Mechano-activated synovial cells instigate OA-like disease progression in the absence of joint injury
- 1Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States; CReATE Motion Center, CMC VA Medical Center, Philadelphia, PA, United
Abstract
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 transcriptional coactivators YAP and TAZ, induced sustained joint hyperalgesia, altered gait, synovial hyperplasia and fibrosis, vascular remodeling, and articular cartilage degeneration in the absence of a destabilizing injury. Single-cell transcriptomics revealed the emergence of Cthrc1+ matrix-remodeling fibroblasts and accumulation of Mrc1+Trem2+ macrophages during this pathological process. Histological analyses showed persistent contractile stromal remodeling and an early macrophage response that partially subsided over four weeks. Conversely, local deletion of Myh9/10, encoding the force-generating heavy chains of non-muscle myosin II, reduced hyperalgesia, synovial lining hyperplasia, alpha-SMA+ cell accumulation, and macrophage infiltration during post-traumatic osteoarthritis (PTOA) pathogenesis. However, this intervention did not detectably reduce cartilage degeneration at eight weeks. These findings establish synovial mechanotransduction as a causal driver of joint disease via immune-stromal remodeling and pain development. In addition, partial suppression of contractility separates symptomatic from structural outcomes in PTOA. Synovial mechanotransduction therefore represents a target for modulating pathological stromal-immune remodeling and joint pain.
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BibTeX
@misc{bernstein2026mechanoactivated,
title = {{Mechano-activated synovial cells instigate OA-like disease progression in the absence of joint injury}},
author = {E. R. Bernstein and G. Kotsaris and A. A. Silverman and T. Bahlibi and B. Croen and R. Flaugh and C. Scanzello and L. Miller and J. D. Boerckel and N. A. Dyment and R. L. Mauck},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756770},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756770v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Mechano-activated synovial cells instigate OA-like disease progression in the absence of joint injury
AU - E. R. Bernstein
AU - G. Kotsaris
AU - A. A. Silverman
AU - T. Bahlibi
AU - B. Croen
AU - R. Flaugh
AU - C. Scanzello
AU - L. Miller
AU - J. D. Boerckel
AU - N. A. Dyment
AU - R. L. Mauck
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756770
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756770v1
AB - 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 transcriptional coactivators YAP and TAZ, induced sustained joint hyperalgesia, altered gait, synovial hyperplasia and fibrosis, vascular remodeling, and articular cartilage degeneration in the absence of a destabilizing injury. Single-cell transcriptomics revealed the emergence of Cthrc1+ matrix-remodeling fibroblasts and accumulation of Mrc1+Trem2+ macrophages during this pathological process. Histological analyses showed persistent contractile stromal remodeling and an early macrophage response that partially subsided over four weeks. Conversely, local deletion of Myh9/10, encoding the force-generating heavy chains of non-muscle myosin II, reduced hyperalgesia, synovial lining hyperplasia, alpha-SMA+ cell accumulation, and macrophage infiltration during post-traumatic osteoarthritis (PTOA) pathogenesis. However, this intervention did not detectably reduce cartilage degeneration at eight weeks. These findings establish synovial mechanotransduction as a causal driver of joint disease via immune-stromal remodeling and pain development. In addition, partial suppression of contractility separates symptomatic from structural outcomes in PTOA. Synovial mechanotransduction therefore represents a target for modulating pathological stromal-immune remodeling and joint pain.
ER -