Age-dependent effects of TRPA1 deficiency on pain and osteoarthritis pathology following joint injury in mice

Transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable cation channel expressed in multiple cell types, including nociceptive C-fibers innervating the knee joint, and is activated by mechanical, inflammatory, and oxidative stimuli. While TRPA1 inhibition reduces pain-related behavior in chemically-induced arthritis, its role in mechanically induced osteoarthritis (OA), and how this relationship changes with age, remains unclear. Here we tested the hypothesis that TRPA1 deficiency alters mechanical sensitivity and OA pathology after joint injury in an age-dependent manner in mice. Male C57BL/6J wildtype (WT) and TRPA1-deficient (TRPA1 −/− ) mice underwent unilateral destabilization of the medial meniscus (DMM) at either 14 weeks (young) or 48 weeks (adult) of age. Mechanical sensitivity was assessed weekly for 7 weeks using von Frey testing. In young mice, gait biomechanics were measured with a force-instrumented running wheel, and voluntary cage activity and energy expenditure were assessed before and after DMM. At 8 weeks post-injury, histologic analyses were performed to evaluate cartilage degeneration and osteophyte formation. In young mice, TRPA1 −/− mice exhibited higher 50% paw-withdrawal thresholds than WT mice at 1 and 3 weeks after DMM ( p < 0.05), consistent with reduced early mechanical hypersensitivity. However, TRPA1 −/− mice showed more severe cartilage degeneration and osteophyte formation in the injured medial compartment ( p < 0.05) and altered gait biomechanics after injury ( p < 0.05). In adult mice, TRPA1 deficiency did not significantly alter OA pathology or withdrawal thresholds, although trends toward genotype differences were observed at select post-injury timepoints. Across genotypes, older mice displayed less hypersensitivity following DMM than younger mice. TRPA1 contributes to early post-injury mechanical sensitivity and gait mechanics following joint injury. TRPA1 deficiency results in altered gait biomechanics and more severe OA development in young mice but not in adult mice. These findings indicate an age-dependent interaction between sensory signaling and joint degeneration, with implications for TRPA1-targeted analgesic strategies in joint disease.