INTRODUCTION: The goal of this study is to understand the molecular basis underlying articular cartilage degeneration. Results from our recent investigations suggest that HTRA1 (high temperature requirement A1, a serine protease) degrades the pericellular matrix of chondrocytes, resulting in enhanced exposure of chondrocytes to collagen type II. Interaction of chondrocytes with collagen type II activates DDR2 (discoidin domain receptor 2, a cell membrane receptor tyrosine kinase for native collagen type II). This, in turn, induces expression of MMP-13 (matrix metalloproteinase 13). The end result is osteoarthritis. In this proposed molecular sequence of events underneath articular cartilage degeneration, a critical question concerns which factor(s) cause induction of HTRA1 in chondrocytes. In this study, we tested whether biomechanical factors (hydrostatic pressure and mechanical injury) and/or biochemical factors (TNFα, and TGF-β1) are implicated in the induction of HTRA1/DDR2.