| 1. |
- Tengvall, Katarina, 1980-, et al.
(författare)
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Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk
- 2019
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Ingår i: 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
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Tidskriftsartikel (refereegranskat)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-DRB1*15: 01 carriage, absence of HLA-A*02: 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.
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| 2. |
- Bostrom, E. A., et al.
(författare)
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Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Tidskriftsartikel (refereegranskat)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.
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| 3. |
- Broqvist, Mari, 1958-, et al.
(författare)
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Beslutsstöd för prioriteringar på individnivå : Exempel från hjälpmedelsverksamhet
- 2019
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Rapport (övrigt vetenskapligt/konstnärligt)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.
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| 4. |
- Djusberg, Erik, et al.
(författare)
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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
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Ingår i: The Prostate. - : Wiley-Blackwell Publishing Inc.. - 0270-4137 .- 1097-0045. ; 77:6, s. 625-638
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Tidskriftsartikel (refereegranskat)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.
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| 5. |
- Esberg, Anders, et al.
(författare)
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Peri-implant crevicular fluid proteome before and after adjunctive enamel matrix derivative treatment of peri-implantitis
- 2019
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Ingår i: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 46:6, s. 669-677
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Tidskriftsartikel (refereegranskat)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.
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| 6. |
- Giannobile, W. V., et al.
(författare)
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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
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Ingår i: Journal of Clinical Periodontology. - : Wiley. - 0303-6979 .- 1600-051X. ; 46, s. 6-11
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Tidskriftsartikel (refereegranskat)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.
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| 7. |
- Holm, Cecilia Koskinen, et al.
(författare)
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Lack of SIRP alpha phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation
- 2016
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 478:1, s. 268-273
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Tidskriftsartikel (refereegranskat)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.
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| 8. |
- Isehed, Catrine, et al.
(författare)
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Effectiveness of enamel matrix derivative on the clinical and microbiological outcomes following surgical regenerative treatment of peri-implantitis : A randomized controlled trial
- 2016
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Ingår i: Journal of Clinical Periodontology. - Hoboken, USA : Wiley-Blackwell Publishing Inc.. - 0303-6979 .- 1600-051X. ; 43:10, s. 863-873
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Tidskriftsartikel (refereegranskat)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.
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| 9. |
- Isehed, Catrine, 1958-
(författare)
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Peri-implantitis : treatment and effects of enamel matrix derivative
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 10. |
- Isehed, Catrine, et al.
(författare)
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Surgical treatment of peri-implantitis using enamel matrix derivative, an RCT : 3- and 5-year follow-up
- 2018
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Ingår i: Journal of Clinical Periodontology. - : Wiley-Blackwell. - 0303-6979 .- 1600-051X. ; 45:6, s. 744-753
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Tidskriftsartikel (refereegranskat)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.
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| 11. |
- Kapferer-Seebacher, Ines, et al.
(författare)
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Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement
- 2016
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Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 99:5, s. 1005-1014
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Tidskriftsartikel (refereegranskat)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.
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| 12. |
- Kapferer-Seebacher, Ines, et al.
(författare)
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Periodontal manifestations of Ehlers-Danlos syndromes : a systematic review
- 2017
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Ingår i: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 44:11, s. 1088-1100
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Forskningsöversikt (refereegranskat)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.
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| 13. |
- Kassem, Ali, et al.
(författare)
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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
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 290:33, s. 20147-20158
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Tidskriftsartikel (refereegranskat)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.
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| 14. |
- Kassem, Ali
(författare)
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Toll-like receptors (TLRs) and inflammatory bone modeling
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 15. |
- Kindstedt, Elin, et al.
(författare)
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Association between marginal jawbone loss and the onset of rheumatoid arhtritis and relationship to plasma levels of RANKL
- 2018
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Ingår i: Arthritis & Rheumatology. - : Wiley-Blackwell. - 2326-5191 .- 2326-5205. ; 70:4, s. 508-515
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Tidskriftsartikel (refereegranskat)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.
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| 16. |
- Kindstedt, Elin, 1991-, et al.
(författare)
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CCL11, a novel mediator of inflammatory bone resorption
- 2017
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)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.
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| 17. |
- Kindstedt, Elin, et al.
(författare)
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Innate lymphoid cells are present in gingivitis and periodontitis
- 2019
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Ingår i: Journal of Periodontology. - : Wiley-Blackwell. - 0022-3492 .- 1943-3670. ; 90:2, s. 200-207
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Tidskriftsartikel (refereegranskat)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.
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| 18. |
- Kindstedt, Elin, 1991-
(författare)
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Novel Insights into Inflammatory Disturbed Bone Remodelling
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 19. |
- Kindstedt, Elin, et al.
(författare)
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Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and Marginal Jawbone Loss Predates the Onset of Rheumatoid Arthritis
- 2017
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Ingår i: Arthritis & Rheumatology. - : Wiley-Blackwell. - 2326-5191 .- 2326-5205. ; 69
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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.
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| 20. |
- Kolan, Shrikant, 1983-, et al.
(författare)
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Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen
- 2015
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Ingår i: PLoS One. - : plos one. - 1932-6203. ; 10:7
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Tidskriftsartikel (refereegranskat)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.
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| 21. |
- Lerner, Ulf H, et al.
(författare)
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The critical interplay between bone resorbing and bone forming cells
- 2019
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Ingår i: Journal of Clinical Periodontology. - : Wiley. - 0303-6979 .- 1600-051X. ; 46:Suppl 21, s. 33-51
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Tidskriftsartikel (refereegranskat)abstract
- Aim In this article, the interplay between bone resorbing and bone forming cells is reviewed. Method This review examines the comprehensive literature on the interaction between bone resorption and bone formation. Results Coupling between bone resorption and bone formation refers to the process within basic multicellular units, in which osteoclastic bone resorption is met by the differentiation of osteoblasts and their bone forming activity. There are many possible signalling molecules that contribute to coupling at the asynchronously working remodelling sites throughout our skeleton. These include growth factors released from the bone matrix during bone resorption, soluble and membrane products of the osteoclasts and their precursors and signals from osteocytes. Conclusions In this review, we describe the potential roles of a number of these factors, whose interactions are essential for a tight control of coupling within individual remodelling units, in order to control skeletal mass. Both pre-clinical evidence and clinical evidence pinpoint that molecules in the WNT signalling pathway could be promising bone augmentation therapeutic targets. Regarding oral implications, there is support, from preclinical studies in rats, that anti-sclerostin antibodies can restore alveolar bone mass.
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| 22. |
- Shungin, Dmitry, et al.
(författare)
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Using genetics to test the causal relationship of total adiposity and periodontitis : Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium
- 2015
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 44:2, s. 638-650
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Tidskriftsartikel (refereegranskat)abstract
- Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI). Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis. Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI: 1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data. Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.
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| 23. |
- Souza, P. P. C., et al.
(författare)
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Activation of Toll-like receptor 2 induces B1 and B2 kinin receptors in human gingival fibroblasts and in mouse gingiva
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of the kallikrein-kinin system is an important mechanism controlling vasodilation and promoting inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) in regulating kinin B-1 and B-2 receptor expression in human gingival fibroblasts and in mouse gingiva. Both P. gingivalis LPS and the synthetic TLR2 agonist Pam(2)CSK(4) increased kinin receptor transcripts. Silencing of TLR2, but not of TLR4, inhibited the induction of kinin receptor transcripts by both P. gingivalis LPS and Pam(2)CSK(4). Human gingival fibroblasts (HGF) exposed to Pam(2)CSK(4) increased binding sites for bradykinin (BK, B-2 receptor agonist) and des-Arg(10)-Lys-bradykinin (DALBK, B-1 receptor agonist). Pre-treatment of HGF for 24 h with Pam(2)CSK(4) resulted in increased PGE(2) release in response to BK and DALBK. The increase of B-1 and B-2 receptor transcripts by P. gingivalis LPS was not blocked by IL-1 beta neutralizing antibody; TNF-alpha blocking antibody did not affect B-1 receptor up-regulation, but partially blocked increase of B-2 receptor mRNA. Injection of P. gingivalis LPS in mouse gingiva induced an increase of B-1 and B-2 receptor mRNA. These data show that activation of TLR2 in human gingival fibroblasts as well as in mouse gingival tissue leads to increase of B-1 and B-2 receptor mRNA and protein.
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