Age-related alterations in TGF beta signaling as a causal factor of cartilage degeneration in osteoarthritis

Biomed Mater Eng. 2014;24(1 Suppl):75-80. doi: 10.3233/BME-140976.


Background: Age is the most important risk factor for primary osteoarthritis (OA). Members of the TGF-β superfamily play a crucial role in chondrocyte differentiation and maintenance of healthy articular cartilage.

Objective: We have investigated whether age-related changes in TGF-β superfamily signaling components play a role in the relationship between OA-related cartilage degradation and aging.

Material and methods: The relationship between age, OA and TGF-β superfamily signaling was studied using murine experimental OA models, aging mice, bovine articular cartilage and human OA cartilage. The effects of TGF-β on cartilage homeostasis was studied with immunohistochemistry, Q-RT-PCR and signaling pathway analysis with Western blotting and the application of specific TGF-β inhibitors.

Results: We have found that TGF-β loses its protective effects in old cartilage. Moreover, we found that on chondrocytes, TGF-β not only signals via the canonical type I receptor ALK5 (TGFBR1) but also via the ALK1 (ACVRL1) receptor. Remarkably, signaling via ALK5 (Smad2/3 route) results in protective while ALK1 signaling (Smad1/5/8 route) results in deleterious responses in articular chondrocytes. In cartilage of aging mice it was detected that the ALK1/ALK5 ratio is significantly increased, favoring TGF-β signaling via the Smad1/5/8 route, inducing changes in chondrocyte differentiation and matrix metalloproteinase-13 (MMP-13) expression. Moreover, human OA cartilage showed a significant correlation between ALK1 and MMP-13 expression. Since in mice aging and OA in often goes hand in hand, we also analyzed age-related expression of TGF-β superfamily related signaling molecules in healthy bovine cartilage in an age range from 6 months to 14 years. In this cohort of aging cartilage, we found that mainly signaling receptors determining the Smad2/3 pathway were decreased with age while Smad1/5/8-related signaling molecules did not alter, confirming our findings in aging mice.

Conclusions: Old cartilage appears to be less protected by TGF-β and shows significant alterations in TGF-β signaling pathways. Loss of the protective Smad2/3 pathway during aging can provide an explanation for the relationship between OA and aging.

Keywords: ALKs; BMPs; Osteoarthritis; TGF-β; aging.

MeSH terms

  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism
  • Aging / physiology*
  • Animals
  • Cartilage Diseases / pathology*
  • Cartilage, Articular / metabolism
  • Cattle
  • Chondrocytes / metabolism
  • Humans
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Mice
  • Osteoarthritis / pathology*
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*


  • Interleukin-1
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Smad3 Protein
  • Transforming Growth Factor beta
  • Activin Receptors, Type II
  • Matrix Metalloproteinase 13