BACKGROUND

Osteoarthritis (OA) is a debilitating joint disease characterized by cartilage degeneration, synovial inflammation, and bone remodeling, with limited therapeutic options targeting the underlying pathophysiology. Mechanosensitive ion channels Piezo1 and Piezo2 play crucial roles in chondrocyte responses to mechanical stress, mediating mechanotransduction pathways that influence chondrocyte survival, matrix production, and inflammatory signaling, but their distinct contributions to OA pathogenesis remain unclear.

METHODS

Using inducible, chondrocyte-specific Aggrecan-Cre () mice, we investigated , , and combined / conditional knockouts (cKOs) using the destabilization of the medial meniscus (DMM) model of post-traumatic OA in male and female mice. Pain and behavioral assessments were conducted at four time points to evaluate OA progression, while cartilage damage, bone remodeling, and synovial inflammation were assessed at the final endpoint of 28 weeks. Statistical analyses included one-way and two-way ANOVA with Tukey's multiple comparisons test.

RESULTS

cKO delayed pain onset but ultimately exacerbated cartilage degradation and synovitis, emphasizing its dual role in protective and pathogenic mechanotransduction. While the cKO reduced pain and preserved activity, it failed to protect cartilage. Notably, cKO provided the greatest protection against cartilage degeneration, synovitis, and pain. Micro-computed tomography analyses revealed that is critical for maintaining trabecular bone integrity, with a cKO leading to decreased bone volume, thickness, and density, independent of injury. cKO also reduced normal meniscal ossification that occurs with age in mice. In contrast, a cKO normalized most bone remodeling parameters observed in cKO mice but did not restore medial tibial plateau thickness, highlighting 's essential role in bone structure.

CONCLUSIONS

These findings demonstrate the overlapping and compensatory roles of and in OA pathogenesis. Dual inhibition of may offer a novel, effective therapeutic strategy targeting both structural and symptomatic aspects of the disease.