J Bone Metab.  2018 May;25(2):65-72. 10.11005/jbm.2018.25.2.65.

Differential Role of Transforming Growth Factor-beta in an Osteoarthritic or a Healthy Joint

• van der Kraan PM

• KMID: 2413367
• DOI: http://doi.org/10.11005/jbm.2018.25.2.65

Abstract

Transforming growth factor-β (TGF-β) is a cytokine that plays an important role in both normal joints and joints affected by osteoarthritis (OA), the most common joint disease. However, the role of this pleiotropic cytokine in a normal healthy joint is very different from its role in an OA joint. In a normal synovial joint, active TGF-β is only present after joint loading and only for a short period. In contrast, permanent and high levels of active TGF-β are detected in OA joints. Due to this difference in levels and exposure period of joint cells to active TGF-β, the function of TGF-β is strikingly different in normal and OA joints. The consequences of this difference in TGF-β levels on joint homeostasis and pathological changes in OA joints are discussed in this review.

Keyword

Cytokines; Osteoarthritis; Transforming growth factor beta

MeSH Terms

Cytokines
Homeostasis
Joint Diseases
Joints*
Osteoarthritis
Transforming Growth Factor beta
Cytokines
Transforming Growth Factor beta

Reference

1. Wallace IJ, Worthington S, Felson DT, et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc Natl Acad Sci U S A. 2017; 114:9332–9336.

2. Newfeld SJ, Wisotzkey RG, Kumar S. Molecular evolution of a developmental pathway: phylogenetic analyses of transforming growth factor-beta family ligands, receptors and Smad signal transducers. Genetics. 1999; 152:783–795.

3. Dickson MC, Martin JS, Cousins FM, et al. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development. 1995; 121:1845–1854.

4. Kulkarni AB, Huh CG, Becker D, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993; 90:770–774.

5. Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992; 359:693–699.

6. Sanford LP, Ormsby I, Gittenberger-de Groot AC, et al. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development. 1997; 124:2659–2670.

7. Proetzel G, Pawlowski SA, Wiles MV, et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet. 1995; 11:409–414.

8. Yingling JM, Wang XF, Bassing CH. Signaling by the transforming growth factor-beta receptors. Biochim Biophys Acta. 1995; 1242:115–136.

9. Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem. 2000; 267:6954–6967.

10. Finnson KW, Parker WL, ten Dijke P, et al. ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J Bone Miner Res. 2008; 23:896–906.

11. Blaney Davidson EN, Remst DF, Vitters EL, et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol. 2009; 182:7937–7945.

12. Remst DF, Blaney Davidson EN, Vitters EL, et al. TGF-ss induces Lysyl hydroxylase 2b in human synovial osteoarthritic fibroblasts through ALK5 signaling. Cell Tissue Res. 2014; 355:163–171.

13. Cao Y, Szabolcs A, Dutta SK, et al. Neuropilin-1 mediates divergent R-Smad signaling and the myofibroblast phenotype. J Biol Chem. 2010; 285:31840–31848.

14. Rudini N, Felici A, Giampietro C, et al. VE-cadherin is a critical endothelial regulator of TGF-beta signalling. EMBO J. 2008; 27:993–1004.

15. Goumans MJ, Valdimarsdottir G, Itoh S, et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002; 21:1743–1753.

16. Morales TI, Joyce ME, Sobel ME, et al. Transforming growth factor-beta in calf articular cartilage organ cultures: synthesis and distribution. Arch Biochem Biophys. 1991; 288:397–405.

17. Albro MB, Nims RJ, Cigan AD, et al. Dynamic mechanical compression of devitalized articular cartilage does not activate latent TGF-beta. J Biomech. 2013; 46:1433–1439.

18. Fava R, Olsen N, Keski-Oja J, et al. Active and latent forms of transforming growth factor beta activity in synovial effusions. J Exp Med. 1989; 169:291–296.

19. Fang PK, Ma XC, Ma DL, et al. Determination of interleukin-1 receptor antagonist, interleukin-10, and transforming growth factor-beta1 in synovial fluid aspirates of patients with temporomandibular disorders. J Oral Maxillofac Surg. 1999; 57:922–928. discussion 8-9.

20. Zielinski S, Bartels K, Cebulski K, et al. Evidence of proteolytic activation of transforming growth factor beta in synovial fluid. Adv Exp Med Biol. 2000; 477:477–481.

21. Hinz B. The extracellular matrix and transforming growth factor-beta1: tale of a strained relationship. Matrix Biol. 2015; 47:54–65.

22. Hinz B. Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep. 2009; 11:120–126.

23. Vanwanseele B, Eckstein F, Knecht H, et al. Knee cartilage of spinal cord-injured patients displays progressive thinning in the absence of normal joint loading and movement. Arthritis Rheum. 2002; 46:2073–2078.

24. Wang Q, Tan QY, Xu W, et al. Cartilage-specific deletion of Alk5 gene results in a progressive osteoarthritis-like phenotype in mice. Osteoarthritis Cartilage. 2017; 25:1868–1879.

25. Wu Q, Kim KO, Sampson ER, et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum. 2008; 58:3132–3144.

26. Yang X, Chen L, Xu X, et al. TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol. 2001; 153:35–46.

27. Serra R, Johnson M, Filvaroff EH, et al. Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol. 1997; 139:541–552.

28. van de Laar IM, Oldenburg RA, Pals G, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011; 43:121–126.

29. Madej W, van Caam A, Blaney Davidson E, et al. 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; 24:1807–1815.

30. Albro MB, Nims RJ, Cigan AD, et al. Accumulation of exogenous activated TGF-beta in the superficial zone of articular cartilage. Biophys J. 2013; 104:1794–1804.

31. Finnson KW, Parker WL, Chi Y, et al. Endoglin differentially regulates TGF-beta-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes. Osteoarthritis Cartilage. 2010; 18:1518–1527.

32. Hellingman CA, Davidson EN, Koevoet W, et al. Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of Smad1/5/8P prevents terminal differentiation and calcification. Tissue Eng Part A. 2011; 17:1157–1167.

33. Retting KN, Song B, Yoon BS, et al. BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development. 2009; 136:1093–1104.

34. Valcourt U, Gouttenoire J, Moustakas A, et al. Functions of transforming growth factor-beta family type I receptors and Smad proteins in the hypertrophic maturation and osteoblastic differentiation of chondrocytes. J Biol Chem. 2002; 277:33545–33558.

35. Zhao W, Wang T, Luo Q, et al. Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-beta signaling. J Orthop Res. 2016; 34:763–770.

36. Day JS, Van Der Linden JC, Bank RA, et al. Adaptation of subchondral bone in osteoarthritis. Biorheology. 2004; 41:359–368.

37. Coughlin TR, Kennedy OD. The role of subchondral bone damage in post-traumatic osteoarthritis. Ann N Y Acad Sci. 2016; 1383:58–66.

38. Funck-Brentano T, Cohen-Solal M. Subchondral bone and osteoarthritis. Curr Opin Rheumatol. 2015; 27:420–426.

39. Zgoda M, Paczek L, Bartlomiejczyk I, et al. Transforming growth factor-beta1, interleukin-1beta and collagenase activity in subchondral bone of the femur and the severity of osteoarthritis of the hip. Clin Exp Rheumatol. 2005; 23:912.

40. Sakao K, Takahashi KA, Arai Y, et al. Asporin and transforming growth factor-beta gene expression in osteoblasts from subchondral bone and osteophytes in osteoarthritis. J Orthop Sci. 2009; 14:738–747.

41. Hayami T, Pickarski M, Wesolowski GA, 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; 50:1193–1206.

42. Zhen G, Wen C, Jia X, et al. Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med. 2013; 19:704–712.

43. Cui Z, Crane J, Xie H, et al. Halofuginone attenuates osteoarthritis by inhibition of TGF-beta activity and H-type vessel formation in subchondral bone. Ann Rheum Dis. 2016; 75:1714–1721.

44. van der Kraan PM, van den Berg WB. Osteophytes: relevance and biology. Osteoarthritis Cartilage. 2007; 15:237–244.

45. van Beuningen HM, van der Kraan PM, Arntz OJ, et al. Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint. Lab Invest. 1994; 71:279–290.

46. Bakker AC, van de Loo FA, van Beuningen HM, et al. Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthritis Cartilage. 2001; 9:128–136.

47. van Beuningen HM, Glansbeek HL, van der Kraan PM, et al. Differential effects of local application of BMP-2 or TGF-beta 1 on both articular cartilage composition and osteophyte formation. Osteoarthritis Cartilage. 1998; 6:306–317.

48. Blaney Davidson EN, Vitters EL, van Beuningen HM, et al. Resemblance of osteophytes in experimental osteoarthritis to transforming growth factor beta-induced osteophytes: limited role of bone morphogenetic protein in early osteoarthritic osteophyte formation. Arthritis Rheum. 2007; 56:4065–4073.

49. Scharstuhl A, Glansbeek HL, van Beuningen HM, et al. Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J Immunol. 2002; 169:507–514.

50. Scharstuhl A, Vitters EL, van der Kraan PM, et al. Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor beta/ bone morphogenetic protein inhibitors during experimental osteoarthritis. Arthritis Rheum. 2003; 48:3442–3451.

51. Blaney Davidson EN, Vitters EL, Bennink MB, et al. Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage. Ann Rheum Dis. 2015; 74:1257–1264.

52. Iwasaki M, Nakata K, Nakahara H, et al. Transforming growth factor-beta 1 stimulates chondrogenesis and inhibits osteogenesis in high density culture of periosteum-derived cells. Endocrinology. 1993; 132:1603–1608.

53. Tuli R, Tuli S, Nandi S, et al. Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. J Biol Chem. 2003; 278:41227–41236.

54. Eymard F, Pigenet A, Citadelle D, et al. Knee and hip intra-articular adipose tissues (IAATs) compared with autologous subcutaneous adipose tissue: a specific phenotype for a central player in osteoarthritis. Ann Rheum Dis. 2017; 76:1142–1148.

55. Mitrovic DR, Riera H. Synovial, articular cartilage and bone changes in rapidly destructive arthropathy (osteoarthritis) of the hip. Rheumatol Int. 1992; 12:17–22.

56. Blaney Davidson EN, Vitters EL, Mooren FM, et al. Connective tissue growth factor/CCN2 overexpression in mouse synovial lining results in transient fibrosis and cartilage damage. Arthritis Rheum. 2006; 54:1653–1661.

57. Remst DF, Blom AB, Vitters EL, et al. Gene expression analysis of murine and human osteoarthritis synovium reveals elevation of transforming growth factor beta-responsive genes in osteoarthritis-related fibrosis. Arthritis Rheumatol. 2014; 66:647–656.

58. Remst DF, Blaney Davidson EN, Vitters EL, et al. Osteoarthritis-related fibrosis is associated with both elevated pyridinoline cross-link formation and lysyl hydroxylase 2b expression. Osteoarthritis Cartilage. 2013; 21:157–164.

59. Morine KJ, Qiao X, Paruchuri V, et al. Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure. Cardiovasc Pathol. 2017; 31:26–33.

60. Muñoz-Félix JM, Perretta-Tejedor N, Eleno N, et al. ALK1 heterozygosity increases extracellular matrix protein expression, proliferation and migration in fibroblasts. Biochim Biophys Acta. 2014; 1843:1111–1122.

61. Muñoz-Félix JM, Cuesta C, Perretta-Tejedor N, et al. Identification of bone morphogenetic protein 9 (BMP9) as a novel profibrotic factor in vitro. Cell Signal. 2016; 28:1252–1261.

62. Burch ML, Zheng W, Little PJ. Smad linker region phosphorylation in the regulation of extracellular matrix synthesis. Cell Mol Life Sci. 2011; 68:97–107.

63. Allen JB, Manthey CL, Hand AR, et al. Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta. J Exp Med. 1990; 171:231–247.

64. Fava RA, Olsen NJ, Postlethwaite AE, et al. Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia. J Exp Med. 1991; 173:1121–1132.

65. Wahl SM, Allen JB, Costa GL, et al. Reversal of acute and chronic synovial inflammation by anti-transforming growth factor beta. J Exp Med. 1993; 177:225–230.

66. Diebold RJ, Eis MJ, Yin M, et al. Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci U S A. 1995; 92:12215–12219.

67. Monteleone G, Mann J, Monteleone I, et al. A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation. J Biol Chem. 2004; 279:3925–3932.

68. Glansbeek HL, van Beuningen HM, Vitters EL, et al. Stimulation of articular cartilage repair in established arthritis by local administration of transforming growth factor-beta into murine knee joints. Lab Invest. 1998; 78:133–142.