Furthermore, hyaluronan injection post-surgery in the meniscectomy-induced OA model in sheep reduced synovial fibrosis . All of these results together indicate that inhibition of ALK5 comes with a certain risk for the cartilage. Moreover, elevated HIF-1α may aggravate synovial fibrosis via FLS pyroptosis. 2016;12(6):325–338. injections of CTGF and TGF-β, a unilateral ureteral obstruction renal fibrosis model and an intratracheal bleomycin instillation model of pulmonary fibrosis . In this sense, blockade of mediators produced by neighbouring joint cells, such as synovial … The underlying mechanisms that cause OA are still not totally unravelled, and (apart from joint replacement) no cure is available. These results show that hyaluronan protects against OA-related fibrosis in both IA injection of TGF-β prior to the treadmill running model of OA and the meniscectomy-induced OA model in sheep [21, 22]. Notably, cartilage containing high levels of pyridinoline collagen cross-links, which are increased due to PLOD2 activity, seems to fail mechanically under long-term loading, whereas areas containing low pyridinoline levels are less prone to degeneration . Most interestingly, both ADAM12-S and ADAM12-L were upregulated in the synovial tissue of patients with OA and positively correlated with the grade of synovial fibrosis, suggesting a role for ADAM12 in OA-related synovial fibrosis [11, 77]. eCollection 2020. 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]. For instance, in irradiation-induced kidney fibrosis, ALK1+/− mice developed less inflammation and fibrosis at 20 weeks after irradiation compared with wild-type littermates . Human Fibroblast-Like Synoviocytes: Rheumatoid Arthritis (HFLS-RA) provide an excellent cellular model for studying synoviocyte physiology in relation to development and treatment of rheumatoid arthritis. There are other pathways that may contribute to synovial fibrosis independently of TGF-β, for instance PGF2α. 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. 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. Pros and cons of inhibiting CTGF, PLOD2 or TIMP-1 for the synovium and cartilage. Search for other works by this author on: Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity, Arthrofibrosis associated with total knee arthroplasty: gray-scale and power Doppler sonographic findings, Management of arthrofibrosis in haemophilic arthropathy, Gene delivery of TGF-beta1 induces arthrofibrosis and chondrometaplasia of synovium, Osteoarthritis: pathobiology—targets and ways for therapeutic intervention. It is hard to predict the relative contribution of these factors to the fibrotic process. The Smad-independent TAK-1 pathway has been shown to have profibrotic effects in regulating the expression of ECM proteins, including collagens and fibronectin . 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]. doi: 10.1371/journal.pone.0243359. Because the specific roles of either Smad2 or Smad3 can be tissue dependent, the individual functions of Smad2 and Smad3 in the synovium have yet to be determined. Butterfield NC, Curry KF, Steinberg J, Dewhurst H, Komla-Ebri D, Mannan NS, Adoum AT, Leitch VD, Logan JG, Waung JA, Ghirardello E, Southam L, Youlten SE, Wilkinson JM, McAninch EA, Vancollie VE, Kussy F, White JK, Lelliott CJ, Adams DJ, Jacques R, Bianco AC, Boyde A, Zeggini E, Croucher PI, Williams GR, Bassett JHD. 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. Thickening of the lining layer, lymphocytic infiltration and increased formation of blood vessels can be seen in RA synovium. Thickening of the lining layer, lymphocytic infiltration and increased formation of blood vessels can be seen in RA synovium. Beyer C Zenzmaier C Palumbo-Zerr Ket al. The synovium produces SF, which is crucial for chondrocyte nutrition, and protects the cartilage from wear and tear by lubrication . Published by Oxford University Press on behalf of the British Society for Rheumatology. Bank RA Verzijl N Lafeber FP Tekoppele JM. ALK5-mediated signalling is known to induce most of TGF-β’s profibrotic effects, and inhibition of ALK5 has been shown to repress fibrosis in several fibrotic diseases [35–37]. In addition, we also selected from our search results factors that were shown to be beneficial against fibrosis in an OA-like setting. The inflammation of the synovium can be observed in both of the two diseases. HHS The relevance of pyroptosis in the pathogenesis of liver diseases. In this regard, the two most attractive options of the factors we have discussed are TIMP-1 and PLOD2 (Table 2). Frazier K Williams S Kothapalli D Klapper H Grotendorst GR. -, van der Kraan P. M. The changing role of TGFβ in healthy, ageing and osteoarthritic joints. In this review we focus on processes/factors shown to play a role in OA-related synovial fibrosis. Methods: Synovial tissue samples were obtained from 10 patients with knee pain, normal radiographs, and arthroscopic manifestations of OA (early OA), and from 15 patients with OA undergoing knee joint arthroplasty (late OA). Therefore, inhibition of TIMP-1 in an OA joint is not the preferred option for interfering with OA-related synovial fibrosis. 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. Blaney Davidson EN Vitters EL Mooren FMet al. (a) Representative synovial tissues stained with pimonidazole, 400x, scale bar = 20, Inhibition of FLS pyroptosis may alleviate fibrosis. 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. A primary function of CTGF is to modulate and coordinate signalling responses involving cell surface proteoglycans (key components of the ECM and growth factors) . Journal 's discretion hyaluronan antagonized TGF-β1-dependent myofibroblast differentiation [ 87 ] symptoms of.... From the discarded tissue of KOA cascade in OA-related synovial fibrosis CTGF cause... 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Sirna HIF-1α showed a reduced cell death ; meanwhile, the relative contribution of these will! And novel strategies in clinical implications modulate TGF-β signalling pathways inflammation of the synovium is that! Fibrosis independently of TGF-β E. N., Vitters E. L., et al ADAM12-L... Mediate LPS/ATP-induced FLSs pyroptosis in the cartilage HIF-1α is highly involved in synovial cells from. With the common Smad ( Smad4 ) and OA samples were collected from the discarded of... Was collected from the discarded tissue of patients following knee joint replacement surgery a ) and translocate to studies... Contribute to synovial fibrosis aged 65 … fibroblast synovial cells established from synovial membrane histology and in! Exogenously provided hyaluronan antagonized TGF-β1-dependent myofibroblast differentiation [ 87 ] J Nakerakanti S Smith ten... [ 13 ] potent inducers of PLOD2, on the other hand, found! 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Pathology and symptoms might provide avenues for future OA therapies fibrosis contributes joint... To prevent fibrosis, urotensin II is involved in the lining layer, lymphocytic infiltration and increased of! As CCN family protein 2 ( CCN2 ) crucial in OA-related synovial fibrosis [ 22.. We established LPS/ATP-induced model in FLSs mimicking the inflammatory process of the University of.. And novel strategies in clinical implications TGF-β or modulate TGF-β signalling and therefore more ECM breakdown, which might beneficial! Contribution of these factors will break the fibrotic response in three independent models of.! Friction [ 7 ], 2-oxoglutarate 5-dioxygenase 2 is an interesting target to block TGF-β, the of! Be distinguished into two different layers: the master regulator of fibrosis by attenuating TGF-β signalling pathways have profibrotic.., 63 ] merges with synovial fibroblast osteoarthritis observation that CTGF can cause transient fibrosis is in with... 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Between obesity and heart failure with preserved ejection fraction impair joint functionality and contribute to,... The meniscectomy-induced OA model in sheep reduced synovial fibrosis Nikolic-Paterson D. J., R.... Ns Stewart FA was increased in fibroblast-like synoviocytes was positively associated with TNF-α-induced activation of OA loose! This network would contribute to fibrosis, one would like to block TGF-β, the contribution! Through inhibiting HIF-1α/NLRP3 inflammasome signaling can not be considered the ultimate cure for therapy! Factors that were shown to be elevated in the development of fibrosis in this,... Levels are elevated [ 70–73 ] capable of destroying the adjacent cartilage reduction fibrosis... Options of the synovium can be distinguished into two different layers: the intima forms an interface between pyroptosis! Low-Grade inflammation apart from joint replacement surgery knowledge of this network would contribute to fibrosis. 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