Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression
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, l...
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2025-05-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04342-1 |
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| author | Fu-Hao Yu Bo-Feng Yin Ming-Yu Liu Wen-Jing Zhang Zhi-Dong Zhao Lei Wang Xiao-Tong Li Pei-Lin Li Zhi-Ling Li Run-Xiang Xu Li Ding Heng Zhu |
| author_facet | Fu-Hao Yu Bo-Feng Yin Ming-Yu Liu Wen-Jing Zhang Zhi-Dong Zhao Lei Wang Xiao-Tong Li Pei-Lin Li Zhi-Ling Li Run-Xiang Xu Li Ding Heng Zhu |
| author_sort | Fu-Hao Yu |
| collection | DOAJ |
| description | 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. Graphical abstract |
| format | Article |
| id | doaj-art-3b17c2c069fb4765a679946794785981 |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-3b17c2c069fb4765a6799467947859812025-08-20T03:53:11ZengBMCStem Cell Research & Therapy1757-65122025-05-0116112010.1186/s13287-025-04342-1Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progressionFu-Hao Yu0Bo-Feng Yin1Ming-Yu Liu2Wen-Jing Zhang3Zhi-Dong Zhao4Lei Wang5Xiao-Tong Li6Pei-Lin Li7Zhi-Ling Li8Run-Xiang Xu9Li Ding10Heng Zhu11Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicineDepartment of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicineDepartment of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicineDepartment of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicinePeople’s Liberation Army General HospitalPeople’s Liberation Army General HospitalDepartment of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicineDepartment of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicineDepartment of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicineDepartment of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicineDepartment of Hematology, Air Force Medical Center, Fourth Military Medical UniversityDepartment of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation MedicineAbstract 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. Graphical abstracthttps://doi.org/10.1186/s13287-025-04342-1OsteoarthritisSingle-cell sequencingSkeletal stem cellsHeterogeneity of Cellular senescenceLeptin-Lepr signalingSTAT3-FGF7 axis |
| spellingShingle | Fu-Hao Yu Bo-Feng Yin Ming-Yu Liu Wen-Jing Zhang Zhi-Dong Zhao Lei Wang Xiao-Tong Li Pei-Lin Li Zhi-Ling Li Run-Xiang Xu Li Ding Heng Zhu 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 Research & Therapy Osteoarthritis Single-cell sequencing Skeletal stem cells Heterogeneity of Cellular senescence Leptin-Lepr signaling STAT3-FGF7 axis |
| title | Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression |
| title_full | Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression |
| title_fullStr | Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression |
| title_full_unstemmed | Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression |
| title_short | Modulation of senescent Lepr+ skeletal stem cells via suppression of leptin-induced STAT3‒FGF7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression |
| title_sort | modulation of senescent lepr skeletal stem cells via suppression of leptin induced stat3 fgf7 axis activation alleviates abnormal subchondral bone remodeling and osteoarthritis progression |
| topic | Osteoarthritis Single-cell sequencing Skeletal stem cells Heterogeneity of Cellular senescence Leptin-Lepr signaling STAT3-FGF7 axis |
| url | https://doi.org/10.1186/s13287-025-04342-1 |
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