2. Academic Validation
  3. RUNX2 Activation in Fibro/Adipogenic Progenitors Promotes Muscle Fibrosis in Muscular Dystrophy

RUNX2 Activation in Fibro/Adipogenic Progenitors Promotes Muscle Fibrosis in Muscular Dystrophy

  • Adv Sci (Weinh). 2025 Dec 22:e10850. doi: 10.1002/advs.202510850.
Pengkai Wu 1 2 3,  Zehua Zhang 1 2 3,  Kai Zheng 4,  Ziqi Zhu 1 2 3,  Yong Zhu 1 2 3,  Abdukahar Kiram 5,  Lei Zhao 6,  Huihui Chen 1 2 3,  Zhu Xu 2 3,  Xihua Li 6,  Beicheng Sun 1 2 3,  Zhijian Li 7 8,  Dengqiu Xu 1 2 3
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 2 MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China.
  • 3 Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China.
  • 4 The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, Jiangsu, China.
  • 5 Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
  • 6 Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.
  • 7 Uyghur Medical Hospital of Xinjiang Uyghur Autonomous Region, Ürümqi, China.
  • 8 Xinjiang Key Laboratory of Evidence-Based and Translation, Hospital Preparation of Traditional Chinese Medicine, Ürümqi, China.
PMID: 41431178 DOI: 10.1002/advs.202510850
Abstract

Clinical evidence indicates concurrent muscle inflammation and fibrosis in muscular dystrophies (MDs); however, the molecular mechanisms underlying inflammation-mediated fibrosis in skeletal muscle remain inadequately understood. This study revealed a molecular link between macrophages and fibro-adipogenic progenitors (FAPs) in both human subjects and mice via the transforming growth factor-beta (TGF-β)-RUNX family transcription factor-2 (RUNX2) axis. RUNX2 mRNA levels correlated positively with both the expression of fibrotic genes and the fibrosis area of MD patients. We demonstrated that specific ablation of RUNX2 in FAPs alleviated muscle fibrosis in an animal model of MD. Mechanistically, injured myofibers activated the transcription of chemokine genes, enhancing macrophage recruitment and the release of TGF-β, which subsequently triggered RUNX2-mediated transcription of fibrogenic genes in FAPs, promoting muscle fibrosis. Additionally, we demonstrated that CADD522, a RUNX2 inhibitor, protects against muscle fibrosis in both dystrophic and denervated mice. Importantly, the anti-inflammatory drug prednisolone alleviated muscle fibrosis in MD patients by inhibiting inflammatory cytokine-mediated RUNX2 activation. Collectively, our findings indicated that the TGF-β-RUNX2 axis is a viable target for alleviating muscle fibrosis and related diseases, highlighting potential future research directions.

Keywords

FAPs; RUNX2; fibrosis; macrophages; muscular dystrophy.

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