UCSF

Osteoarthritis (OA) is a degenerative joint disease characterized by disruption of multiple joint tissues, including articular cartilage and subchondral bone, resulting in chronic joint pain. The precise contributions of articular cartilage and subchondral bone in the etiology of OA are yet to be established, but growing evidence suggests that crosstalk between these two tissues is critical for joint homeostasis. Among the factors important for skeletal health is transforming growth factor beta (TGFβ) signaling, which is known to play an important role in each of the tissues of the synovial joint. The careful regulation of TGFβ signaling in the joint is dose-dependent and relies upon coordinated downstream signaling, mechanical cues, and tissue-specific function. This work identifies osteocytic TGFβ signaling as a key component of bone-cartilage crosstalk and the mechanosensitive response to joint injury. In mice, increased joint loading due to injury represses osteocytic TGFβ signaling at the subchondral bone plate. Furthermore, the subchondral bone in transgenic mice with an osteocyte-intrinsic loss of TGFβ signaling is unable to respond to mechanical changes with injury, identifying a bidirectional role for osteocytic TGFβ signaling in joint injury. Without osteocytic TGFβ signaling, articular cartilage degeneration is worsened due to disrupted mechanosensation. Additionally, this work investigates the transient receptor potential vanilloid 4 (TRPV4) calcium ion channel as a possible calibrator of osteocytic TGFβ signaling. Findings from this work reveal osteocytes, and specifically osteocytic TGFβ signaling, as major contributors to joint homeostasis and OA progression.