Goldring SR, Goldring MB. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol. 2016;2016:632–44.

Article  Google Scholar 

Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;2012:616–30.

Article  CAS  Google Scholar 

Morikawa M, Derynck R, Miyazono K. TGF-beta and the TGFbeta family: context dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol. 2016;2016: 8(5), a021873.

Ayyaz A, Attisano L, Wrana JL. Recent advances in understanding contextual TGFbeta signaling. F1000Res. 2017;2017:749.

Article  CAS  Google Scholar 

Derynck R, Budi EH. Specificity, versatility, and control of TGFbeta family signaling. Sci Signal. 2019;2019: 12(570), eaav5183.

Wrana JL. Signaling by the TGFbeta superfamily. Cold Spring Harb Perspect Biol. 2013;2013:a011197.

Google Scholar 

Miyazawa K, Miyazono K. Regulation of TGF-beta family signaling by inhibitory smads. Cold Spring Harb Perspect Biol. 2016;2017: 9(3), a022095.

Cisternas MG, Murphy L, Sacks JJ, Solomon DH, Pasta DJ, Helmick CG. Alternative methods for defining osteoarthritis and the impact on estimating prevalence in a US population-based survey. Arthritis Care Res (Hoboken). 2015;2016:574–80.

Google Scholar 

Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;2012:2197–223.

Article  Google Scholar 

van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;2011:121–6.

Article  CAS  Google Scholar 

van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, Bierma-Zeinstra SM, et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet. 2011;2012:47–57.

Google Scholar 

Hopwood B, Tsykin A, Findlay DM, Fazzalari NL. Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-beta/bone morphogenic protein signalling. Arthritis Res Ther. 2007;2007:R100.

Article  CAS  Google Scholar 

Dequeker J, Mohan S, Finkelman RD, Aerssens J, Baylink DJ. Generalized osteoarthritis associated with increased insulin-like growth factor types I and II and transforming growth factor beta in cortical bone from the iliac crest. Possible mechanism of increased bone density and protection against osteoporosis. Arthritis Rheum. 1993;1993:1702–8.

Article  Google Scholar 

Kumarasinghe DD, Perilli E, Tsangari H, Truong L, Kuliwaba JS, Hopwood B, et al. Critical molecular regulators, histomorphometric indices and their correlations in the trabecular bone in primary hip osteoarthritis. Osteoarthritis Cartilage. 2010;2010:1337–44.

Article  Google Scholar 

Truong LH, Kuliwaba JS, Tsangari H, Fazzalari NL. Differential gene expression of bone anabolic factors and trabecular bone architectural changes in the proximal femoral shaft of primary hip osteoarthritis patients. Arthritis Res Ther. 2006;2006:R188.

Article  CAS  Google Scholar 

Aref-Eshghi E, Liu M, Razavi-Lopez SB, Hirasawa K, Harper PE, Martin G, et al. SMAD3 is upregulated in human osteoarthritic cartilage independent of the promoter DNA methylation. J Rheumatol. 2015;2016:388–94.

Google Scholar 

Hsueh MF, Zhang X, Wellman SS, Bolognesi MP, Kraus VB. Synergistic roles of macrophages and neutrophils in osteoarthritis progression. Arthritis Rheumatol. 2020;2020.

Yao JY, Wang Y, An J, Mao CM, Hou N, Lv YX, et al. Mutation analysis of the Smad3 gene in human osteoarthritis. Eur J Hum Genet. 2003;2003:714–7.

Article  CAS  Google Scholar 

Valdes AM, Spector TD, Tamm A, Kisand K, Doherty SA, Dennison EM, et al. Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum. 2010;2010:2347–52.

Article  CAS  Google Scholar 

Hackinger S, Trajanoska K, Styrkarsdottir U, Zengini E, Steinberg J, Ritchie GRS, et al. Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus. Hum Mol Genet. 2017;2017:3850–8.

Article  CAS  Google Scholar 

Lu C, Shu J, Han Y, Ren XY, Xu K, Fan H, et al. The polymorphism of SMAD3 rs1065080 is associated with increased risk for knee osteoarthritis. Mol Biol Rep. 2019;2019:4501–5.

Article  CAS  Google Scholar 

Zhao T, Zhao J, Ma C, Wei J, Wei B, Liu J. Common variants in LTBP3 gene contributed to the risk of hip osteoarthritis in Han Chinese population. Biosci Rep. 2020; 2020: 40(6), BSR20192999.

•• Zengini E, Hatzikotoulas K, Tachmazidou I, Steinberg J, Hartwig FP, Southam L, et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat Genet. 2018;2018:549–58. This study employs the UK Biobank dataset and genome-wide analyses to uncover causal variants for OA, including variants in TGFβ related genes.

Article  CAS  Google Scholar 

•• Tachmazidou I, Hatzikotoulas K, Southam L, Esparza-Gordillo J, Haberland V, Zheng J, et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019;2019:230–6. This study leverages the UK Biobank and Arthritis Research UK Osteoarthritis Genetics resources for genome-wide association studies, identifying a single variant within the TGFB1 gene as causal for OA development.

Article  CAS  Google Scholar 

Rys JP, Monteiro DA, Alliston T. Mechanobiology of TGFbeta signaling in the skeleton. Matrix Biol. 2016;2016:413–25.

Article  CAS  Google Scholar 

Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007;2007:1311–23.

Article  CAS  Google Scholar 

Rys JP, DuFort CC, Monteiro DA, Baird MA, Oses-Prieto JA, Chand S, et al. Discrete spatial organization of TGFbeta receptors couples receptor multimerization and signaling to cellular tension. Elife. 2015;2015:e09300.

Article  Google Scholar 

Monteiro DA, Dole NS, Campos JL, Kaya S, Schurman CA, Belair CD, et al. Fluid shear stress generates a unique signaling response by activating multiple TGFbeta family type I receptors in osteocytes. FASEB J. 2021;2021:e21263.

Google Scholar 

Haudenschild DR, Chen J, Pang N, Lotz MK, D’Lima DD. Rho kinase-dependent activation of SOX9 in chondrocytes. Arthritis Rheum. 2009;2010:191–200.

Google Scholar 

Allen JL, Cooke ME, Alliston T. ECM stiffness primes the TGFbeta pathway to promote chondrocyte differentiation. Mol Biol Cell. 2012;2012:3731–42.

Article  Google Scholar 

Albro MB, Nims RJ, Cigan AD, Yeroushalmi KJ, Alliston T, Hung CT, et al. Accumulation of exogenous activated TGF-beta in the superficial zone of articular cartilage. Biophys J. 2013;2013:1794–804.

Article  CAS  Google Scholar 

Albro MB, Cigan AD, Nims RJ, Yeroushalmi KJ, Oungoulian SR, Hung CT, et al. Shearing of synovial fluid activates latent TGF-beta. Osteoarthritis Cartilage. 2012;2012:1374–82.

Article  Google Scholar 

Albro MB, Nims RJ, Cigan AD, Yeroushalmi KJ, Shim JJ, Hung CT, et al. Dynamic mechanical compression of devitalized articular cartilage does not activate latent TGF-beta. J Biomech. 2013;2013:1433–9.

Article  Google Scholar 

Madej W, van Caam A, Blaney Davidson EN, van der Kraan PM, Buma P. Physiological and excessive mechanical compression of articular cartilage activates Smad2/3P signaling. Osteoarthritis Cartilage. 2014;2014:1018–25.

Article  Google Scholar 

Madej W, van Caam A, Blaney Davidson E, Buma P, van der Kraan PM. Unloading results in rapid loss of TGFbeta signaling in articular cartilage: role of loading-induced TGFbeta signaling in maintenance of articular chondrocyte phenotype? Osteoarthritis Cartilage. 2016;2016:1807–15.

Article  Google Scholar 

Blaney Davidson EN, Remst DF, Vitters EL, van Beuningen HM, Blom AB, Goumans MJ, et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol. 2009;2009:7937–45.

Article  CAS  Google Scholar 

van Caam A, Madej W, Thijssen E, Garcia de Vinuesa A, van den Berg W, Goumans MJ, et al. Expression of TGFbeta-family signalling components in ageing cartilage: age-related loss of TGFbeta and BMP receptors. Osteoarthritis Cartilage. 2016;2016:1235–45.

Article  Google Scholar 

Madej W, van Caam A, Davidson EN, Hannink G, Buma P, van der Kraan PM. Ageing is associated with reduction of mechanically-induced activation of Smad2/3P signaling in articular cartilage. Osteoarthritis Cartilage. 2015;2016:146–57.

Google Scholar 

Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, et al. Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med. 2013;2013:704–12.

Article  CAS  Google Scholar 

Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;2011:229–38.

Article  CAS  Google Scholar 

Dole NS, Mazur CM, Acevedo C, Lopez JP, Monteiro DA, Fowler TW, et al. Osteocyte-intrinsic TGF-beta signaling regulates bone quality through perilacunar/canalicular remodeling. Cell Rep. 2017;2017:2585–96.

Article  CAS  Google Scholar 

Dole NS, Yee CS, Mazur CM, Acevedo C, Alliston T. TGFbeta Regulation of Perilacunar/Canalicular remodeling is sexually dimorphic. J Bone Miner Res. 2020;2020:1549–61.

Article  CAS  Google Scholar 

• Bailey KN, Nguyen J, Yee CS, Dole NS, Dang A. Alliston T. Mechanosensitive control of articular cartilage and subchondral bone homeostasis requires osteocytic TGFbeta signaling. Arthritis Rheumatol. 2020;2021: 73(3), 414-425. This study demonstrates that osteocytic TGFβ signaling is required for articular cartilage health and the mechanosensitive response to joint injury.

Scharstuhl A, Glansbeek HL, van Beuningen HM, Vitters EL, van der Kraan PM, van den Berg WB. Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J Immunol. 2002;2002:507–14.

Article  Google Scholar 

Kumarasinghe DD, Sullivan T, Kuliwaba JS, Fazzalari NL, Atkins GJ. Evidence for the dysregulated expression of TWIST1, TGFbeta1 and SMAD3 in differentiating osteoblasts from primary hip osteoarthritis patients. Osteoarthritis Cartilage. 2012;2012:1357–66.

Article  Google Scholar 

Massicotte F, Lajeunesse D, Benderdour M, Pelletier JP, Hilal G, Duval N, et al. Can altered production of interleukin-1beta, interleukin-6, transforming growth factor-beta and prostaglandin E(2) by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients. Osteoarthritis Cartilage. 2002;2002:491–500.

Article  Google Scholar 

Couchourel D, Aubry I, Delalandre A, Lavigne M, Martel-Pelletier J, Pelletier JP, et al. Altered mineralization of human osteoarthritic osteoblasts is attributable to abnormal type I collagen production. Arthritis Rheum. 2009;2009:1438–50.

Article  Google Scholar 

Chan TF, Couchourel D, Abed E, Delalandre A, Duval N, Lajeunesse D. Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts. J Bone Miner Res. 2011;2011:1399–410.

Article  CAS  Google Scholar 

Abed E, Bouvard B, Martineau X, Jouzeau JY, Reboul P, Lajeunesse D. Elevated hepatocyte growth factor levels in osteoarthritis osteoblasts contribute to their altered response to bone morphogenetic protein-2 and reduced mineralization capacity. Bone. 2015;2015:111–9.

Article  CAS  Google Scholar 

Kang JS, Alliston T, Delston R, Derynck R. Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J. 2005;2005:2543–55.

Article  CAS  Google Scholar 

• Mazur CM, Woo JJ, Yee CS, Fields AJ, Acevedo C, Bailey KN, et al. Osteocyte dysfunction promotes osteoarthritis through MMP13-dependent suppression of subchondral bone homeostasis. Bone Res. 2019;2019:34 This study demonstrates a causal role for osteocytes in osteoarthritis.

Tang SY, Alliston T. Regulation of postnatal bone homeostasis by TGFbeta. Bonekey Rep. 2014;2013:255.

Google Scholar 

Kaneda T, Nojima T, Nakagawa M, Ogasawara A, Kaneko H, Sato T, et al. Endogenous production of TGF-beta is essential for osteoclastogenesis induced by a combination of receptor activator of NF-kappa B ligand and macrophage-colony-stimulating factor. J Immunol. 2000;2000:4254–63.

Article  Google Scholar 

Oursler MJ. Osteoclast synthesis and secretion and activation of latent transforming growth factor beta. J Bone Miner Res. 1994;1994:443–52.

Google Scholar 

Fuller K, Lean JM, Bayley KE, Wani MR, Chambers TJ. A role for TGFbeta(1) in osteoclast differentiation and survival. J Cell Sci. 2000;2000:2445–53.

Article  Google Scholar 

Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004;2004:1193–206.

Article  CAS