Dickkopf-related protein 3: A factor linking cartilage development and degeneration?

Abstract

Purpose: We and others have previously shown that periostin expression is dramatically elevated in human OA cartilage and in three surgical models of OA (medial menisectomy and anterior crucial ligament, partial meniscectomy) in rodents. In vitro periostin promotes collagen and proteoglycan degradation in human chondrocytes via activation of MMP-13 and ADAMTS4 expression. Therefore, we hypothesized that periostin-deficient mice may be protected from surgically-induced posttraumatic OA. Periostin has been shown to control gene expression in bone cells by interacting with avb3 integrin. However, the nature of periostin receptor(s) in chondrocytes is unknown. DDR1, a receptor tyrosine kinase, is highly expressed in chondrocytes and controls MMP-13 expression during chondrogenesis. Therefore, we hypothesized that the effect of periostin on chondrocytes is mediated by DDR1. Methods: Periostin (Postn) knockout (PostnÀ/À) mice were purchased from Jackson Laboratory (B6;129-Postntm1Jmol/J Stock No: 009067). We subjected 3-months old littermates (Postnþ/þ, Postnþ/À and PostnÀ/À) to partial medial menisectomy (PMX) or sham surgery, and harvested the knee joints 8 week post-surgery for histological assessment of OA progression. Human OA cartilage explant cultures were incubated in the presence or absence of the DDR1 inhibitor DDR1-IN-1 dihydrochloridein (100e500 nM) for 2 h before addition of periostin (1 mg/ml) or control vehicle to the culture medium. MMP-13 levels were determined by ELISA-24 h post stimulation. Results: PostnÀ/À deficient mice showed reduced PMX-induced cartilage degeneration and osteophyte formation relative to Postnþ/þ mice. We also observed reduced subchondral bone thickening in both Postnþ/À and PostnÀ/À mice relative to Postnþ/þ controls. In ex vivo studies, pre-incubation of human cartilage explants with the DDR1 inhibitor, DDR1-IN-1 dihydrochloridein, inhibited both constitutive and periostin-induced MMP-13 expression in a dose-dependent manner ( Fig. 1). In contrast, neutralizing antibody to avb3 integrin had no effect on periostin-induced MMP-13 expression. Conclusions: PostnÀ/À mice are protected from surgically-induced post-traumatic OA showing that periostin promotes cartilage degeneration.. DDR1 mediates the stimulatory effect of periostin on MMP-13 expression. Further studies are in progress to investigate the potential of periostin as a druggable target for the treatment of OA.Purpose: The aim of this study was to identify the expression of Latexin of chondrocytes from the three zones of the cartilage and their possible role during the OA pathogenesis in an animal model. Methods: We conducted a proteomic study of osteoarthritic cartilage during the early stages of OA using an experimental rat model. Then, we identify and evaluated the presence of Latexin (Lxn) in the three zones of the cartilage during OA pathogenesis. Results: In this work, we performed a proteomic study of osteoarthritic cartilage during the early stages of an experimental OA rat model. Ten proteins were differentially e...