 24.9; 95% CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLADRB1*04: 01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95% CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.
4.	ALi, Kassem, et al. (author) Toll-like receptor induced inflammation causes local bone formation Other publication (other academic/artistic)abstract It is well established that inflammatory processes in the vicinity of bone often induce osteoclast formation and bone resorption. Effects on bone formation by inflammatory processes are much less studied and available information is partly contradictory. In the present study, we have assessed the effect on bone formation by locally induced inflammation. LPS from Porphyromonas gingivalis and Pam2, used as Toll-like receptor (TLR) 2 agonists, and flagellin from Salmonella typhimurium, used as TLR5 agonist, were injected subcutaneously on the top of mouse skull bones. After 1-5 days, the calvarial bones were dissected and processed either for histological or gene expression analyses. Femur was dissected for analysis with microCT and histology. At day 5, all three agonists induced bone formation on periosteal and endosteal sites, as well as in the bone marrow compartment of the calvaria. This response was seen both in close vicinity to, but also apart from, osteoclasts and bone resorption cavities. In areas close to new bone formation, abundance of proliferating cells was observed as assessed by Ki67 labelling. Gene expression analyses showed that Pam2 treatment resulted in increased mRNA expression at day 5 of genes encoding bone matrix proteins, alkaline phosphatase and of the osteoblastic transcription factors Runx2 and osterix. Robust Runx2 protein was observed in osteoblasts in areas with new bone formation. Pam2 treatment also increased the mRNA expression of cytokines in the IL-6 family, as well as of their cognate receptors and common signaling transduction subunit gp130. At day 5, the mRNA expression of Bmp2, Bmp4, Tgfb1, Lrp5, Lrp6 and Wnt7b was increased, whereas Sost was decreased. In the femur, excessive osteoclast formation and trabecular bone loss was found at day 5, but new bone formation was not observed. In conclusion, these data show that inflammatory processes not only induce osteoclastogenesis but also have the capacity to activate osteoblasts and stimulate new bone formation distinct from bone remodeling sites. Stimulation of inflammation- induced new bone formation may be due to enhanced gp130 signaling. Osteoblast activation in the inflammatory processes may also involve the BMP and WNT signaling systems.
5.	Andersson, Martin K, et al. (author) Effects on osteoclast and osteoblast activities in cultured mouse calvarial bones by synovial fluids from patients with a loose joint prosthesis and from osteoarthritis patients. 2007 In: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 9:1 Journal article (peer-reviewed)abstract Aseptic loosening of a joint prosthesis is associated with remodelling of bone tissue in the vicinity of the prosthesis. In the present study, we investigated the effects of synovial fluid (SF) from patients with a loose prosthetic component and periprosthetic osteolysis on osteoclast and osteoblast activities in vitro and made comparisons with the effects of SF from patients with osteoarthritis (OA). Bone resorption was assessed by the release of calcium 45 (45Ca) from cultured calvariae. The mRNA expression in calvarial bones of molecules known to be involved in osteoclast and osteoblast differentiation was assessed using semi-quantitative reverse transcription-polymerase chain reaction (PCR) and real-time PCR. SFs from patients with a loose joint prosthesis and patients with OA, but not SFs from healthy subjects, significantly enhanced 45Ca release, effects associated with increased mRNA expression of calcitonin receptor and tartrate-resistant acid phosphatase. The mRNA expression of receptor activator of nuclear factor-kappa-B ligand (rankl) and osteoprotegerin (opg) was enhanced by SFs from both patient categories. The mRNA expressions of nfat2 (nuclear factor of activated T cells 2) and oscar (osteoclast-associated receptor) were enhanced only by SFs from patients with OA, whereas the mRNA expressions of dap12 (DNAX-activating protein 12) and fcrgamma (Fc receptor common gamma subunit) were not affected by either of the two SF types. Bone resorption induced by SFs was inhibited by addition of OPG. Antibodies neutralising interleukin (IL)-1alpha, IL-1beta, soluble IL-6 receptor, IL-17, or tumour necrosis factor-alpha, when added to individual SFs, only occasionally decreased the bone-resorbing activity. The mRNA expression of alkaline phosphatase and osteocalcin was increased by SFs from patients with OA, whereas only osteocalcin mRNA was increased by SFs from patients with a loose prosthesis. Our findings demonstrate the presence of a factor (or factors) stimulating both osteoclast and osteoblast activities in SFs from patients with a loose joint prosthesis and periprosthetic osteolysis as well as in SFs from patients with OA. SF-induced bone resorption was dependent on activation of the RANKL/RANK/OPG pathway. The bone-resorbing activity could not be attributed solely to any of the known pro-inflammatory cytokines, well known to stimulate bone resorption, or to RANKL or prostaglandin E2 in SFs. The data indicate that SFs from patients with a loose prosthesis or with OA stimulate bone resorption and that SFs from patients with OA are more prone to enhance bone formation.
6.	Baldock, Paul A., et al. (author) Novel role of Y1 receptors in the coordinated regulation of bone and energy homeostasis 2007 In: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 282:26, s. 19092-19102 Journal article (peer-reviewed)abstract The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1(-/-) mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1(-/-) mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.
7.	Bostrom, E. A., et al. (author) Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines 2015 In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8 Journal article (peer-reviewed)abstract Periodontitis is a chronic inflammatory disease of tooth supporting tissues resulting in periodontal tissue destruction, which may ultimately lead to tooth loss. The disease is characterized by continuous leukocyte infiltration, likely mediated by local chemokine production but the pathogenic mechanisms are not fully elucidated. There are no reliable serologic biomarkers for the diagnosis of periodontitis, which is today based solely on the degree of local tissue destruction, and there is no available biological treatment tool. Prompted by the increasing interest in periodontitis and systemic inflammatory mediators we mapped serum cytokine and chemokine levels from periodontitis subjects and healthy controls. We used multivariate partial least squares (PLS) modeling and identified monocyte chemoattractant protein-1 (MCP-1) and eotaxin as clearly associated with periodontitis along with C-reactive protein (CRP), years of smoking and age, whereas the number of remaining teeth was associated with being healthy. Moreover, body mass index correlated significantly with serum MCP-1 and CRP, but not with eotaxin. We detected higher MCP-1 protein levels in inflamed gingival connective tissue compared to healthy but the eotaxin levels were undetectable. Primary human gingival fibroblasts displayed strongly increased expression of MCP-1 and eotaxin mRNA and protein when challenged with tumor necrosis factor-alpha (TNF-alpha and interleukin-1 beta (IL-1 beta), key mediators of periodontal inflammation. We also demonstrated that the upregulated chemokine expression was dependent on the NF-kappa B pathway. In summary, we identify higher levels of CRP, eotaxin and MCP-1 in serum of periodontitis patients. This, together with our finding that both CRP and MCP-1 correlates with BMI points towards an increased systemic inflammatory load in patients with periodontitis and high BMI. Targeting eotaxin and MCP-1 in periodontitis may result in reduced leukocyte infiltration and inflammation in periodontitis and maybe prevent tooth loss.
8.	Boström, Elisabeth A., et al. (author) The Newly Discovered Cytokine IL-34 Is Expressed in Gingival Fibroblasts, Shows Enhanced Expression by Pro-Inflammatory Cytokines, and Stimulates Osteoclast Differentiation 2013 In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12, s. e81665- Journal article (peer-reviewed)abstract Background: Interleukin-34 (IL-34) is a recently discovered cytokine functionally overlapping macrophage colony stimulating factor (M-CSF), a mediator of inflammation and osteoclastogenesis in bone-degenerative diseases such as rheumatoid arthritis. The objective of this study was to assess the expression of IL-34 in human gingival fibroblasts and investigate if the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and Interleukin-1B (IL-1 beta) modulate its expression, and moreover if IL-34 could contribute to recruitment of bone-resorbing osteoclasts. Methods: IL-34 expression was evaluated in gingival fibroblasts by real time PCR following stimulation by TNF-alpha, IL-1 beta, and treatment with inhibitors of intracellular pathways. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining of bone marrow macrophages treated with IL-34 or M-CSF in addition to receptor activator of nuclear factor kappa-B ligand (RANKL). Results: IL-34 was expressed in gingival fibroblasts. The expression was enhanced by TNF-alpha and IL-1 beta, regulated by the transcription factor nuclear factor kappa B (NF-kappa B) and activation of c-Jun N-terminal kinase (JNK). Further, IL-34 supports RANKL-induced osteoclastogensis of bone marrow macrophages, independently of M-CSF. Summary: In conclusion, this study shows for the first time IL-34 expression in human gingival fibroblasts, stimulated by TNF-alpha and IL-1 beta, key mediators of periodontal inflammation. Furthermore, IL-34 can be substituted for M-CSF in RANKL-induced osteoclastogenesis. IL-34 may contribute to inflammation and osteoclastogenesis in bone-degenerative diseases such as periodontitis.
9.	Broqvist, Mari, 1958-, et al. (author) Beslutsstöd för prioriteringar på individnivå : Exempel från hjälpmedelsverksamhet 2019 Reports (other academic/artistic)abstract Alltsedan 1997 då den etiska plattformen för resursfördelning introducerades i den svenska hälso- och sjukvården har metodutveckling pågått i syfte att stödja vårdens aktörer i de svåra avvägningar som prioriteringar ofta innebär. Fokus har varit på de stora frågorna, om resursfördelning på regionnivå och policybeslut i olika verksamheter, men det stora antalet prioriteringar görs på daglig basis i mötet mellan personal och patienter.Den här rapporten vänder sig till er som vill arbeta med att göra prioriteringar på individnivå på mer likvärdiga grunder i linje med de riktlinjer om prioriteringar som riksdagen beslutat om. Här presenteras ett verktyg, Beslutsstöd för prioriteringar på individnivå, som syftar till att styra insamlandet och analys gällande vårdbehov så att behovs-solidaritetsprincipen och kostnadseffektivitetsprincipen i riksdagens riktlinjer för prioriteringar beaktas vid bedömningen. Beslutsstödet är resultatet av ett mångårigt utvecklingsarbete, byggt på erfarenheter framför allt inom hjälpmedelsverksamheter i flera olika regioner. Utöver att användas vid hjälpmedelsförskrivning är beslutsstödet även tänkt att kunna prövas för andra typer av hälso- och sjukvårdsåtgärder.Beslutsstödet som används för att avgöra hur prioriterat en persons hälsoproblem och en tänkt åtgärd bör vara består av ett bedömningsformulär och en manual. Svårighetsgrad, patientnytta och patientnytta i relation till kostnad bedöms där i ett antal bedömningspunkter som styr bedömningen mot en prioriteringsgrad.Ett syfte med beslutsstödet är att skapa prioriteringar på mer lika grunder. Infört på ett välorganiserat sätt, kan det bidra till att skapa förståelse och acceptans för gemensamma grunder och en större öppenhet i prioriteringar. I den här rapporten ges ett exempel på en genomtänkt implementeringsprocess från hjälpmedelsverksamheten i Region Jönköpings län. En viktig slutsats av det arbetet är att stöd från ledning och politiker, metodstöd till användarna av beslutsstödet samt uthållighet är huvudingredienser för att lyckas i ett sådant arbete.
10.	Divaris, K., et al. (author) Phenotype Harmonization in the GLIDE2 Oral Health Genomics Consortium 2022 In: Journal of Dental Research. - : Sage Publications. - 0022-0345 .- 1544-0591. ; 101:11, s. 1408-1416 Journal article (peer-reviewed)abstract Genetic risk factors play important roles in the etiology of oral, dental, and craniofacial diseases. Identifying the relevant risk loci and understanding their molecular biology could highlight new prevention and management avenues. Our current understanding of oral health genomics suggests that dental caries and periodontitis are polygenic diseases, and very large sample sizes and informative phenotypic measures are required to discover signals and adequately map associations across the human genome. In this article, we introduce the second wave of the Gene-Lifestyle Interactions and Dental Endpoints consortium (GLIDE2) and discuss relevant data analytics challenges, opportunities, and applications. In this phase, the consortium comprises a diverse, multiethnic sample of over 700,000 participants from 21 studies contributing clinical data on dental caries experience and periodontitis. We outline the methodological challenges of combining data from heterogeneous populations, as well as the data reduction problem in resolving detailed clinical examination records into tractable phenotypes, and describe a strategy that addresses this. Specifically, we propose a 3-tiered phenotyping approach aimed at leveraging both the large sample size in the consortium and the detailed clinical information available in some studies, wherein binary, severity-encompassing, and “precision,” data-driven clinical traits are employed. As an illustration of the use of data-driven traits across multiple cohorts, we present an application of dental caries experience data harmonization in 8 participating studies (N = 55,143) using previously developed permanent dentition tooth surface–level dental caries pattern traits. We demonstrate that these clinical patterns are transferable across multiple cohorts, have similar relative contributions within each study, and thus are prime targets for genetic interrogation in the expanded and diverse multiethnic sample of GLIDE2. We anticipate that results from GLIDE2 will decisively advance the knowledge base of mechanisms at play in oral, dental, and craniofacial health and disease and further catalyze international collaboration and data and resource sharing in genomics research.
11.	Djusberg, Erik, et al. (author) High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases 2017 In: The Prostate. - : Wiley-Blackwell Publishing Inc.. - 0270-4137 .- 1097-0045. ; 77:6, s. 625-638 Journal article (peer-reviewed)abstract BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.
12.	Esberg, Anders, et al. (author) LIGHT protein : a novel gingival crevicular fluid biomarker associated with increased probing depth after periodontal surgery 2024 In: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 51:7, s. 852-862 Journal article (peer-reviewed)abstract Aim: To evaluate the protein profiles in gingival crevicular fluid (GCF) in relation to clinical outcomes after periodontal surgery and examine if any selected proteins affect the mRNA expression of pro-inflammatory cytokines in human gingival fibroblasts.Materials and Methods: This exploratory study included 21 consecutive patients with periodontitis. GCF was collected, and the protein pattern (n = 92) and clinical parameters were evaluated prior to surgery and 3, 6 and 12 months after surgery. Fibroblastic gene expression was analysed by real-time quantitative polymerase chain reaction.Results: Surgical treatment reduced periodontal pocket depth (PPD) and changed the GCF protein pattern. Twelve months after surgery, 17% of the pockets showed an increase in PPD. Levels of a number of proteins in the GCF decreased after surgical treatment but increased with early signs of tissue destruction, with LIGHT being one of the proteins that showed the strongest association. Furthermore, LIGHT up-regulated the mRNA expression of pro-inflammatory cytokines interleukin (IL)-6, IL-8 and MMP9 in human gingival fibroblasts.Conclusions: LIGHT can potentially detect subjects at high risk of periodontitis recurrence after surgical treatment. Moreover, LIGHT induces the expression of inflammatory cytokines and tissue-degrading enzymes in gingival fibroblasts.
13.	Esberg, Anders, et al. (author) Peri-implant crevicular fluid proteome before and after adjunctive enamel matrix derivative treatment of peri-implantitis 2019 In: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 46:6, s. 669-677 Journal article (peer-reviewed)abstract Aim: The aim of this study was to explore which peri‐implant crevicular fluid (PICF) protein pattern is associated with the active peri‐implantitis process.Materials and methods: Peri‐implant crevicular fluid from 25 peri‐implantitis sites were subjected to proteomic analysis using liquid chromatography–tandem mass spectrometry before and at 3, 6 and 12 months after treatment, to identify associations between PICF protein pattern and implant loss, bleeding on probing, pocket depth and enamel matrix derivative (EMD) treatment.Results: Clustering of subjects based on their 3–12 months PICF proteomic profiles by principal component analysis defined two major clusters. Cluster 2 differentiated from cluster 3 by 52 proteins (R2 = 90%, Q2 = 80%) and belonging to cluster 2 was associated with implant loss (p = 0.009) and bleeding on probing (p = 0.001). Cluster 3 was associated with implant survival and EMD treatment (p = 0.044).Conclusion: Here, we demonstrate that a specific PICF proteomic profile associates with active peri‐implantitis process and implant loss.
14.	Esberg, Anders, et al. (author) PICF proteome before and after adjunctive EMD treatment of peri-implantitis Other publication (other academic/artistic)abstract Aim: The aim of this study was to explore which peri-implant crevicular fluid (PICF) protein patter that are associated with the active peri-implantitis process.Materials and methods: PICF from 25 peri-implantitis sites were subjected to proteomic analysis using liquid chromatography-tandem mass spectrometry before and at 3, 6 and 12 months after treatment, to identify associations between protein expression and implant loss, radiographic bone level change, bleeding on probing, pocket depth, and enamel matrix derivative (EMD) treatment. Results: Clustering of subjects based on their 3 to 12 months PICF proteomic profiles by principal component analysis defined two major clusters. Cluster 2 was differentiated from cluster 3 by 52 proteins (R2=90%, Q2=80%) and belonging to cluster 2 had an odds ratio for implant loss of 7.9 (95% confidence interval 1.8 to 35.9). Cluster 3 was related to implant survival (p=0.007) after 5 years and associated with EMD treatment (p=0.044). Furthermore, cluster 2 was associated with radiographic bone loss (p<0.0001) and bleeding on probing (p=0.001). Conclusion: EMD treatment was associated with the PICF proteomic profile related to implant survival. EMD reduced number of proteins, dominated by proteins associated with implant loss. However, whether these effects are direct or indirect requires further exploration.
15.	Esberg, Anders, et al. (author) Serum proteins associated with periodontitis relapse post-surgery: A pilot study 2021 In: Journal of Periodontology. - : John Wiley & Sons. - 0022-3492 .- 1943-3670. ; 92:12, s. 1805-1814 Journal article (peer-reviewed)abstract Background: The knowledge of which genes and proteins that are connected to the susceptibility to gingivitis with subsequent local tissue degradation seen in periodontitis is insufficient. Changes of serum proteins associated with recurrence of bleeding on probing (BOP) and increased periodontal pocket depths (PPD) after surgical treatment of periodontitis could reveal molecules that could be early signals of tissue destruction and/or of importance for systemic effects in other tissues or organs.Methods: We performed a longitudinal pilot study and followed 96 inflammation-related proteins over time in serum from patients who underwent surgical treatment of periodontitis (n= 21). The samples were taken before (time 0), and then at 3, 6, and 12 months after surgery. Changes in protein levels were analysed in relation to the clinical outcome measures, that is, proportion of surfaces affected by BOP and PPD. Results: Changes in treatment outcomes with early signs of relapse in periodontitis after surgical treatment, for example, increased BOP and PPDs, were during 12-months follow up associated with increased serum levels of high-sensitivity C-reactive protein (hs-CRP) and programmed death-ligand 1 (PD-L1), and reduced serum levels of cystatin-D protein.Conclusion: This study shows that clinical signs of recurrence of periodontitis after surgery are reflected in serum, but larger studies are needed for verification. Our novel findings of an association between increased PD-L1- and decreased cystatin D-levels and recurrence in periodontitis are interesting because PD-L1 has been shown to facilitate bacterial infections and chronic inflammation and cystatin D to inhibit tissue destruction. Our results justify mechanistic studies regarding the role of these molecules in periodontitis.
16.	Giannobile, W. V., et al. (author) Biological factors involved in alveolar bone regeneration Consensus report of Working Group 1 of the 15(th) European Workshop on Periodontology on Bone Regeneration 2019 In: Journal of Clinical Periodontology. - : Wiley. - 0303-6979 .- 1600-051X. ; 46, s. 6-11 Journal article (peer-reviewed)abstract Background and Aims To describe the biology of alveolar bone regeneration. Material and Methods Four comprehensive reviews were performed on (a) mesenchymal cells and differentiation factors leading to bone formation; (b) the critical interplay between bone resorbing and formative cells; (c) the role of osteoimmunology in the formation and maintenance of alveolar bone; and (d) the self-regenerative capacity following bone injury or tooth extraction were prepared prior to the workshop. Results and Conclusions This summary information adds to the fuller understanding of the alveolar bone regenerative response with implications to reconstructive procedures for patient oral rehabilitation. The group collectively formulated and addressed critical questions based on each of the reviews in this consensus report to advance the field. The report concludes with identified areas of future research.
17.	Gluch, Pernilla, 1968, et al. (author) Environmental attitudes, management and performance 2010 In: Performance Improvement in Construction Management (eds. Atkin and Borgbrant). ; , s. 158-172 Book chapter (other academic/artistic)
18.	Gluch, Pernilla, 1968, et al. (author) Miljöbarometern för bygg- och fastighetssektorn 2006 - en kartläggning av sektorns miljöarbete 2007 Reports (other academic/artistic)abstract Studien har kartlagt företagens syn på miljöutmaningen, responsen på densamma samt resultatet av genomfört miljöarbete. Enkätstudien som genomfördes under hösten 2006 riktades till miljöansvariga i inom svensk bygg- och fastighetssektor, av totalt 542 företag svarade 246. Resultaten visar att företagen upplever att miljöproblemen minskat något eller varit oförändrade under den senaste fyraårsperioden, men också att sektorn fortfarande kämpar med energifrågan och bruk av ej förnyelsebara material. Företagen fortsätter dessutom att lägga resurser på avfallshantering och miljöledningssystem. Företagen uppskattar att de främst uppnått resultat inom källsortering och kemikalieanvändning. I grova drag har bygg- och fastighetsföretagen under den senaste perioden satsat ännu mer på det man redan satsat mycket på. Resultaten visar att hindren för att göra gröna affärer idag upplevs mer framträdande, vilket lett till att fler tappat tron på marknadsmekanismer som lösning på problemen. Istället har lagstiftande åtgärder som främsta lösning stärkts. Under perioden har konceptet hållbar utveckling fått genomslag, även om det hittills inte påverkat organiseringen av arbetet i företagen. Slutsatsen som dras är att företagen inom bygg- och fastighetssektorn har ett aktivt miljöarbete men att utvecklingen på området uppvisar en viss utvecklingströghet. Studien identifierar sex möjliga orsaker till denna tröghet vilka presenteras i rapporten.
19.	Gluch, Pernilla, 1968, et al. (author) What makes it slow? A questionnaire survey of environmental attitudes, management and performance 2007 In: 4th Nordic Conference on Construction Economics and Organisation, 14th-15th June 2007, Luleå, Sweden. Conference paper (peer-reviewed)abstract Over the last two decades the Swedish building industry has made much effort to develop green building practices. Researchers within the field have provided theoretical knowledge on how to design green buildings and analytical environmental management tools have been developed to guide practitioners. Information campaigns have raised the general environmental awareness among building practitioners. In spite of these efforts, mainstream building practices do not seem to have undergone any marked changes. This raises the question of how environmental issues actually are dealt with in the building industry. Has the development stagnated and, if so, why? What causes green innovation inertia in the Swedish building industry? What makes it slow? This paper provides some answers to these questions by empirically examining environmental attitudes, management and performance in the industry. The paper is based on a structured questionnaire survey directed to environmental managers at all companies in Sweden with at least 50 employees within technical consultants, building constructors, and property owners and managers and companies with at least 20 employees within architecture. The response rate was 45.4% which corresponds to 246 respondents. The study detects possible causes to deficiencies and creates larger understanding as to why the development, despite much effort, sometimes does not go in the direction as intended by top management. Focusing on relations between the definition of environmental challenge, measures adopted and results from measures, the paper identifies trends and institutionalising processes that hinder sustainable development within the building industry.
20.	Granholm, Susanne, et al. (author) Calcitonin inhibits osteoclast formation in mouse haematopoetic cells independently of transcriptional regulation by receptor activator of NF-{kappa}B and c-Fms. 2007 In: The Journal of endocrinology. - 1479-6805. ; 195:3, s. 415-27 Journal article (peer-reviewed)abstract The effects of calcitonin (CT) on osteoclast formation and gene expression have been studied in cultured mouse spleen cells and mouse bone marrow macrophages (BMMs). CT inhibited the formation of multinucleated osteoclasts and resorption pits in spleen cell cultures and BMM as well as in CD115(+) CD3(-) CD45R(-)sorted BMM cultures, incubated in the presence of macrophage colony-stimulating factor and receptor activator of NF-kappaB ligand (RANKL). No effect on apoptosis by CT was observed. CT did not affect the mRNA expressions of RANK and c-Fms, or the mRNA expressions of a wide variety of transcription factors and genes important for osteoclast differentiation and activity. CT induced inhibition of tartrate-resistant acid phosphatase (TRAP), positive multinucleated osteoclast formation was not associated with any decrease of total TRAP activity, resulting in a large number of TRAP(+) mononucleated cells in CT-treated cultures. CT did not affect the mRNA expression of dendritic cell-specific transmembrane protein, d2 isoform of vacuolar (H(+)) ATPase v(o) domain, a disintegrin and metalloproteinase domain 8 (ADAM8), ADAM12, DNAX-activating protein or Fc receptor common gamma chain suggested to be involved in fusion of mononucleated osteoclast progenitor cells. The inhibitory effect by CT was mimicked not only by compounds activating cAMP and protein kinase A (PKA) but also by a cAMP analogue activating the exchange protein directly activated by cAMP (Epac) pathway. It is concluded that CT, through cAMP/PKA/Epac cascades, inhibits osteoclast formation and that this effect is not associated with decreased transcription of genes known to be important for osteoclast progenitor cell differentiation, fusion or function.
21.	Granholm, Susanne, et al. (author) Calcitonin inhibits osteoclast formation in mouse hematopoetic cells independently of transcriptional regulation by RANK and c-Fms 2007 In: Journal of endocrinology. - 0022-0795. ; 195:3, s. 415-427 Journal article (peer-reviewed)
22.	Granholm, Susanne, et al. (author) Expression of the calcitonin receptor, calcitonin receptor-like receptor, and receptor activity modifying proteins during osteoclast differentiation. 2008 In: Journal of cellular biochemistry. - : Wiley. - 1097-4644 .- 0730-2312. ; 104:3, s. 920-33 Journal article (peer-reviewed)abstract The expressions of the calcitonin receptor (CTR), the calcitonin receptor-like receptor (CLR), the receptor activity-modifying proteins (RAMP) 1-3, and of the receptor component protein (RCP) have been studied in mouse bone marrow macrophages (BMM) during osteoclast differentiation, induced by treatment with M-CSF and RANKL. Analyses of mRNA showed that CLR and RAMP1-3, but not CTR, were expressed in M-CSF stimulated BMM. RANKL gradually increased CTR mRNA, transiently enhanced CLR and transiently decreased RAMP1 mRNA, but did not affect RAMP2, RAMP3, or RCP mRNA. However, RANKL did not affect protein levels of CLR or RAMP1-3 as assessed by Western blots or FACS analyses, whereas immunocytochemistry showed enhanced CTR protein. Analyses of cAMP production showed that BMM cells expressed functional receptors for calcitonin gene-related peptide (CGRP), amylin, adrenomedullin, and intermedin, but not for calcitonin and calcitonin receptor stimulating peptide (CRSP), but that RANKL induced the expression of receptors for calcitonin and CRSP as well. Calcitonin, CGRP, amylin, adrenomedullin, intermedin, and CRSP all down regulated the CTR mRNA, but none of the peptides caused any effects on the expression of CLR or any of the RAMPs. Our data show that BMM cells express receptors for CGRP, amylin, adrenomedullin, and intermedin and that RANKL induces the formation of receptors for calcitonin and CRSP in these cells. We also show, for the first time, that the CTR is not only down regulated by signaling through the CTR but also by the peptides signaling through CLR/RAMPs.
23.	Granholm, Susanne, 1975- (author) The calcitonin gene family of peptides : receptor expression and effects on bone cells 2008 Doctoral thesis (other academic/artistic)abstract The calcitonin gene family of peptides consists of calcitonin (CT), two calcitonin gene related peptides (α-CGRP, β-CGRP), adrenomedullin (ADM), amylin (AMY), three calcitonin receptor activating peptides (CRSP1-3) and intermedin/adrenomedullin2 (IMD). These peptides bind to one of two G protein -coupled receptors, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CRLR). The receptor specificity to different ligands is dependent on the formation of a complex with one of three receptor activity-modifying proteins (RAMP1-3). The aim of this study was to analyse effects of this family of peptides on the formation of osteoclasts and bone resorption, and the expression of the receptor components in bone cells. CT inhibited the formation of multinucleated osteoclasts in spleen cell cultures and in bone marrow macrophage cultures (BMM) without affecting a number of genes important for osteoclast differentiation, activity or fusion of osteoclast progenitor cells. All members of the CT family, except ADM, inhibited osteoclastogenesis in BMM. The inhibitory effect seemed to involve activation of both protein kinase A and the exchange protein directly activated by cyclic AMP (Epac) signalling. BMM expressed the CRLR, RAMP1-3 and the receptor component protein (RCP). AMY, ADM, CGRP and IMD, but not CRSP and CT, increased cyclic AMP (cAMP) levels in these cells, indicating the presence of functional receptors. Stimulation of BMM with RANKL gradually increased the levels of CTR mRNA as well as the capacity of the cells to respond to the stimulation by CRSP and CT. The response to stimulation of ADM was, on the contrary, decreased by RANKL. Stimulation of RANKL caused a transiently enhanced CRLR mRNA expression and transiently decreased RAMP1, but did not affect RAMP2, RAMP3, or RCP mRNA. However, RANKL did not affect protein levels of CRLR or RAMP1-3. CT, CGRP, AMY, ADM, IMD and CRSP all down regulated the CTR mRNA, but none of the peptides caused any effects on the expression of CRLR or any of the RAMPs. All members of the CT family, except ADM, rapidly and transiently, inhibited bone resorption in mouse calvarial bones. CT, CGRP, AMY and CRSP also significantly stimulated cAMP formation in the calvaria. cAMP analogues specifically stimulating the PKA or the Epac pathways did not cause inhibition of bone resorption in the calvaria. An unspecific cAMP analogue, stimulating both pathways did, however, cause inhibition. Analyses of an osteoblastic cell line, MC3T3-E1, showed that these cells express the mRNA for CRLR and all three RAMP proteins. In conclusion, the results of this thesis show that all peptides in CT family of peptides, except ADM, inhibit of bone resorption and osteoclast formation and that these effects involve the adenylate cyclase-cAMP pathway. Furthermore, expressions of CRLR and RAMP1-3 mRNA have been demonstrated on osteoclasts, as well as in an osteoblastic cell line.
24.	Hansson, Anna, et al. (author) The WHO (Ten) well-being index as a screening instrument for major depression in i population-based sample 2007 In: European psychiatry. - 0924-9338 .- 1778-3585. ; 22, s. 314-315 Journal article (peer-reviewed)
25.	Haworth, Simon, et al. (author) Using national register data to estimate the heritability of periodontitis 2021 In: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 48:6, s. 756-764 Journal article (peer-reviewed)abstract Aim: To identify whether periodontal traits derived from electronic dental records are biologically informative and heritable.Materials and methods: The study included 11,974 adult twins (aged 30–92 years) in the Swedish Twin Registry. Periodontal records from dental examinations were retrieved from a national register and used to derive continuous measures of periodontal health. A latent class approach was used to derive categorial measures of periodontal status. The correlation patterns in these traits were contrasted in monozygotic and dizygotic twin pairs using quantitative genetic models to estimate the heritability of the traits.Results: For continuous traits, heritability estimates ranged between 41.5% and 48.3% with the highest estimates for number of missing tooth surfaces and rate of change in number of deep periodontal pockets (≥6 mm). For categorial traits, the latent class approach identified three classes (good periodontal health, mild periodontitis signs and severe signs of periodontitis) and there was a clear difference in the hazard for subsequent tooth loss between these three classes. Despite this, the class allocations were only slightly more heritable than a conventional dichotomous disease definition (45.2% vs. 42.6%).Conclusions: Periodontitis is a moderately heritable disease. Quantitative periodontal traits derived from electronic records are an attractive target for future genetic association studies.
26.	Holm, Cecilia Koskinen, et al. (author) Lack of SIRP alpha phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation 2016 In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 478:1, s. 268-273 Journal article (peer-reviewed)abstract Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on intricate cellular signaling pathways, including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRP alpha) have both been suggested to regulate bone cell differentiation. Here we investigated osteoblastic differentiation of bone marrow stromal cells from SIRP alpha mutant mice lacking the cytoplasmic signaling domain of SIRPa. An impaired osteoblastogenesis in SIRP alpha-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. This reduced osteoblastic differentiation potential in SIRPa-mutant stromal cells was associated with a significantly reduced expression of Runx2, osterix, osteocalcin, and alkaline phosphatase mRNA, as well as a reduced phosphorylation of SHP-2 and Akt2, as compared with that in wild-type stromal cells. Addition of a PI3K-inhibitor to wild-type stromal cells could mimic the impaired osteoblastogenesis seen in SIRP alpha-mutant cells. In conclusion, our data suggest that SIRPa signaling through SHP-2-PI3K-Akt2 strongly influences osteoblast differentiation from bone marrow stromal cells.
27.	Isehed, Catrine, et al. (author) Effectiveness of enamel matrix derivative on the clinical and microbiological outcomes following surgical regenerative treatment of peri-implantitis : A randomized controlled trial 2016 In: Journal of Clinical Periodontology. - Hoboken, USA : Wiley-Blackwell Publishing Inc.. - 0303-6979 .- 1600-051X. ; 43:10, s. 863-873 Journal article (peer-reviewed)abstract Objective: This randomized clinical trial aimed at comparing radiological, clinical and microbial effects of surgical treatment of peri-implantitis alone or in combination with enamel matrix derivative (EMD).Methods: Twenty-six subjects were treated with open flap debridement and decontamination of the implant surfaces with gauze and saline preceding adjunctive EMD or no EMD. Bone level (BL) change was primary outcome and secondary outcomes were changes in pocket depth (PD), plaque, pus, bleeding and the microbiota of the peri-implant biofilm analyzed by the Human Oral Microbe Identification Microarray over a time period of 12 months.Results: In multivariate modelling, increased marginal BL at implant site was significantly associated with EMD, the number of osseous walls in the peri-implant bone defect and a Gram+/aerobic microbial flora, whereas reduced BL was associated with a Gram-/anaerobic microbial flora and presence of bleeding and pus, with a cross-validated predictive capacity (Q(2) ) of 36.4%. Similar, but statistically non-significant, trends were seen for BL, PD, plaque, pus and bleeding in univariate analysis.Conclusion: Adjunctive EMD to surgical treatment of peri-implantitis was associated with prevalence of Gram+/aerobic bacteria during the follow-up period and increased marginal BL 12 months after treatment.
28.	Isehed, Catrine, 1958- (author) Peri-implantitis : treatment and effects of enamel matrix derivative 2018 Doctoral thesis (other academic/artistic)abstract Biological complications affecting osseointegrated dental implants are a growing treatment problem in clinical practice. Since the number of implant carriers has increased in recent decades, this is an urgent topic in dentistry. Peri-implantitis, inflammatory degradation of the implant-supporting jawbone, affects approximately 20% of all implant carriers and approximately 10% of all implants.Implant surfaces are colonised by microbes that may cause an inflammatory process in the soft tissue around the implant. In some sensitive individuals, the inflammatory response leads to disturbed jawbone remodelling, with increased recruitment and activity of bone-resorbing osteoclasts, which could ultimately lead to implant loss. The corresponding degradation of the bone supporting the teeth is denoted as periodontitis. The current view is that factors such as proinflammatory cytokines and prostaglandins, produced by leukocytes and cells of mesenchymal origin in the inflamed connective tissue, are responsible for local osteoclast recruitment and activation. Pro-inflammatory factors and tissue degradation products will leak into the exudate in the peri-implant sulci and the gingival pockets around the teeth. Analysis of the exudate could be of use for predicting and monitoring peri-implantitis, as well as identifying new targets for treatment.The standard treatment for peri-implantitis is surgery in combination with mechanical cleaning of the implant surface and optimisation of oral hygiene, with the goal of achieving infection control and pocket reduction. This treatment has a moderate effect on healing of the peri-implantitis lesion around the dental implant. The use of adjunctive bone grafts, membranes and antimicrobials has thus far not been shown to achieve a more successful outcome. Adjunctive treatment with enamel matrix derivative (EMD) during regenerative periodontal surgery contributes to wound healing and increased tissue support, but the adjunctive effect of EMD during surgical treatment of peri-implantitis remains unknown.The overall aim of this thesis was to investigate the outcome of a regenerative surgical treatment approach with and without adjunctive EMD treatment from the short- and long-term perspectives and to increase our knowledge of microbial flora and biomarkers in the peri-implant sulci before and after treatment. Furthermore, an additional aim of this work was to investigate whether EMD could directly affect osteoclast formation and activity.We performed a randomised controlled clinical trial of a surgical intervention for peri-implantitis with and without EMD. In multivariate modelling, an increased marginal bone level at the implant site 12 months after surgery was significantly associated with EMD, the number of osseous walls in the peri-implant bone defect and a gram-positive/aerobic microbial flora, whereas a reduced bone level was associated with a gram-negative/anaerobic microbial flora and the presence of bleeding and pus, with a cross-validated predictive capacity (Q2) of 36.4%. Similar trends were observed for bone level, pocket depth, plaque, pus and bleeding, but these associations were statistically non-significant in the univariate analysis. Five years after treatment, no significant differences in bone level changes were observed between groups, but fewer implants were lost to follow-up due to reinfections in the EMD-treated group.We used mass spectrometry to analyse the protein content in peri-implant crevicular fluid (PICF) before and up to 12 months after treatment. The total protein amount and diversity displayed decreasing trends 3, 6 and 12 months after treatment. Multivariate analysis of the PICF protein content revealed two major groups, cluster 2 and cluster 3, of which cluster 2 was associated with an increased risk of implant loss. EMD treatment was associated with cluster 3, which was in turn associated with increased implant survival.To test whether EMD affects osteoclast formation or bone resorption, we added purified EMD to RANKL-stimulated mouse bone marrow macrophage cultures in plastic dishes and counted the number of osteoclasts. We also cultured the cells on bone slices and measured the secretion of TRAP5b and the release of CTX-1 into the culture medium as biomarkers of osteoclast numbers and bone resorption, respectively, but no effect of EMD was observed.In conclusion, adjunctive EMD during surgical treatment of peri-implantitis changed the microbial flora to a less pathogenic microbiota, and similar changes in the inflammatory protein profile of PICF were observed; these effects were associated with implant survival. However, the trend toward a positive healing response after EMD treatment was not associated with a significant radiographic bone gain in this study and needs to be further explored. In addition, our finding that EMD did not affect osteoclast formation or bone resorption in vitro indicates that the effect of EMD on bone regeneration, as seen in periodontitis treatment, does not seem to depend on a direct inhibitory effect on osteoclast formation or bone resorption.
29.	Isehed, Catrine, et al. (author) Surgical treatment of peri-implantitis using enamel matrix derivative, an RCT : 3- and 5-year follow-up 2018 In: Journal of Clinical Periodontology. - : Wiley-Blackwell. - 0303-6979 .- 1600-051X. ; 45:6, s. 744-753 Journal article (peer-reviewed)abstract OBJECTIVE: To assess the clinical and radiographic outcomes 3 and 5 years after the surgical treatment of peri-implantitis per se or in combination with an enamel matrix derivative (EMD).MATERIALS AND METHODS: At baseline, 29 patients were randomized to surgical treatment with adjunctive EMD or no EMD. One year after the surgical treatment of peri-implantitis, 25 patients remained eligible for survival analyses at the 3- and 5-year follow-up. The primary outcomes were implant loss and bone level (BL) change measured on radiographs, and the secondary outcomes, bleeding on probing, pus and plaque at each implant, were analyzed in 18 and14 patients at the 3- and 5-year follow-up, respectively.RESULTS: After exclusion of 4 patients who discontinued the study, at the 3-year follow-up, 13 (100%) implants survived in the EMD group, and 10 of 12 (83%) in the non-EMD group. At the 5-year follow-up, 11 of 13 (85%) implants in the EMD group and 9 of 12 (75%) in the non-EMD group survived. In multivariate modelling, BL changes and EMD-treatment were positively associated with implant survival. Similarly, the same trend was seen in univariate analysis.CONCLUSIONS: An exploratory analysis suggests that adjunctive EMD is positively associated with implant survival up to five years, but larger studies are needed. This article is protected by copyright. All rights reserved.
30.	Jernberg, Emma, et al. (author) Molecular features of prostate cancer bone metastases harboring androgen receptor gene amplification Other publication (other academic/artistic)abstract The relation between AR amplification and other mechanisms behind castration-resistance in prostate cancer, such as increased expression of AR splice variants and steroid-converting enzymes in CRPC metastases, has been poorly examined. Specific aims of this study were therefore to examine AR amplification in hormone-naïve and castration-resistant prostate cancer (CRPC) bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying molecular targets for treatment of CRPC bone metastases. AR amplification was assessed by fluorescence in situ hybridization and verified in 16 (53 %) of the CRPC bone metastases (n=30), and in none of the untreated bone metastases (n=10). AR amplification was associated with increased expression of AR and its constitutively active AR-V7 splice variant as well as with co-amplification of genes in the AR proximity at Xq12, such as of YIPF6. Furthermore, gene expression pattern pointed at decreased osteoclast activity, and consequently decreased bone resorption and increased bone mineral density in AR amplified metastases. In conclusion, our results indicated a sclerotic phenotype in CRPC bone metastases with AR amplification that may be of both biological and clinical relevance. This is a novel hypothesis that requires to be thoroughly examined.
31.	Kapferer-Seebacher, Ines, et al. (author) Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement 2016 In: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 99:5, s. 1005-1014 Journal article (peer-reviewed)abstract Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.
32.	Kapferer-Seebacher, Ines, et al. (author) Periodontal manifestations of Ehlers-Danlos syndromes : a systematic review 2017 In: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 44:11, s. 1088-1100 Research review (peer-reviewed)abstract Aim: Ehlers-Danlos syndromes (EDS) are a group of inherited connective tissue disorders, characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Periodontal EDS (pEDS) is a specific EDS subtype caused by heterozygous mutations in complement 1 subunit genes C1R and C1S, with early severe periodontitis as predominant clinical feature. We aimed to systematically assess the spectrum of periodontal abnormalities in all EDS subtypes.Materials and Methods: An electronic and manual search was conducted in three databases (Medline, LIVIVO, CENTRAL). Publications of all study designs written in English/German without date restriction evaluating periodontal features in EDS were included.Results: Thirty articles on pEDS and thirteen articles on other EDS subtypes were analysed. In pEDS, early severe periodontitis (98.4%) and gingival recession (87.1%) are the predominant features. Reports on periodontal manifestations in other EDS subtypes are rare. Described were severe gingival enlargement in dermatosparaxis EDS, and localized periodontal breakdown related to teeth with shortened roots in classical EDS (n=3, respectively).Conclusion: Early severe periodontitis is the hallmark of pEDS; there is no evidence that it is part of the clinical phenotype of other EDS subtypes. Stringent analyses of periodontal manifestations in most EDS subtypes are missing. Prospero registration number CRD42017056889.
33.	Kassem, Ali, et al. (author) Porphyromonas gingivalis Stimulates Bone Resorption by Enhancing RANKL (Receptor Activator of NF-kappa B Ligand) through Activation of Toll-like Receptor 2 in Osteoblasts 2015 In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 290:33, s. 20147-20158 Journal article (peer-reviewed)abstract Periodontitis has been associated with rheumatoid arthritis. In experimental arthritis, concomitant periodontitis caused by oral infection with Porphyromonas gingivalis enhances articular bone loss. The aim of this study was to investigate how lipopolysaccharide (LPS) from P. gingivalis stimulates bone resorption. The effects by LPS P. gingivalis and four other TLR2 ligands on bone resorption, osteoclast formation, and gene expression in wild type and Tlr2-deficient mice were assessed in ex vivo cultures of mouse parietal bones and in an in vivo model in which TLR2 agonists were injected subcutaneously over the skull bones. LPS P. gingivalis stimulated mineral release and matrix degradation in the parietal bone organ cultures by increasing differentiation and formation of mature osteoclasts, a response dependent on increased RANKL (receptor activator of NF-kappa B ligand). LPS P. gingivalis stimulated RANKL in parietal osteoblasts dependent on the presence of TLR2 and through a MyD88 and NF-kappa B-mediated mechanism. Similarly, the TLR2 agonists HKLM, FSL1, Pam2, and Pam3 stimulated RANKL in osteoblasts and parietal bone resorption. LPS P. gingivalis and Pam2 robustly enhanced osteoclast formation in periosteal/endosteal cell cultures by increasing RANKL. LPS P. gingivalis and Pam2 also up-regulated RANKL and osteoclastic genes in vivo, resulting in an increased number of periosteal osteoclasts and immense bone loss in wild type mice but not in Tlr2-deficient mice. These data demonstrate that LPS P. gingivalis stimulates periosteal osteoclast formation and bone resorption by stimulating RANKL in osteoblasts via TLR2. This effect might be important for periodontal bone loss and for the enhanced bone loss seen in rheumatoid arthritis patients with concomitant periodontal disease.
34.	Kassem, Ali, et al. (author) Stimulation of bone resorption in calvarial bones by toll-like2 receptor through enhanced rankl 2012 In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 71, s. A68-A68 Journal article (other academic/artistic)
35.	Kassem, Ali (author) Toll-like receptors (TLRs) and inflammatory bone modeling 2015 Doctoral thesis (other academic/artistic)abstract Patients with inflammatory or infectious conditions such as periodontitis, peri-implantitis, osteomyelitis, rheumatoid arthritis, septic arthritis and loosened joint prosthesis display varying severity of destruction in the adjacent bone tissue. Bone loss in inflammatory diseases is considered a consequence of cytokine induced RANKL and subsequent enhanced osteoclast formation. Hence, osteotropic cytokines and their receptors have been suggested to be important for the pathogenesis of inflammation-induced osteolysis. It is, here, suggested that bacterial components, so called “pathogen associated molecular patterns=PAMPs”, may also be involved. Varieties of cells express receptors for PAMPs, including Toll-like receptors (TLRs) which are the first line of defence in the innate immune system. LPS (lipopolysaccharide), fimbria and lipoproteins from pathogenic bacteria such as P. gingivalis, S. aureus are ligands for TLR2 and flagellin from pathogenic flagellated bacteria like S. typhimurium is a ligand for TLR5. Since the susceptibility to, or the severity of inflammation-associated bone diseases are likely related to differences in the tissue response, and the mechanisms by which PAMPs interact with bone cells are not fully understood, we aimed to elucidate the importance of different TLRs for inflammation induced bone loss by conducting in vitro and in vivo investigations.Activation of TLR2 and TLR5 in organ cultured mouse parietal bones increased bone resorption in a time- and concentration-dependent manner by a process inhibited by OPG and bisphosphonate, showing the crucial role of RANKL-induced osteoclast formation. In addition, the number of osteoclasts, expression of osteoclastic genes and osteoclastogenic transcription factors were increased. In the bones and in osteoblasts isolated from the bones, TLR2 agonists increased the expression of RANKL without affecting OPG, while TLR5 activation resulted in enhanced RANKL and decreased OPG. Activation of both TLR2 and TLR5 stimulated the expression in both bones and osteoblasts of prostaglandins and pro-inflammatory cytokines, known to stimulate RANKL. By blocking the cytokines and prostaglandin, we showed that TLR2 and TLR5 induced bone resorption and RANKL expression are independent of these molecules.Activation of TLR2, but not TLR5, in mouse bone marrow macrophage cultures inhibited RANKL-induced osteoclast formation, an effect not observed in committed pre-osteoclasts.Local administration in vivo of TLR2 and TLR5 agonists on the top of mouse skull bones enhanced local and systemic osteoclast formation and bone resorption. Using knockout mice, we showed that the effects by LPS from P. gingivalis (used as TLR2 agonist) and flagellins (used as TLR5 agonists) are explicit for TLR2 and TLR5 ex vivo and in vivo, respectively.These data show that stimulation of TLR2 and TLR5 results in bone resorption in vitro and in vivo mediated by increased RANKL in osteoblasts and thus may be one mechanism for developing inflammatory bone loss.Interestingly, histological analyses of skull bones of mice treated locally with TLR2 and TLR5 agonists revealed that the bones not only reacted with locally increased osteoclastogenesis (osteoclast formation), but also with locally increased new bone formation. This was observed on both periosteal and endosteal sides of the bones, as well as in the bone marrow compartment. The formation of new bone was seen close to osteoclasts in some parts, but also in other areas, distant from these cells. The response was associated with active, cuboidal osteoblasts, extensive cell proliferation and increased expression of genes coding for bone matrix proteins and osteoblastic transcription factors.In conclusion, activation of TLR2 and TLR5 in osteoblasts results in bone loss associated with enhanced osteoclast formation and bone resorption, as well as with increased osteoblast differentiation and new bone formation, indicating that inflammation causes bone modeling. The data provide an explanation why LPS from P. gingivalis and flagellin from flagella-expressing bacteria can stimulate bone loss. Since TLR2 and TLR5 can be activated not only by bacterial components, but also by endogenous ligands produced in inflammatory processes, the data also contribute to the understanding of inflammation induced bone loss in autoimmune diseases. Hopefully, these findings will contribute to the development of treatment strategies for inflammation induced bone loss.
36.	Kindstedt, Elin, et al. (author) Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL 2018 In: Arthritis & Rheumatology. - : Wiley-Blackwell. - 2326-5191 .- 2326-5205. ; 70:4, s. 508-515 Journal article (peer-reviewed)abstract Objective: To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti–citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls.Methods: Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme‐linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity.Results: Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01–1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL‐positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA.Conclusion: Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL‐positive presymptomatic subjects compared with RANKL‐negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.
37.	Kindstedt, Elin, 1991-, et al. (author) CCL11, a novel mediator of inflammatory bone resorption 2017 In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7:1 Journal article (peer-reviewed)abstract Normal bone homeostasis, which is regulated by bone-resorbing osteoclasts and bone-forming osteoblasts is perturbed by inflammation. Inchronic inflammatory disease with disturbed bone remodelling, e.g. rheumatoid arthritis, patients show increased serum levels of the chemokine eotaxin-1 (CCL11). Herein, we demonstrate an inflammatory driven expression of CCL11 in bone tissue and a novel role of CCL11 in osteoclast migration and resorption. Using an inflammatory bone lesion model and primary cell cultures, we discovered that osteoblasts express CCL11 in vivo and in vitro and that expression increased during inflammatory conditions. Osteoclasts did not express CCL11, but the high affinity receptor CCR3 was significantly upregulated during osteoclast differentiation and found to colocalise with CCL11. Exogenous CCL11 was internalised in osteoclast and stimulated the migration of pre-osteoclast and concomitant increase in bone resorption. Our data pinpoints that the CCL11/CCR3 pathway could be a new target for treatment of inflammatory bone resorption.
38.	Kindstedt, Elin, et al. (author) Discovery of Innate Lymphoid Cells in Gingivitis and Periodontitis Other publication (other academic/artistic)abstract AIM: Innate lymphoid cells (ILCs) are the most recently identified leukocytes of the immune system and these cells are increasingly acknowledged to play important roles in host defence and tissue repair. ILCs can also contribute to inflammatory diseases such as asthma and colitis. We analysed the presence and proportions of the different ILC subsets (ILC1, ILC2 and ILC3) in gingivitis and periodontitis. Furthermore, we investigated if ILCs express nuclear factor kappa-B ligand (RANKL), a cytokine crucial for osteoclast differentiation and bone resorption.MATERIALS AND METHODS: We collected gingivitis and periodontitis soft tissue and characterised ILC subsets including RANKL expression in single cell suspensions using flow cytometry. RESULTS: Although not statistically significant, the total number of ILCs detected was twice as many in periodontitis compared to gingivitis. The majority of ILCs, in both conditions, were ILC1s with a 2.5-fold increase of ILC1s in periodontitis compared to gingivitis. Furthermore, we found RANKL expression exclusively expressed on ILC1s.CONCLUSIONS: Our discovery of the presence of ILCs in gingivitis and periodontitis and concomitant expression of RANKL in ILC1 suggest that these cells may be of importance in periodontal disease. In addition, our findings provide new insights into the field of oral immunology.
39.	Kindstedt, Elin, et al. (author) Innate lymphoid cells are present in gingivitis and periodontitis 2019 In: Journal of Periodontology. - : Wiley-Blackwell. - 0022-3492 .- 1943-3670. ; 90:2, s. 200-207 Journal article (peer-reviewed)abstract BACKGROUND: Innate lymphoid cells (ILCs) are the most recently identified leukocytes of the immune system and these cells are increasingly acknowledged to play important roles in host defence and tissue repair. ILCs are also contributors of inflammatory diseases such as asthma and colitis. We analyzed the presence and relative proportions of the different ILC subsets (ILC1, ILC2 and ILC3) in gingivitis and periodontitis. Further, we investigated if ILCs express receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine crucial for osteoclast differentiation and bone resorption.METHODS: We collected gingivitis and periodontitis soft tissue and characterized ILC subsets including RANKL expression in single-cell suspensions using flow cytometry.RESULTS: ILCs were detected both in gingivitis and periodontitis. The majority of ILCs, in both conditions, were ILC1s. Furthermore, RANKL expression was detected on a fraction of the ILC1s.CONCLUSIONS: Our discovery of the presence of ILCs both in gingivitis and periodontitis and concomitant expression of RANKL on a fraction of the ILC1 population suggest that these cells may be of importance in periodontal disease. In addition, our findings provide a new insight into the field of oral immunology.
40.	Kindstedt, Elin, et al. (author) Marginal jawbone loss is associated with onset of rheumatoid arthritis and is related to plasma level of receptor activator of nuclear factor kappa-B-ligand (RANKL) Other publication (other academic/artistic)abstract OBJECTIVES: We investigated whether periodontitis, displayed as marginal jawbone loss, preceded onset of symptoms of RA. Furthermore, we analysed plasma levels of receptor activator of nuclear factor kappa-B (RANKL), a cytokine crucial for bone resorption and of anti-citrullinated peptide antibodies (ACPA) in pre-symptomatic individuals compared with controls.METHODS: Marginal jawbone levels were measured on dental radiographs from the premolar/molar regions of the jaws of 176 subjects of whom 93 had developed RA. Of these, 47 had documented radiographs predating symptom onset and for 45 of them sex, age and smoking status referents could be matched. The plasma RANKL concentrations were analysed using ELISA. The receiver operating characteristic curve was used to define the cut-off value.RESULTS: Compared with matched referents, bone loss was significantly higher in never-smoking, pre-symptomatic subjects and increasing levels of bone loss was associated with higher risk to develop subsequent RA (hazard ratio=1.06, 95%CI 1.01, 1.11). No association was found in smokers. In the pre- symptomatic RANKL-positive individuals a significantly higher extent of marginal jawbone loss, and those who were both RANKL- and ACPA positive displayed an even more pronounced jawbone loss.CONCLUSIONS: Marginal jawbone loss preceded clinical onset of symptoms of RA but the difference was only manifested in non-smokers. Moreover, pre- symptomatic RA-individuals, who were RANKL positive, displayed a significantly higher degree of marginal jawbone loss, particularly in ACPA positive individuals.
41.	Kindstedt, Elin, 1991- (author) Novel Insights into Inflammatory Disturbed Bone Remodelling 2017 Doctoral thesis (other academic/artistic)abstract Bone is a dynamic tissue that is continuously remodelled, a process that requires equal amounts of osteoclastic bone resorption and osteoblastic bone formation. Inflammation may disturb the equilibrium and result in local and/or systemic bone loss. Negative bone mass balance occurs in several chronic inflammatory diseases, e.g. periodontitis and rheumatoid arthritis (RA). The aetiology of periodontitis is infectious, while RA is an autoimmune disease. Despite aetiological differences, an association between the two diseases has been established but it is not known if they are causally related. Periodontitis may develop when the inflammatory process, initially restricted to the gingiva (gingivitis), further invades the periodontium and causes bone resorption. The cellular and molecular mechanisms underlying the transition from gingivitis to periodontitis are not fully elucidated. Osteoclast formation is dependent on receptor activator of nuclear factor kappa B ligand (RANKL), but how osteoclast precursors are recruited to the jawbone is poorly understood. A family of cytokines named chemokines has been reported to possess such properties and increasing evidence points towards their involvement in the pathogenesis of chronic inflammatory diseases.The overall aim of this thesis was to gain extended knowledge about the role of chemokines and a newly discovered family of leukocytes named innate lymphoid cells (ILCs) in periodontitis and concomitant inflammatory disturbed bone remodelling. Furthermore, the aim was also to study the association between periodontitis and RA.We identified increased serum levels of monocyte chemoattractant protein (MCP)-1 and CCL11 in individuals with periodontitis. Moreover, a robust correlation between the two chemokines and periodontitis was detected in a weighted analysis of inflammatory markers, subject characteristics and periodontitis parameters. We detected higher MCP-1 levels in periodontitis tissue compared to non-inflamed. Furthermore we demonstrated that human gingival fibroblasts express MCP-1 and CCL11 in response to pro-inflammatory cytokines through NF-κB signalling. Using an inflammatory bone lesion model and primary cell cultures, we discovered that osteoblasts express CCL11 in vivo and in vitro and that the expression increased under inflammatory conditions. Osteoclasts did not express CCL11, but its high affinity receptor CCR3 was upregulated during osteoclast differentiation and found to co-localise with CCL11 on the surface of osteoclasts. Exogenous CCL11 was internalised in osteoclasts, stimulated the migration of osteoclast precursors and increased bone resorption in vitro.To analyse if periodontitis precedes RA we analysed marginal jawbone loss in dental radiographs taken in pre-symptomatic RA cases and matched controls. The prevalence of jawbone loss was higher among cases, and the amount of jawbone loss correlated with plasma levels of RANKL.In the search of the newly discovered ILCs, we performed flow cytometry analyses on gingivitis and periodontitis tissue samples. We detected twice as many ILCs in periodontitis as in gingivitis. In addition we found RANKL expression on ILC1s (an ILC subset).In conclusion, we demonstrated that CCL11 is systemically and locally increased in periodontitis and that the CCL11/CCR3 axis may be activated in inflammatory disturbed bone remodelling. We also found that marginal jawbone loss correlated with plasma levels of RANKL and preceded clinical onset of symptoms of RA. Furthermore, we demonstrated that ILCs are present in periodontitis and represent a previously unknown source of RANKL.
42.	Kindstedt, Elin, et al. (author) Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and Marginal Jawbone Loss Predates the Onset of Rheumatoid Arthritis 2017 In: Arthritis & Rheumatology. - : Wiley-Blackwell. - 2326-5191 .- 2326-5205. ; 69 Journal article (other academic/artistic)abstract Background/Purpose: Previous studies have shown a higher incidence of alveolar bone loss in patients with rheumatoid arthritis (RA) and that patients with periodontitis are at a greater risk for developing RA. Periodontitis, displayed as marginal jawbone loss was analysed in individuals prior to symptom onset of RA and related to plasma levels of receptor activator of nuclear factor kappa-B (RANKL), a cytokine crucial for bone resorption. Methods: A case-control study performed within the Medical Biobank of Northern Sweden included 232 pre-symptomatic individuals with blood samples donated before symptom onset and 194 controls. A questionnaire on self-assed dental status and smoking status was retrieved. Dental radiographs to evaluate marginal jawbone levels were available from 93 pre-symptomatic individuals (mean age; 56.8 95%CI55.9, 57.7 years and pre-dating time; -5.3 95%CI -12.2, -0.2, 74.2% females) and 83 controls (mean age; 55.5 95%CI54.6, 56.5, 73.5% females) . Of these individuals 45 had radiograph documentations prior to development of RA symptoms and to whom sex, age and smoking status could be matched among the controls. Plasma were analysed for RANKL (BioVendor, Karasek, Czech Republic), and anti-citrullinated peptide antibodies (ACPA) (anti-CCP2 test, Eurodiagnostics, Sweden) from similar time points. Results: Compared to matched controls, total bone loss was significantly higher in never-smokers who developed RA but not in smokers and increasing levels on total jawbone loss was associated with a significantly higher odds to be diagnosed with RA later (OR=1.06, 95%CI 1.01, 1.11). Regardless of smoking status, the number of unaffected teeth did not differ significantly between those who were subsequently diagnosed with RA and their matched controls. In the pre-symptomatic individuals RANKL positive individuals had significantly higher extent of marginal jawbone loss, which was further increased in ACPA positive individuals. Previously documented association between smoking and ageing and marginal jawbone loss was verified. Conclusion: Marginal jawbone loss preceded onset of symptoms of RA but the difference was only manifested in non-smokers. Moreover, marginal jawbone loss and plasma RANKL levels were related in the pre-symptomatic individuals particularly in ACPA positive individuals.
43.	Kolan, Shrikant, 1983-, et al. (author) Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen 2015 In: PLoS One. - : plos one. - 1932-6203. ; 10:7 Journal article (peer-reviewed)abstract B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlofollicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice.
44.	Koskinen, Cecilia, 1979- (author) CD47–SIRPα : an interaction of importance for bone cell differentiation 2014 Doctoral thesis (other academic/artistic)abstract Bone tissue is continuously remodeled by bone-forming osteoblasts and bone-resorbing osteoclasts, in processes tightly regulated by hormones, cytokines and growth factors. CD47, a ubiquitously expressed protein, and one of its ligands, signal-regulatory protein alpha (SIRPα), are two cell-surface proteins belonging to the immunoglobulin (Ig)-superfamily. The interaction between CD47 and SIRPα is important for, amongst other processes, the fusion of macrophages into giant cells, which are closely related to osteoclasts.The aim of the present study was to gain knowledge about the role of CD47–SIRPα interaction and resultant downstream signaling pathways in bone cell differentiation, formation and function.The addition of antibodies against CD47 or SIRPα inhibited the formation of multinucleated osteoclasts from bone marrow monocytes (BMMs) in culture. Moreover, a significant decrease in the number of osteoclasts was detected in CD47-/- BMM cultures compared to CD47+/+ cultures. In line with these in vitro results, we found fewer osteoclasts in vivo in the trabecular bone of CD47-/- mice, as compared to CD47+/+ bone. Interestingly, an extended analysis of the trabecular bone of CD47-/- mice revealed that the bone volume, mineralizing surface, mineral apposition rate, bone formation rate and osteoblast number were also significantly reduced compared with CD47+/+ mice, indicating the importance of CD47 in osteoblast differentiation. In vitro studies of bone marrow stromal (BMS) cells from CD47-/- mice or SIRPα-mutant mice (mice lacking the signaling domain of SIRPa) showed a blunted expression of osteoblast-associated genes. Moreover, these altered genotypes were associated with reduced activity of the bone mineralization-associated enzyme alkaline phosphatase as well as a reduced ability to form mineral. To reveal the molecular mechanisms by which CD47 activation of SIRPα is important for BMS cell differentiation, we studied signaling downstream of SIRPα in the absence of CD47. In BMS cells lacking CD47, a considerable reduction in the levels of tyrosine phosphorylated SIRPα was detected, and the subsequent recruitment of the Src-homology-2 (SH2) domain-containing protein tyrosine phosphatase (SHP-2)–phosphoinositide 3-kinase (PI3K)–Akt2 signaling module was nearly abolished.In conclusion, the interaction between CD47 and SIRPα results in the activation of the SHP-2–PI3K–Akt2 pathway, which is necessary for normal osteoblast differentiation. In CD47-/- mice and SIRPα-mutant mice, this interaction is perturbed, which prevents normal osteoblast differentiation and subsequent mineral formation. In addition, the altered BMS cell phenotype results in an impaired ability to stimulate osteoclast differentiation.
45.	Koskinen, Cecilia, et al. (author) Lack of CD47 impairs bone cell differentiation and results in an osteopenic phenotype in vivo due to impaired signal regulatory protein α (SIRPα) signaling 2013 In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 288:41, s. 29333-29344 Journal article (peer-reviewed)abstract Here, we investigated whether the cell surface glycoprotein CD47 was required for normal formation of osteoblasts and osteoclasts and to maintain normal bone formation activity in vitro and in vivo. In parathyroid hormone or 1α,25(OH)2-vitamin D3 (D3)-stimulated bone marrow cultures (BMC) from CD47(-/-) mice, we found a strongly reduced formation of multinuclear tartrate-resistant acid phosphatase (TRAP)(+) osteoclasts, associated with reduced expression of osteoclastogenic genes (nfatc1, Oscar, Trap/Acp, ctr, catK, and dc-stamp). The production of M-CSF and RANKL (receptor activator of nuclear factor κβ ligand) was reduced in CD47(-/-) BMC, as compared with CD47(+/+) BMC. The stromal cell phenotype in CD47(-/-) BMC involved a blunted expression of the osteoblast-associated genes osterix, Alp/Akp1, and α-1-collagen, and reduced mineral deposition, as compared with that in CD47(+/+) BMC. CD47 is a ligand for SIRPα (signal regulatory protein α), which showed strongly reduced tyrosine phosphorylation in CD47(-/-) bone marrow stromal cells. In addition, stromal cells lacking the signaling SIRPα cytoplasmic domain also had a defect in osteogenic differentiation, and both CD47(-/-) and non-signaling SIRPα mutant stromal cells showed a markedly reduced ability to support osteoclastogenesis in wild-type bone marrow macrophages, demonstrating that CD47-induced SIRPα signaling is critical for stromal cell support of osteoclast formation. In vivo, femoral bones of 18- or 28-week-old CD47(-/-) mice showed significantly reduced osteoclast and osteoblast numbers and exhibited an osteopenic bone phenotype. In conclusion, lack of CD47 strongly impairs SIRPα-dependent osteoblast differentiation, deteriorate bone formation, and cause reduced formation of osteoclasts.
46.	Koskinen, Cecilia, et al. (author) Lack of CD47 leads to impaired bone cell differentiation and results in an osteopenic bone phenotype 2012 In: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:Supplement 1, s. S42-S43 Journal article (peer-reviewed)
47.	Koskinen, Cecilia, 1979-, et al. (author) Reduced SIRPα phosphorylation and concommitant SHP-2–PI3K–Akt2 signaling decrease osteoblast differentiation Other publication (other academic/artistic)abstract Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on an intricate cellular signaling including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRPα) are suggested to regulate bone cell differentiation. In the present study, we investigated osteoblastic differentiation of bone marrow stromal cells from SIRPα mutant mice lacking the cytoplasmic signaling domain of SIRPα. Moreover, we compared downstream signaling events of SIRPα in wild-type and CD47-deficient mouse bone marrow stromal cells. SIRPα-mutant stromal cells showed significantly less expression of Runx2, Sp7 (osterix), Bglap (osteocalcin), and Akp1 (alkaline phosphatase) mRNA compared to stromal cells from wild-type mice. An impaired osteoblastogenesis in SIRPα-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. Western blot analyses showed that CD47 expression was required for Src homology-2 domain containing protein tyrosine phosphatase- 2 (SHP-2) to associate with SIRPa. As a result, SHP-2 and Akt2 in stromal cells from CD47 deficient mice were less phosphorylated, as compared to that in wild-type stromal cells. In conclusion, we here show that CD47-dependent SIRPα signaling through SHP-2–PI3K–Akt2 strongly influences osteogenic differentiation of bone marrow stromal cells.
48.	Lepperdinger, Ulrike, et al. (author) Oral characteristics in adult individuals with periodontal Ehlers-Danlos syndrome 2022 In: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 49:12, s. 1244-1252 Journal article (peer-reviewed)abstract Aim: Periodontal Ehlers-Danlos syndrome (pEDS) is a monogenic type of Ehlers-Danlos syndrome characterized by periodontal destruction at a young age. The present study aimed to document the oral phenotype of pEDS based on prospective clinical investigations.Materials and Methods: Thirty-five adult individuals from 13 families with a clinically and genetically confirmed diagnosis of pEDS underwent a systematic oral assessment.Results: Periodontitis stage 3 or 4 or edentulism due to periodontal destruction were diagnosed in 94% of the individuals. First permanent tooth loss was reported at the age of 21.5 years (median; range 13–43 years). Deep periodontal pockets were infrequent, with 94% measuring <4 mm. However, there was increased clinical attachment loss (CAL) averaging 8 mm (range 4–13 mm), and the probability of being edentate between the age of 35 and 44 years was 28–47% compared with less than 0.25% of the general population. Radiographic anomalous findings were only found in a portion of subjects and consisted of fused roots of maxillary second molars (81%), root hypoplasia (57%), taurodontism (26%) and tooth rotation of premolars (67%). As such, radiographic findings are not considered common characteristics of pEDS.Conclusions: Characteristic oral traits of pEDS in adults are severe CAL with shallow probing depths and marked gingival recession. This is complemented by a lack of attached gingiva. These indications need to be paralleled by genetic analyses to diagnose pEDS unambiguously.
49.	Lerner, Ulf H, et al. (author) Kinins and neuro-osteogenic factors 2008 In: Principles of bone biology. 3rd edition. - San Diego : Acadamic Press. - 9780123738844 ; , s. 1025-57 Book chapter (other academic/artistic)
50.	Lerner, Ulf H, 1946-, et al. (author) Skelettet vid hälsa och sjukdom 2008 In: Tandläkartidningen. - 0039-6982. ; 100:5, s. 84-90 Journal article (other academic/artistic)abstract Hur ombyggnaden av benvävnaden i käkar och skelett fungerar och hur processen påverkas vid sjukdomstillstånd som parodontit, benskörhet, tumörer med mera är föremål för omfattande forskning i Umeå.

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