Modulation Of Tgf- Activity By Latent Tgf--Binding Protein 1 In Human Osteoarthritis Fibroblast-Like Synoviocytes

Osteoarthritis (OA) is a common degenerative joint disease; however, its underlying pathogenesis remains to be elucidated. Previous studies have demonstrated that the transforming growth factor- (TGF-) signaling pathway has a role in the initiation and development of OA. Additionally, latent TGF--binding protein-1 (LTBP-1) modulates the activity of the TGF--mothers against decapentaplegic (Smad) signaling pathway in numerous diseases, including malignant glioma. The present study demonstrated that expression of LTBP-1 is increased in OA synovial tissues compared with normal synovial tissues. The effect of TGF- was identified to be mediated by phosphorylated(p)-(Smad)2/3, which may activate activin-like kinase (ALK)5 receptor, and by p-Smad1/5/8, which may induce ALK1, thereby stimulating expression of matrix metalloproteinase-(MMP)-13 in OA fibroblast-like synoviocytes (FLS). Compared with normal FLS, OA FLS demonstrated an increased p-Smad1/5/8:p-Smad2 ratio, which led to elevated MMP-13 expression and aggravation of OA. Furthermore, knockdown of the LTBP-1 gene by siRNA transfection in OA FLS reduced p-Smad1/5/8 expression without affecting TGF- mRNA levels, although p-Smad2 expression increased. It was also demonstrated that OA FLS exhibited increased proliferation compared with normal FLS in vitro. Furthermore, siRNA-mediated downregulation of LTBP-1 reduced proliferation of OA FLS. In conclusion, the present study demonstrated that an alteration in the p-Smad1/5/8:p-Smad2 ratio as well as association between p-Smad1/5/8 and MMP-13 expression in human OA FLS, may contribute to the development of OA. The results of the present study suggested that LTBP-1 is a modulator of the TGF- signaling pathway in human OA FLS, which may aid in elucidating the mechanism underlying the pathology of OA.