Yu Fu-Hao, Yin Bo-Feng, Liu Ming-Yu, Zhang Wen-Jing, Zhao Zhi-Dong, Wang Lei, Li Xiao-Tong, Li Pei-Lin, Li Zhi-Ling, Xu Run-Xiang, Ding Li, Zhu Heng
Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.
Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
Stem Cell Res Ther. 2025 May 5;16(1):227. doi: 10.1186/s13287-025-04342-1.
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.
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.
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.
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.
近期研究表明，针对关节组织中的衰老细胞可能会减轻骨关节炎（OA）的进展。然而，这一策略面临重大挑战，部分原因是骨关节炎组织中细胞异质性程度较高。此外，与分化细胞相比，骨骼干细胞（SSC）衰老在OA进展中的作用知之甚少。
在本研究中，对创伤后骨关节炎（PTOA）小鼠膝关节的关节软骨和软骨下骨进行了单细胞RNA测序（scRNA-seq）。通过微计算机断层扫描（microCT）、病理分析以及功能获得和缺失实验，进一步进行体内和体外研究，以揭示衰老SSC在OA病变发展和进展过程中的作用及机制。多组数据分析采用单因素方差分析。
scRNA-seq和病理数据表明，瘦素受体（Lepr）阳性的SSC在OA进展过程中发生细胞衰老。此外，瘦素-Lepr信号通路诱导SSC中信号转导和转录激活因子3（STAT3）的表达，从而增加成纤维细胞生长因子7（FGF7）的转录。进一步的scRNA-seq和体内分析表明，FGF7通过增强骨形成和抑制骨吸收加剧了软骨下骨的异常骨重塑和OA进展。体外分析表明，FGF7以浓度依赖的方式诱导SSC的成骨分化，但抑制破骨细胞生成。
总之，我们的研究结果表明，在OA进展过程中，瘦素-Lepr信号通路通过激活STAT3-FGF7轴促进SSC衰老并加剧软骨下骨重塑，这可能为OA的新治疗策略提供线索。
