Nature Reviews Nephrology. fibroblast synovial cells and chondrocytes [13]. Obese osteoarthritis patients exhibit an inflammatory synovial fibroblast phenotype, which is regulated by the long non coding RNA MALAT1 November 2019 Arthritis and Rheumatology 72(4) Because we focused on the synovium, mTOR and lysophosphatidic acid were not described in greater detail, as these factors were only found to be elevated in chondrocytes/cartilage and not in synovial fibroblasts or the synovium. eCollection 2019. Bank RA Verzijl N Lafeber FP Tekoppele JM. In the past, OA was considered a disease of the cartilage only. The Smad-independent TAK-1 pathway has been shown to have profibrotic effects in regulating the expression of ECM proteins, including collagens and fibronectin [41]. OBJECTIVE: Changes in rheumatoid arthritis synovial fibroblast (RASF) gene expression are usually defined by a comparison to osteoarthritis synovial fibroblasts (OASFs). CTGF, like TGF-β, is found to be elevated in many fibrotic diseases. Pros and cons of inhibiting CTGF, PLOD2 or TIMP-1 for the synovium and cartilage. . This elevation suggests that PLOD2 may be crucial in OA-related synovial fibrosis. doi: 10.1016/S0140-6736(14)60802-3. van der Slot AJ Zuurmond AM van den Bogaerdt AJet al. All of these results together indicate that inhibition of ALK5 comes with a certain risk for the cartilage. Zhang L, Xing R, Huang Z, Zhang N, Zhang L, Li X, Wang P. Mediators Inflamm. The fibroblast activation protein alpha+ (FAPα+) thymus cell antigen 1+(THY1+) FLS, located in the synovial sub-lining, selectively promotes inflammation in arthritis with little effect on the bone and cartilage destruction and the FAPα+THY1- We treated N-SF and OA-SF with or without mechanical loading for 48h after … Synovium in the pathophysiology of osteoarthritis Osteoarthritis Osteoarthritis (OA) is the most common form of arthritis and is among the most prevalent chronic human health disorders in an aging population. Oxford University Press is a department of the University of Oxford. In contrast, there are papers that propose that the alternative pathway for TGF-β1 signalling, through ALK5/Smad2/3, causes the transition of chondrocytes and chondroprogenitors to a fibrogenic phenotype, resulting in many of the destructive processes of OA [92]. (a) Representative synovial tissues stained with…, NLM The majority of these profibrotic factors are either downstream of TGF-β or modulate TGF-β signalling. To validate CTGF as a potential antifibrotic target, it is important to determine whether CTGF is necessary for the persistence of TGF-β-induced synovial fibrosis, especially since a CTGF blocking antibody (FG-3019) is available. Remst DF Blaney Davidson EN Vitters ELet al. 2019 May;20(5):701-712. doi: 10.1111/obr.12828. 7 However, in TMJ osteoarthritis (OA), the cartilage may be damaged by some of the growth factors and inflammatory cytokines in the synovial fluid. Please enable it to take advantage of the complete set of features! Osteoarthritis (OA) affects the integrity of the entire joint including the synovium. Although dividing synoviopathy into different subtypes may help in grouping OA patients and/or disease progression, we have to keep in mind that the observation of synovial fibrosis at different time points is patient and site dependent. All rights reserved. Multiple studies have shown that the synovia of patients suffering from early or advanced OA have some form of pathology [7–10]. Synovial pathology may impair joint functionality and contribute to disease progression by, for example, increased joint friction [7]. Therefore, more knowledge is needed about the interplay between urotensin II and TGF-β signalling in synovial fibroblasts and about its potential role in synovial fibrosis. Taken together, our findings indicate that increased HIF-1α is highly involved in the KOA synovial fibrosis. -. There is growing evidence that activated synovial fibroblasts, as part of a complex cellular network, play an important role in the pathogenesis of rheumatoid arthritis. Prevents that he collagen becomes harder to degrade and therefore prevents long lasting collagen accumulation [, Cartilage areas containing low pyridinoline levels are less prone to degeneration compared with cartilage containing high levels of pyridinoline collagen cross-links, which seems to fail mechanically under long-term loading [, More collagen degradation (as a result of more MMP activity) may reverse the fibrosis [, More collagen degradation (due to more MMP activity), causing more cartilage damage [, Copyright © 2021 British Society for Rheumatology. Fibrosis is a non-physiological wound-healing process characterized by excessive extracellular matrix (ECM) deposition, which is typically the result of inflammation or tissue damage. Would you like email updates of new search results? Synovial fibrosis is often found in OA, contributing heavily to joint pain and joint stiffness, the main symptoms of OA. The subintima is composed of loose connective tissue and merges with the dense collagen-rich fibrous outer layer of the joint capsule. 2020 Sep;86:106745. doi: 10.1016/j.intimp.2020.106745. Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Fibrosis was abundantly present in both the fibrotic and detritus-rich synoviopathy and only to a minor extent in the inflammatory subgroup. Synovial inflammation is probably involved in the genesis of pain, as inflammatory mediators, such as prostaglandin E 2, bradykinin, 5-hydroxy- tryptamine and histamine, are released within the joint and increase the sensitivity of periph-eral pain receptors [10]. Injection of hyaluronan 24 h after TGF-β injection in the TGF-β prior to treadmill running model of OA inhibited the cascade of OA-like joint changes, including gait changes and synovial fibrosis. The underlying mechanisms that cause OA are still not totally unravelled, and (apart from joint replacement) no cure is available. (a) The severity of synovial…, HIF-1 α siRNA attenuates the LPS+ATP-induced cell pyroptosis in FLS. There are two different splice variants: a shorter secreted form (ADAM12-S) and a longer membrane-bound form (ADAM12-L) [75]. In addition, CTGF is expressed in wound healing, vascular diseases and fibrosis [47–49]. We found that TIMP-1 is elevated in the synovium of both human end-stage OA patients and mice with experimental OA [12]. The aim of the study was to gain insight into how these factors contribute to the fibrotic process and to determine the best targets for therapy in synovial fibrosis. Fibroblast-like synoviocytes (FLS) represent a specialised cell type located inside joints in the synovium.These cells play a crucial role in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis.. Fibroblast-like synoviocytes in normal tissues. Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. These outcomes also support the study of Haraoui et al.. [8], who reported that the amount of fibrosis is inversely proportional to the extent of cellular infiltrate in the OA synovium, and that fibrosis is mainly but not exclusively found in late-stage OA. Synovial fluid was collected from non-OA and OA patients, which was centrifuged to isolate cells. Not only are levels of miR203 raised in longstanding RA compared to osteoarthritis and normal synovial fibroblasts, but expression in the earliest phases of RA when disease is not fully differentiated occurs at an intermediate level, suggesting that the epigenetic control of synovial fibroblast behaviour remains plastic in the earliest phases of disease [69]. Understanding how synovial fibrosis contributes to OA pathology and symptoms might provide avenues for future OA therapies. For scleroderma fibroblasts, it was demonstrated that ALK5-dependent upregulation of collagen and CTGF does not involve Smad2/3 activation, but is mediated by ALK1/Smad1 and the TGF-β-induced non-Smad-dependent extracellular signal-regulated kinase (ERK)1/2 pathways [31, 32]. Increased expression of Plod2 mRNA is found in a range of fibrotic fibroblasts [62]. In line with these data, it was shown in hepatic stellate cells that adding ADAM12 stimulates TGF-β-induced phosphorylation of Smad2/3, whereas treatment of cells with antisense to ADAM12 diminishes the TGF-β-dependent induction of TGF-β-induced Smad2P (Smad3P was not measured in this study) as well as COL1A2 mRNA expression [82, 83]. However, TGF-β is a regulator of many crucial cellular processes. Osteoarthritis; Synovial fibroblast; Cytokine; Phorbol ester; Human endothelial cells in blood vessels, were demonstrated to ex- press PTHrP by immunohistochemistry [9]. We look forward to an experiment where PLOD2 is blocked in an OA model accompanied by fibrosis in order to determine whether this approach indeed prevents synovial fibrosis. Thank you for submitting a comment on this article. We choose to describe hyaluronan in more detail because this factor has been found to be effective against OA-related fibrosis by multiple groups in a range of species, whereas the other factors have only been described by one group and for one species. Frazier K Williams S Kothapalli D Klapper H Grotendorst GR. Your comment will be reviewed and published at the journal's discretion. Because it is estimated that over half of all OA patients suffer from synovial fibrosis, it is important that this pathological process receives more attention, especially as fibrosis is one of the main causes of joint stiffness [2–4, 101]. However, it has not yet been determined whether PTHrP is actually produced in synovial cells established from synovial membrane in cul- ture. In this review we discuss factors that have been reported to be involved in synovial fibrosis. To our knowledge no blocking or overexpression studies of PLOD2 currently exist that determine its direct function in the fibrotic process. It has been suggested by Wang et al. IGF-R1 = insulin growth factor receptor 1; IL = interleukin; OASF = osteoarthritis synovial fibroblast; RA = rheumatoid arthritis; RASF = rheumatoid arthritis synovial fibroblast. Comparative intra-articular gene transfer of seven adeno-associated virus serotypes reveals that AAV2 mediates the most efficient transduction to mouse arthritic chondrocytes. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. However, one or more additional factors, elevated by TGF-β, seem to be required to induce persistent fibrosis [52, 60]. Boldt JG Munzinger UK Zanetti M Hodler J. Haraoui B Pelletier JP Cloutier JM Faure MP Martel-Pelletier J. Oehler S Neureiter D Meyer-Scholten C Aigner T. Bastiaansen-Jenniskens YM Wei W Feijt Cet al. ADAM12 is primarily involved in cell adhesion and fusion, ECM restructuring and cell signalling. NLRP1 and NLRP3 inflammasomes mediate LPS/ATP‑induced pyroptosis in knee osteoarthritis. This will aid in choosing the best targets to interfere with OA-related fibrosis in future studies. Where others have demonstrated that only the combination of TGF-β and CTGF leads to persistent fibrosis, we have previously published that overexpression of TGF-β alone causes persistent synovial fibrosis, whereas CTGF alone in the murine knee joint causes only transient synovial fibrosis [27, 28, 57, 58]. Life Sci. Osteoarthritis. The PGF2α isoforms 8-iso-PGF2α and 15-keto-dihydro-PGF2α were found to be significantly increased in the SF of patients with OA [86]. -, Remst D. F., Blaney Davidson E. N., Vitters E. L., et al. These results indicate a shift from the inflammatory to the fibrotic subgroup, which may suggest that the factors inducing fibrosis are upregulated in the inflammatory phase. eCollection 2020. Disclosure statement: The authors have declared no conflicts of interest. Furthermore, CTGF decreases Smad7, an inhibitory Smad that can inhibit TGF-β signalling on multiple levels and, via this mechanism, promote TGF-β signalling [53]. Moreover, the authors of these articles suggest that urotensin II is involved in the development of fibrosis. Urotensin II is a potent vasoconstrictor that is involved in cardiac remodelling, and it may influence cardiovascular homeostasis and pathology [68, 69]. Whether inhibition of ALK1 in an OA joint has pro- or antifibrotic effects remains to be elucidated. PGF2α normally regulates a number of important physiological functions, like uterine contraction and bronchoconstriction. However, one proposed mechanism is by induction of TIEG-1, which is upregulated via the TrkA signalling receptors for CTGF [54, 55]. Biernacka A Dobaczewski M Frangogiannis NG. . Osteoarthritis (A) and rheumatoid arthritis (RA) synovium (B). This suggests that the role of ALK1 is not only cell type and tissue dependent, but may also be influenced by the ailment of the tissue [34]. Nat Commun. This suggests that inhibition of PLOD2, besides the potential antifibrotic effects, may also favour cartilage repair in an OA joint. 2021 Jan 20;12(1):467. doi: 10.1038/s41467-020-20761-5. Finnson KW Parker WL ten Dijke P Thorikay M Philip A. van der Slot-Verhoeven AJ van Dura EA Attema Jet al. Furthermore, in a TGF-β-driven murine model of dermal fibrosis, inhibition of TGF-β-dependent ERK phosphorylation showed strong and dose-dependent antifibrotic effects on skin thickening [42]. . In these cells, Smad3 is profibrotic, whereas Smad2 protects against Smad3-mediated fibrosis [38–40]. Additional and background information was acquired via PubMed Thorikay M Philip A. van der Slot AJ van EA., whereas Smad2 protects against Smad3-mediated fibrosis [ 22 ] strategies in clinical implications S Smith E Dijke... Merges with the observation that exogenously provided hyaluronan antagonized TGF-β1-dependent myofibroblast differentiation [ 87 ] been in. Sign in to an existing account, or purchase an annual subscription profibrotic, whereas protects! Besides the potential antifibrotic effects remains to be beneficial in the sublining layer of synovium... ( N-SF ) and OA samples were collected from the discarded tissue of patients following knee replacement! A. J., Lan H. Y. TGF-β: the authors of these factors will break the cascade. Synovial tissue of KOA rats was in a different model system can result in a of! Of a different model system can result in serious side effects and can... 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