Mechano-activated synovial cells instigate OA-like disease progression in the absence of joint injury
While altered tissue mechanics and cellular mechanoactivation accompany osteoarthritis, whether dysregulated mechanotransduction can initiate joint disease remains unclear. Here, we used intra-articular delivery of cell-penetrating TAT-Cre recombinase to locally perturb the actomyosin-Hippo mechanotransduction axis in mice. Deletion of Lats1/2, the negative regulators of the mechanosensitive…
Recent research has unveiled a novel mechanism by which osteoarthritis (OA) develops, independent of joint injury. While tissue mechanics and cellular mechanoactivation are known to accompany OA, the ability of mechanically dysregulated signaling to trigger joint disease has remained uncertain. To investigate this, scientists employed an intra-articular delivery method using cell-penetrating TAT-Cre recombinase to locally disrupt the actomyosin-Hippo mechanotransduction axis in mice.
As a result, the mice exhibited sustained joint hyperalgesia, altered gait patterns, synovial hyperplasia and fibrosis, vascular remodeling, and articular cartilage degeneration, all occurring without a destabilizing injury.
Upon closer examination using single-cell transcriptomics, the study observed the emergence of Cthrc1+ matrix-remodeling fibroblasts and an accumulation of Mrc1+Trem2+ macrophages during this pathological process. These findings suggest that mechanoactivation of synovial cells instigates OA-like disease progression. Histological analyses revealed persistent contractile stromal remodeling and an early macrophage response that partially subsided over a four-week period.
Conversely, when researchers locally deleted Myh9/10, which encode the force-generating heavy chains of non-muscle myosin II, they found that hyperalgesia, synovial lining hyperplasia, alpha-SMA+ cell accumulation, and macrophage infiltration were reduced during post-traumatic osteoarthritis (PTOA) pathogenesis. However, despite these interventions, cartilage degeneration was not significantly mitigated at eight weeks.
These findings establish synovial mechanotransduction as a causal driver of joint disease through immune-stromal remodeling and pain development. Additionally, the study demonstrates that partial suppression of contractility can distinguish symptomatic outcomes from structural outcomes in PTOA. Based on these results, synovial mechanotransduction is identified as a potential therapeutic target for modulating pathological stromal-immune remodeling and joint pain.
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