Fibrotic remodeling and stromal reprogramming in osteoarthritis: mechanisms, mechanobiology, and emerging therapeutic perspectives
4 affiliations
- 1Nanyang Central Hospital
- 2School of Osteopathy, Henan University of Chinese Medicine
- 3National Medical Products Administration (NMPA) Key Laboratory for Quality Control of In Vitro Diagnostics, Henan Medical Products Administration
- 4State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Henan Key Laboratory of Health Medicine and Liver Disease Prevention & Treatment, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University
Abstract
Osteoarthritis (OA) has traditionally been regarded as a degenerative joint disorder characterized primarily by cartilage erosion. However, growing evidence suggests that OA is a disorder of maladaptive whole-joint remodeling in which fibrotic remodeling represents an important yet underappreciated contributor to disease progression. Fibrotic remodeling is best documented in the synovium and joint capsule, with related stromal and extracellular matrix (ECM) changes also occurring in the infrapatellar fat pad and other joint compartments. Recent studies suggest that OA-associated fibrotic remodeling extends beyond passive scar formation and involves persistent stromal reprogramming, chronic inflammatory signaling, and mechanobiological adaptation. In this review, stromal reprogramming is used as a conceptual framework describing persistent alterations in stromal cell state that extend beyond transient fibroblast activation or fibroblast-to-myofibroblast transition (FMT). These alterations may involve sustained transcriptional programs, altered mechanosensitivity, metabolic or epigenetic adaptation, and incomplete restoration of tissue homeostasis. However, direct evidence demonstrating stable long-term stromal reprogramming in human OA remains limited. Advances in single-cell omics, spatial transcriptomics, and systems biology approaches have revealed substantial heterogeneity among stromal and immune cell populations, providing new insights into fibrosis-associated cellular states and potential opportunities for biomarker-guided patient stratification. Nevertheless, whether these states represent stable biological entities, transitional disease stages, or secondary responses to advanced OA remains unresolved. This review focuses on the unresolved transition from adaptive tissue repair to persistent fibrotic remodeling and proposes a conceptual framework linking stromal reprogramming, inflammatory signaling, ECM remodeling, and mechanobiological feedback during OA progression. Throughout, we distinguish direct evidence from human OA and experimental OA models from mechanistic insights derived from rheumatoid arthritis and other fibrotic diseases. We further discuss emerging precision medicine strategies and future opportunities for biomarker-guided and mechanobiology-informed antifibrotic interventions. Although this Review adopts a whole-joint perspective, current mechanistic evidence remains predominantly synovium-centered, highlighting the need for further investigation of fibrotic remodeling across additional joint compartments.
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BibTeX
@article{liang2026fibrotic,
title = {{Fibrotic remodeling and stromal reprogramming in osteoarthritis: mechanisms, mechanobiology, and emerging therapeutic perspectives}},
author = {Yanbing Liang and Yuxiao Xiang and Weijia Li and Juanli Zhang and Jianxiang Shi},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1901489},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901489/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Fibrotic remodeling and stromal reprogramming in osteoarthritis: mechanisms, mechanobiology, and emerging therapeutic perspectives
AU - Yanbing Liang
AU - Yuxiao Xiang
AU - Weijia Li
AU - Juanli Zhang
AU - Jianxiang Shi
PY - 2026
DA - 2026/10/08
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1901489
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901489/full
AB - Osteoarthritis (OA) has traditionally been regarded as a degenerative joint disorder characterized primarily by cartilage erosion. However, growing evidence suggests that OA is a disorder of maladaptive whole-joint remodeling in which fibrotic remodeling represents an important yet underappreciated contributor to disease progression. Fibrotic remodeling is best documented in the synovium and joint capsule, with related stromal and extracellular matrix (ECM) changes also occurring in the infrapatellar fat pad and other joint compartments. Recent studies suggest that OA-associated fibrotic remodeling extends beyond passive scar formation and involves persistent stromal reprogramming, chronic inflammatory signaling, and mechanobiological adaptation. In this review, stromal reprogramming is used as a conceptual framework describing persistent alterations in stromal cell state that extend beyond transient fibroblast activation or fibroblast-to-myofibroblast transition (FMT). These alterations may involve sustained transcriptional programs, altered mechanosensitivity, metabolic or epigenetic adaptation, and incomplete restoration of tissue homeostasis. However, direct evidence demonstrating stable long-term stromal reprogramming in human OA remains limited. Advances in single-cell omics, spatial transcriptomics, and systems biology approaches have revealed substantial heterogeneity among stromal and immune cell populations, providing new insights into fibrosis-associated cellular states and potential opportunities for biomarker-guided patient stratification. Nevertheless, whether these states represent stable biological entities, transitional disease stages, or secondary responses to advanced OA remains unresolved. This review focuses on the unresolved transition from adaptive tissue repair to persistent fibrotic remodeling and proposes a conceptual framework linking stromal reprogramming, inflammatory signaling, ECM remodeling, and mechanobiological feedback during OA progression. Throughout, we distinguish direct evidence from human OA and experimental OA models from mechanistic insights derived from rheumatoid arthritis and other fibrotic diseases. We further discuss emerging precision medicine strategies and future opportunities for biomarker-guided and mechanobiology-informed antifibrotic interventions. Although this Review adopts a whole-joint perspective, current mechanistic evidence remains predominantly synovium-centered, highlighting the need for further investigation of fibrotic remodeling across additional joint compartments.
SN - 1664-3224
ER -