Conserved Fibroblast Subsets Drive Shared Fibrotic Mechanisms in Osteoarthritis Synovium and Systemic Sclerosis Skin
- 1Institute for Biomechanics, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
Abstract
Osteoarthritis (OA) and systemic sclerosis (SSc) are diseases with distinct etiologies but similar disease phenotypes, most prominently fibrosis, a process governed by the pathological activation of fibroblasts. Mechanisms underpinning fibrosis in these diseases are widely studied, though have yet to be directly compared. We employed single-cell RNA-seq and high-resolution spatial transcriptomics to describe the functional plasticity and the range of fibroblast activation states in both diseases. We identified disease-enriched fibroblast subsets conserved in both diseases, including fibrogenic myofibroblast-like cells, chemokine- and cytokine-expressing inflammatory fibroblasts, and lining-like fibroblasts. These subsets exhibited convergent fibrotic programs also observed in idiopathic pulmonary fibrosis, as well as overlapping osteochondral transcriptional programs. Xenium 5K spatial transcriptomics revealed that conserved, disease-associated fibroblasts reside in highly similar anatomic niches in OA synovium and SSc skin. These consisted of a fibrotic ECM-rich niche harboring myofibroblast-like cells and an inflammatory niche containing inflammatory fibroblasts adjacent to infiltrating immune cells. Disease-associated transcriptional remodeling converged on shared functional pathways and common putative upstream molecular regulators. These findings identify conserved cellular states, spatial niches, and regulatory programs across OA and SSc, suggesting that fibrotic disease is underpinned by shared pathogenic stromal states and candidate targets for therapeutic strategies are applicable across both diseases.
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BibTeX
@misc{mohan2026conserved,
title = {{Conserved Fibroblast Subsets Drive Shared Fibrotic Mechanisms in Osteoarthritis Synovium and Systemic Sclerosis Skin}},
author = {A. Mohan and M. D. Newton and N. Bhate and A. Khmelevskaya and T. M. Hanna and E. DiCarlo and C. Ospelt and D. Orange and J. Varga and T. Maerz},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756653},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756653v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Conserved Fibroblast Subsets Drive Shared Fibrotic Mechanisms in Osteoarthritis Synovium and Systemic Sclerosis Skin
AU - A. Mohan
AU - M. D. Newton
AU - N. Bhate
AU - A. Khmelevskaya
AU - T. M. Hanna
AU - E. DiCarlo
AU - C. Ospelt
AU - D. Orange
AU - J. Varga
AU - T. Maerz
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756653
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756653v1
AB - Osteoarthritis (OA) and systemic sclerosis (SSc) are diseases with distinct etiologies but similar disease phenotypes, most prominently fibrosis, a process governed by the pathological activation of fibroblasts. Mechanisms underpinning fibrosis in these diseases are widely studied, though have yet to be directly compared. We employed single-cell RNA-seq and high-resolution spatial transcriptomics to describe the functional plasticity and the range of fibroblast activation states in both diseases. We identified disease-enriched fibroblast subsets conserved in both diseases, including fibrogenic myofibroblast-like cells, chemokine- and cytokine-expressing inflammatory fibroblasts, and lining-like fibroblasts. These subsets exhibited convergent fibrotic programs also observed in idiopathic pulmonary fibrosis, as well as overlapping osteochondral transcriptional programs. Xenium 5K spatial transcriptomics revealed that conserved, disease-associated fibroblasts reside in highly similar anatomic niches in OA synovium and SSc skin. These consisted of a fibrotic ECM-rich niche harboring myofibroblast-like cells and an inflammatory niche containing inflammatory fibroblasts adjacent to infiltrating immune cells. Disease-associated transcriptional remodeling converged on shared functional pathways and common putative upstream molecular regulators. These findings identify conserved cellular states, spatial niches, and regulatory programs across OA and SSc, suggesting that fibrotic disease is underpinned by shared pathogenic stromal states and candidate targets for therapeutic strategies are applicable across both diseases.
ER -