2. Academic Validation
  3. Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression

Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression

  • Stem Cell Res Ther. 2025 May 5;16(1):227. doi: 10.1186/s13287-025-04342-1.
Fu-Hao Yu # 1 2 3 4,  Bo-Feng Yin # 1 2,  Ming-Yu Liu # 1 2 3 4,  Wen-Jing Zhang # 1 2,  Zhi-Dong Zhao 5,  Lei Wang 5,  Xiao-Tong Li 1 2,  Pei-Lin Li 1 2,  Zhi-Ling Li 1 2,  Run-Xiang Xu 1 2 3 4,  Li Ding 6 7 8,  Heng Zhu 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.
  • 2 Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
  • 3 Department of Hematology, Air Force Medical Center, Fourth Military Medical University, Road Fucheng 30, Beijing, 10142, People's Republic of China.
  • 4 Graduate School, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, People's Republic of China.
  • 5 People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, People's Republic of China.
  • 6 Department of Hematology, Air Force Medical Center, Fourth Military Medical University, Road Fucheng 30, Beijing, 10142, People's Republic of China. dingli7578@163.com.
  • 7 Graduate School, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, People's Republic of China. dingli7578@163.com.
  • 8 Anhui Medical University, Hefei, People's Republic of China. dingli7578@163.com.
  • 9 Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China. zhudingdingabc@163.com.
  • 10 Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China. zhudingdingabc@163.com.
  • 11 School of Life Sciences, Hebei University, Baoding, People's Republic of China. zhudingdingabc@163.com.
  • 12 Anhui Medical University, Hefei, People's Republic of China. zhudingdingabc@163.com.
  • # Contributed equally.
PMID: 40325465 DOI: 10.1186/s13287-025-04342-1
Abstract

Background: Recent studies have suggested that targeting senescent cells in joint tissues may alleviate osteoarthritis (OA) progression. However, this strategy encounters significant challenges, partially due to the high degree of cellular heterogeneity in osteoarthritic tissues. Moreover, little information is available on the role of skeletal stem cell (SSC) senescence, as compared to differentiated cells, in OA progression.

Methods: In this study, single-cell RNA Sequencing (scRNA-seq) on articular cartilages and subchondral bones of the knee joints of mice with post-traumatic osteoarthritis (PTOA) were performed. Further in vivo and in vitro studies were performed to reveal the role and mechanisims of senescent SSCs during the development of OA lesions and progression by microCT, pathological analysis, and functional gain and loss experiments. The one-way ANOVA was used in multiple group data analysis.

Results: scRNA-seq and pathological data demonstrated that the Leptin receptors (Lepr) positive SSCs underwent cellular senescence during OA progression. In addition, the leptin-Lepr signaling pathway induced signal transducer and activator of transcription 3 (STAT3) expression in SSCs, which consequently augmented the transcription of Fibroblast Growth Factor 7 (FGF7). Further scRNA-seq and in vivo analyses revealed that FGF7 exacerbated abnormal bone remodeling in subchondral bones and OA progression by enhancing bone formation and suppressing bone resorption. In vitro analysis revealed that FGF7 induced the osteogenic differentiation of SSCs but inhibited osteoclastogenesis in a concentration-dependent manner.

Conclusions: In summary, our findings demonstrate that the leptin-Lepr signaling pathway promotes SSC senescence and exacerbates subchondral bone remodeling by activating the STAT3-FGF7 axis during OA progression, which may shed light on novel therapeutic strategies for OA.

Keywords

Heterogeneity of Cellular senescence; Leptin-Lepr signaling; Osteoarthritis; STAT3-FGF7 axis; Single-cell sequencing; Skeletal stem cells.

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