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| 2. |
- Reker, D., et al.
(författare)
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Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Sprifermin, recombinant human fibroblast growth factor 18 (rhFGF18), induces cartilage regeneration in knees of patients with osteoarthritis (OA). We hypothesized that a temporal multiphasic process of extracellular matrix (ECM) degradation and formation underlie this effect. We aimed to characterize the temporal ECM remodeling of human knee OA articular cartilage in response to sprifermin treatment. Articular cartilage explants from patients with knee OA (npatients = 14) were cultured for 70 days, with permanent exposure to sprifermin (900, 450, 225 ng/mL), FGF18 (450 ng/mL), insulin-like growth factor-1 (100 ng/mL, positive control) or vehicle (nreplicates/treatment/patient = 2). Metabolic activity (AlamarBlue) and biomarkers of type IIB collagen (PIIBNP) formation (Pro-C2 enzyme-linked immunosorbent assay [ELISA]) and aggrecanase-mediated aggrecan neo-epitope NITEGE (AGNx1 ELISA) were quantified once a week. At end of culture (day 70), gene expression (quantitative reverse transcription polymerase chain reaction) and proteoglycan content (Safranin O/Fast green staining) were quantified. The cartilage had continuously increased metabolic activity, when treated with sprifermin/FGF18 compared to vehicle. During days 7–28 PIIBNP was decreased and NITEGE was increased, and during days 35–70 PIIBNP was increased. At end of culture, the cartilage had sustained proteoglycan content and relative expression of ACAN < COL2A1 < SOX9 < COL1A1, indicating that functional chondrocytes remained in the explants. Sprifermin induces a temporal biphasic cartilage remodeling in human knee OA articular cartilage explants, with early-phase increased aggrecanase activity and late-phase increased type II collagen formation.
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| 4. |
- Englund, E, et al.
(författare)
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Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer
- 2016
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 35:43, s. 5585-5596
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Tidskriftsartikel (refereegranskat)abstract
- Cartilage oligomeric matrix protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Tissue microarrays derived from two cohorts of patients with breast cancer (n=122 and n=498) were immunostained, revealing varying expression of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and decreased recurrence-free survival. Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdc(scid)/Rj) mice. Tumors expressing COMP were significantly larger and were more prone to metastasize as compared with control, mock-transfected, tumors. In vitro experiments confirmed that COMP-expressing cells had a more invasive phenotype, which could in part be attributed to an upregulation of matrix metalloprotease-9. Furthermore, microarray analyses of gene expression in tumors formed in vivo showed that COMP expression induced higher expression of genes protecting against endoplasmic reticulum stress. This observation was confirmed in vitro as COMP-expressing cells showed better survival as well as a higher rate of protein synthesis when treated with brefeldin A, compared with control cells. Further, COMP-expressing cells appeared to undergo a metabolic switch, that is, a Warburg effect. Thus, in vitro measurement of cell respiration indicated decreased mitochondrial metabolism. In conclusion, COMP is a novel biomarker in breast cancer, which contributes to the severity of the disease by metabolic switching and increasing invasiveness and tumor cell viability, leading to reduced survival in animal models and human patients.
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| 7. |
- Eriksson, P, et al.
(författare)
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Neonatal exposure to DDT and its fatty acid conjugate: effects on cholinergic and behavioural variables in the adult mouse
- 1990
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Ingår i: NeuroToxicology. - 1872-9711. ; 11:2, s. 345-354
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Tidskriftsartikel (refereegranskat)abstract
- We have recently observed that DDT and a DDT metabolite, DDOH, conjugated to a fatty acid, palmitic acid, DDOH-PA, affects muscarinic cholinergic receptors (MAChR) in the neonatal mouse brain when given to suckling mice during rapid brain growth. This early exposure of the neonatal mouse also affects the behaviour of the animals as adults. When DDT and DDOH-PA was given as a single low oral dose of 1.4 mumol/kg body weight, DDT (0.5 mg), DDOH-PA (0.7 mg) and a 20% fat emulsion vehicle (10 ml) per kg body weight to 10-day-old NMRI mice, behavioural tests at adult age of four months, indicated disruption of a simple, non-associative learning process, i.e. habituation, in both DDT and DDOH-PA treated mice. There was also a significant increase in the potassium evoked release of ACh from slices of cerebral cortex and a tendency towards a decrease in the density of MAChR in mice receiving DDT. These effects in the adult mice could not be correlated to the concentration of DDT in the adult brain since DDT one month after its administration to the 10-day-old mouse no longer is present in the brain.
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| 8. |
- Rysinska, A., et al.
(författare)
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Aseptic loosening after total hip arthroplasty and the risk of cardiovascular disease: A nested case-control study
- 2018
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:11
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Tidskriftsartikel (refereegranskat)abstract
- Background Patients with surgically treated osteoarthritis of the hip have an increased risk of cardiovascular morbidity and mortality many years after the operation compared with controls. Our hypothesis is that this increased risk after total hip arthroplasty (THA) is mediated by development of periprosthetic osteolysis leading to aseptic loosening of the implant. Methods We conducted a nation-wide, nested, case-control study consisting of patients receiving a cemented THA due to osteoarthritis between the years 1992 and 2005. Our study population included a total of 14,430 subjects identified in the Swedish hip arthroplasty register and linked to the Swedish National Patient Register. The case group consisted of patients (n = 2,886) who underwent reoperation of the treated hip due to osteolysis or aseptic loosening at any time within five years after the index surgery. Each case was matched with four controls (n = 11,544) who had not undergone reoperation. The main outcomes were cardiovascular events i.e. myocardial infarction, heart failure and cerebral infarction according to ICD-codes and time to the first cardiovascular event during the exposure period. Outcomes were subgrouped into cardiac and cerebral events. We used regression models to calculate the incidence rates and adjusted our results for confounders. Findings Overall, 5.1% of patients had cardiac events, with slightly more overall cardiovascular events occurring in the control group (8.1% vs. 6.7%, odds ratio 0.8, 95% confidence interval (CI) 0.7 to 1.0). After adjusting for confounders, the case group had an increased relative risk of 1.3 (95% confidence interval (CI) 1.1 to 1.3) for total number of cardiovascular events. Similar effect sizes were observed for time to first event. Interpretation Patients with osteoarthritis who received THA and subsequently underwent a revision operation due to loosening had a higher relative risk of developing cardiovascular events than controls. Thus there is an association which could be explained by a common inflammatory disease pathway that requires further experimental research. Copyright: © 2018 Rysinska et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 9. |
- Thalin, C, et al.
(författare)
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Trousseau's Syndrome, a Previously Unrecognized Condition in Acute Ischemic Stroke Associated With Myocardial Injury
- 2014
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Ingår i: Journal of investigative medicine high impact case reports. - : SAGE Publications. - 2324-7096. ; 2:2, s. 2324709614539283-
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Tidskriftsartikel (refereegranskat)abstract
- Trousseau’s syndrome is a well-known malignancy associated hypercoagulative state leading to venous or arterial thrombosis. The pathophysiology is however poorly understood, although multiple mechanisms are believed to be involved. We report a case of Trousseau’s syndrome resulting in concomitant cerebral and myocardial microthrombosis, presenting with acute ischemic stroke and markedly elevated plasma troponin T levels suggesting myocardial injury. Without any previous medical history, the patient developed multiple cerebral infarctions and died within 11 days of admission. The patient was postmortem diagnosed with an advanced metastatic adenocarcinoma of the prostate with disseminated cerebral, pulmonary, and myocardial microthrombosis. Further analyses revealed, to the best of our knowledge for the first time in stroke patients, circulating microvesicles positive for the epithelial tumor marker CK18 and citrullinated histone H3 in thrombi, markers of the recently described cancer-associated procoagulant DNA-based neutrophil extracellular traps. We also found tissue factor, the main in vivo initiator of coagulation, both in thrombi and in metastases. Troponin elevation in acute ischemic stroke is common and has repeatedly been associated with an increased risk of mortality. The underlying pathophysiology is however not fully clarified, although a number of possible explanations have been proposed. We now suggest that unexplainable high levels of troponin in acute ischemic stroke deserve special attention in terms of possible occult malignancy.
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| 10. |
- Aspberg, A., et al.
(författare)
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Cartilage oligomeric matrix protein forms protein complexes with synovial lubricin via non-covalent and covalent interactions
- 2017
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Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 25:9, s. 1496-1504
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Understanding the cartilage surface structure, lost in arthritic disease, is essential for developing strategies to effectively restore it. Given that adherence of the lubricating protein, lubricin, to the cartilage surface is critical for boundary lubrication, an interaction with cartilage oligomeric matrix protein (COMP) was investigated. COMP, an abundant cartilage protein, is known to be important for matrix formation. Design: Synovial fluid (SF) from arthritic patients was used to detect possible COMP-lubricin complexes by immunological methods. Recombinant (RC) COMP and lubricin fragments were expressed to characterize this bonding and mass spectrometry employed to specifically identify the cysteines involved in inter-protein disulfide bonds. Results: COMP-lubricin complexes were identified in the SF of arthritic patients by Western blot, co-immunoprecipitation and sandwich ELISA. RC fragment solid-phase binding assays showed that the C-terminal (amino acids (AA) 518-757) of COMP bound non-covalently to the N-terminal of lubricin (AA 105-202). Mass spectrometry determined that although cysteines throughout COMP were involved in binding with lubricin, the cysteines in lubricin were primarily focused to an N-terminal region (AA 64-86). The close proximity of the non-covalent and disulfide binding domains on lubricin suggest a two-step mechanism to strongly bind lubricin to COMP. Conclusion: These data demonstrate that lubricin forms a complex network with COMP involving both non-covalent and covalent bonds. This complex between lubricin and the cartilage protein COMP can be identified in the SF of patients with arthritis conditions including osteoarthritis (OA) and rheumatoid arthritis (RA). (C) 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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| 11. |
- Aspberg, Anders, et al.
(författare)
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Cartilage proteoglycans
- 2016
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Ingår i: Cartilage: Volume 1: Physiology and Development. - Cham : Springer International Publishing. - 9783319295688 - 9783319295664 ; 1, s. 1-22
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Bokkapitel (refereegranskat)abstract
- Proteoglycans are key components of the cartilage extracellular matrix and essential for normal tissue function. The core protein and the glycosaminoglycan chains both contribute to function and provide different properties of the individual proteoglycans. This review is focused on the two main families of cartilage proteoglycans.The first of these is the lectican family, including aggrecan, versican, and the cartilage link protein. The aggregating proteoglycan network formed by aggrecan, link protein, and hyaluronan provides biomechanical properties that give the tissue its ability to withstand and distribute load.The second group discussed is the small leucine-rich repeat proteoglycan family, which includes decorin, biglycan, asporin, fibromodulin, lumican, keratocan, osteoadherin, proline-/arginine-rich end leucine-rich repeat protein, epiphycan, mimecan, opticin, chondroadherin, and chondroadherin-like. These proteoglycans bind collagens and are important regulators of cartilage extracellular matrix assembly. In addition, some of these proteoglycans bind and regulate growth factors and their receptors and regulate innate immunity through interactions with Toll-like receptors or the complement system.This review will give an overview of the structure and function of the different aggregating proteoglycans and small leucine-rich repeat proteoglycans in normal cartilage extracellular matrix.
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| 16. |
- Lorenzo, P., et al.
(författare)
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Quantification of cartilage oligomeric matrix protein (COMP) and a COMP neoepitope in synovial fluid of patients with different joint disorders by novel automated assays
- 2017
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Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 25:9, s. 1436-1442
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To develop automated immunoassays for the quantification of Cartilage Oligomeric Matrix Protein (COMP) and a COMP neoepitope in synovial fluid and to investigate their diagnostic potential in different joint conditions. Methods: Two sandwich immunoassays were developed for the quantification of COMP and a COMP neoepitope, using an automated analyser (IDS-iSYS, Immunodiagnostic Systems, Boldon, UK). Assay performance was evaluated in terms of sensitivity, recovery, linearity, and intra- and inter-assay precision. Clinical performance was evaluated by analysing synovial fluid from patients diagnosed with rheumatoid arthritis (RA), reactive arthritis (ReA), osteoarthritis (OA) or acute trauma (AT). Results: Both automated assays showed good performance for all parameters tested. Quantification of these biomarkers showed the highest median values for Total COMP in the OA group, followed by the AT group, the ReA group, and the RA group. For the COMP neoepitope the AT group showed the highest median value, followed by the ReA group, the OA group, and the RA group. The ratio COMP neoepitope/Total COMP showed distinct differences between the patients groups, as well as between RA patients with slow or rapid progression of joint damage. Conclusions: The newly developed automated assays have a good technical performance, can reliably quantify different epitopes on the COMP molecule and show different levels of the two biomarkers in synovial fluid in patients with different joint diseases. The combination of these two assays, measuring their ratio, shows promise for early detection of patients with RA with different prognosis regarding progression of joint damage.
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| 17. |
- Martínez, Marycarmen Arévalo, et al.
(författare)
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Vascular smooth muscle–specific YAP/TAZ deletion triggers aneurysm development in mouse aorta
- 2023
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Ingår i: JCI Insight. - 2379-3708. ; 8:17
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Tidskriftsartikel (refereegranskat)abstract
- Inadequate adaption to mechanical forces, including blood pressure, contributes to development of arterial aneurysms. Recent studies have pointed to a mechanoprotective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we identified reduced expression of YAP1 in human aortic aneurysms. Vascular SMC–specific knockouts (KOs) of YAP/TAZ were thus generated using the integrin α8–Cre (Itga8-Cre) mouse model (i8-YT-KO). i8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within 2 weeks of KO induction and in smaller arteries at later times. The vascular specificity of Itga8-Cre circumvented gastrointestinal effects. Aortic aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of proteoglycans and immune cell populations. RNA sequencing, proteomics, and myography demonstrated decreased contractile differentiation of SMCs and impaired vascular contractility. This associated with partial loss of myocardin expression, reduced blood pressure, and edema. Mediators in the inflammatory cGAS/STING pathway were increased. A sizeable increase in SOX9, along with several direct target genes, including aggrecan (Acan), contributed to proteoglycan accumulation. This was the earliest detectable change, occurring 3 days after KO induction and before the proinflammatory transition. In conclusion, Itga8-Cre deletion of YAP and TAZ represents a rapid and spontaneous aneurysm model that recapitulates features of human abdominal aortic aneurysms.
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