Mechanical stress determines the configuration of TGFβ activation in articular cartilage

Our incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy. The functional relationship between subchondral bone (SB) and articular cartilage (AC) is unclear. Here, we found that the changes of SB architecture altered the distribution of mechanical stress on AC. Importantly, the latter is well aligned with the pattern of transforming growth factor beta (TGF beta) activity in AC, which is essential in the regulation of AC homeostasis. Specifically, TGF beta activity is concentrated in the areas of AC with high mechanical stress. A high level of TGF beta disrupts the cartilage homeostasis and impairs the metabolic activity of chondrocytes. Mechanical stress stimulates talin-centered cytoskeletal reorganization and the consequent increase of cell contractile forces and cell stiffness of chondrocytes, which triggers alpha V integrin-mediated TGF beta activation. Knockout of alpha V integrin in chondrocytes reversed the alteration of TGF beta activation and subsequent metabolic abnormalities in AC and attenuated cartilage degeneration in an OA mouse model. Thus, SB structure determines the patterns of mechanical stress and the configuration of TGF beta activation in AC, which subsequently regulates chondrocyte metabolism and AC homeostasis. The functional relationship between subchondral bone and articular cartilage is unclear. Here, the authors show that transforming growth factor-beta propagates the mechanical impact of subchondral bone on articular cartilage through alpha V integrin-talin mechanical transduction system in chondrocytes.