Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Jan 3.
Published in final edited form as: Ann Rheum Dis. 2016 Aug 19;75(11):e72. doi: 10.1136/annrheumdis-2016-210312

Differential roles of TGF-β signalling in joint tissues during osteoarthritis development

Ting Yu Wang 1, Di Chen 2
PMCID: PMC5207340  NIHMSID: NIHMS839884  PMID: 27543413

Osteoarthritis (OA) is the most common degenerative joint disease. The aetiology of OA is multifactorial, including joint injury, obesity, ageing and heredity. Inactivation of transforming growth factor beta (TGF-β) or its downstream molecules may be an important signalling event contributing to OA pathogenesis because mutations of Smad3, a central molecule in TGF-β signalling, have been found in patients with early-onset OA.1–3 It has been known for many years that TGF-β promotes matrix protein synthesis, inhibits chondrocyte hypertrophy and stimulates expression of Prg4, which encodes for lubricin, a critical molecule for lessening joint friction.4 Lubricin, which is present in synovial fluid and on the surface (superficial layer) of articular cartilage, plays an important role in joint lubrication and synovial homeostasis.

The disease of OA affects the entire joint.5 TGF-β signalling may play differential roles in joint tissues during OA development. For example, Smad3 global knockout (KO) mice showed inhibition of chondrocyte hypertrophy and OA-like articular cartilage damage.6 The deletion of Tgfbr2, encoding for type II TGF-β receptor,7 or Smad38 in articular chondrocytes consistently led to an OA-like phenotype. In contrast, the activation of TGF-β signalling in mesenchymal progenitor cells of subchondral bone also caused OA-like lesions.9 These findings suggest that TGF-β signalling may play differential roles in the various joint tissues.

A recent report in the Annals of the Rheumatic Diseases demonstrated that the disruption of decorin-restricted TGF-β signalling led to increased articular cartilage matrix stiffness, rendering joints more resistant to OA.10 This suggests that the loss of Dcn could decelerate OA development because of the release of endogenous TGF-β into the joint. To further understand the functional significance of decorin in regulation of TGF-β signalling and in OA development, it will be important to generate Dcn conditional KO mice targeting different tissues in the joint. It will also be interesting to determine whether mutation(s) of Dcn can be detected in patients with an aneurysms–OA syndrome in which Smad3 has been proposed as a disease-causing gene for some patients.

Acknowledgments

Funding National Nature Science Foundation of China (grant nos. 81301531, 81572104).

Footnotes

Contributors TYW: concept and writing; DC: concept and revising.

Competing interests None declared.

Patient consent Obtained.

Provenance and peer review Not commissioned; internally peer reviewed.

REFERENCES

  • 1.Valdes AM, Spector TD, Tamm A, et al. Genetic variation in the Smad3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum. 2010;62:2347–2352. doi: 10.1002/art.27530. [DOI] [PubMed] [Google Scholar]
  • 2.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. doi: 10.1038/ng.744. [DOI] [PubMed] [Google Scholar]
  • 3.van de Laar IM, van der Linde D, Oei EH, et al. Phenotypic spectrum of the Smad3-related aneurysms-osteoarthritis syndrome. J Med Genet. 2012;49:47–57. doi: 10.1136/jmedgenet-2011-100382. [DOI] [PubMed] [Google Scholar]
  • 4.Cuellar A, Reddi AH. Stimulation of Superficial Zone Protein/Lubricin/PRG4 by Transforming Growth Factor-β in Superficial Zone Articular Chondrocytes and Modulation by Glycosaminoglycans. Tissue Eng Part A. 2015;21:1973–1981. doi: 10.1089/ten.tea.2014.0381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Loeser RF, Goldring SR, Scanzello CR, et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64:1697–1707. doi: 10.1002/art.34453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Yang X, Chen L, Xu X, et al. TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol. 2001;153:35–46. doi: 10.1083/jcb.153.1.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Shen J, Li J, Wang B, et al. Deletion of the transforming growth factor-β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum. 2013;65:3107–3119. doi: 10.1002/art.38122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Chen CG, Thuillier D, Chin EN, et al. Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheum. 2012;64:3278–3289. doi: 10.1002/art.34566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Zhen G, Wen C, Jia X, et al. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med. 2013;19:704–712. doi: 10.1038/nm.3143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Gronau T, Krüger K, Prein C, et al. Forced exercise-induced osteoarthritis is attenuated in mice lacking the small leucine-rich proteoglycan decorin. Ann Rheum Dis. 2016 doi: 10.1136/annrheumdis-2016-209319. Published Online First 4 July 2016. [DOI] [PubMed] [Google Scholar]

RESOURCES