PIEZO1 mediates mechanosensing and myofibroblastic activation of synovial fibroblasts in post-traumatic osteoarthritis
- 1ETH Zurich
Abstract
Fibrosis and inflammation of the synovium are common pathological features of joint diseases. In osteoarthritis (OA), extensive evidence supports that synovial pathology drives symptoms and disease progression, yet the mechanisms underpinning pathological synovial remodeling, including fibrosis, remain unclear. Here, we identify the mechanosensitive ion channel PIEZO1 as a critical regulator of myofibroblast-like activation of synovial fibroblasts (SFs) in post-traumatic osteoarthritis (PTOA). Using multi-omic assessments in human and murine synovium, a murine model of joint injury, histopathology, and functional in vitro phenotyping, we demonstrate that joint injury triggers expansion of myofibroblast-like SFs concurrent with fibrotic remodeling and mechanical stiffening of the synovium. Myofibroblastic commitment of synovial progenitors was associated with activation of the YAP1 regulon, and PIEZO1 agonism drove nuclear accumulation of YAP1 in SFs. PIEZO1 was enriched in synovia of injured joints, and in cultured SFs pharmacologic PIEZO1 activation promoted SMA enrichment and increased matrix contraction, which were both ablated by YAP1 inhibition. PIEZO1 silencing abrogated TGF-{beta}-induced contractility and markedly altered the transcriptomic response to mechanical loading in vitro, including ECM production and neuroinflammatory programs. In vivo, acute intra-articular pharmacologic PIEZO1 activation induced a pro-fibrotic, pro-inflammatory, and anti-adipogenic transcriptomic program in synovium. Collectively, these findings establish PIEZO1 as a key mediator of the pathogenic activation of SFs and identify aberrant mechanosensing as a mechanism underlying synovial fibrosis in PTOA.
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BibTeX
@misc{farrell2026piezo1,
title = {{PIEZO1 mediates mechanosensing and myofibroblastic activation of synovial fibroblasts in post-traumatic osteoarthritis}},
author = {E. C. Farrell and A. Mohan and A. M. Kahn and E. Knight and H. Stabile and M. Whitaker and S. Y. Kim and L. Lammlin and M. D. Newton and G. Esteve and R. R. Singh and S. C. Howser and S. Z. Lin and H. X. Tran and D. M. Nguyen and K. Bevc and S. Gonzalez-Nolde and L. Han and R. L. Mauck and C. R. Scanzello and K. Hankenson and A. J. Knights and T. Maerz},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.758946},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.758946v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - PIEZO1 mediates mechanosensing and myofibroblastic activation of synovial fibroblasts in post-traumatic osteoarthritis
AU - E. C. Farrell
AU - A. Mohan
AU - A. M. Kahn
AU - E. Knight
AU - H. Stabile
AU - M. Whitaker
AU - S. Y. Kim
AU - L. Lammlin
AU - M. D. Newton
AU - G. Esteve
AU - R. R. Singh
AU - S. C. Howser
AU - S. Z. Lin
AU - H. X. Tran
AU - D. M. Nguyen
AU - K. Bevc
AU - S. Gonzalez-Nolde
AU - L. Han
AU - R. L. Mauck
AU - C. R. Scanzello
AU - K. Hankenson
AU - A. J. Knights
AU - T. Maerz
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.758946
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.758946v1
AB - Fibrosis and inflammation of the synovium are common pathological features of joint diseases. In osteoarthritis (OA), extensive evidence supports that synovial pathology drives symptoms and disease progression, yet the mechanisms underpinning pathological synovial remodeling, including fibrosis, remain unclear. Here, we identify the mechanosensitive ion channel PIEZO1 as a critical regulator of myofibroblast-like activation of synovial fibroblasts (SFs) in post-traumatic osteoarthritis (PTOA). Using multi-omic assessments in human and murine synovium, a murine model of joint injury, histopathology, and functional in vitro phenotyping, we demonstrate that joint injury triggers expansion of myofibroblast-like SFs concurrent with fibrotic remodeling and mechanical stiffening of the synovium. Myofibroblastic commitment of synovial progenitors was associated with activation of the YAP1 regulon, and PIEZO1 agonism drove nuclear accumulation of YAP1 in SFs. PIEZO1 was enriched in synovia of injured joints, and in cultured SFs pharmacologic PIEZO1 activation promoted SMA enrichment and increased matrix contraction, which were both ablated by YAP1 inhibition. PIEZO1 silencing abrogated TGF-{beta}-induced contractility and markedly altered the transcriptomic response to mechanical loading in vitro, including ECM production and neuroinflammatory programs. In vivo, acute intra-articular pharmacologic PIEZO1 activation induced a pro-fibrotic, pro-inflammatory, and anti-adipogenic transcriptomic program in synovium. Collectively, these findings establish PIEZO1 as a key mediator of the pathogenic activation of SFs and identify aberrant mechanosensing as a mechanism underlying synovial fibrosis in PTOA.
ER -