Department of Pharmacology, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea.
Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
Exp Mol Med. 2021 May;53(5):848-863. doi: 10.1038/s12276-021-00616-9. Epub 2021 May 14.
STAT5 is a transcription factor that is activated by various cytokines, hormones, and growth factors. Activated STAT5 is then translocated to the nucleus and regulates the transcription of target genes, affecting several biological processes. Several studies have investigated the role of STAT5 in adipogenesis, but unfortunately, its role in adipogenesis remains controversial. In the present study, we generated adipocyte-specific Stat5 conditional knockout (cKO) (Stat5;Apn-cre) mice to investigate the role of STAT5 in the adipogenesis of bone marrow mesenchymal stem cells (BMSCs). BMSC adipogenesis was significantly inhibited upon overexpression of constitutively active STAT5A, while it was enhanced in the absence of Stat5 in vitro. In vivo adipose staining and histological analyses revealed increased adipose volume in the bone marrow of Stat5 cKO mice. ATF3 is the target of STAT5 during STAT5-mediated inhibition of adipogenesis, and its transcription is regulated by the binding of STAT5 to the Atf3 promoter. ATF3 overexpression was sufficient to suppress the enhanced adipogenesis of Stat5-deficient adipocytes, and Atf3 silencing abolished the STAT5-mediated inhibition of adipogenesis. Stat5 cKO mice exhibited reduced bone volume due to an increase in the osteoclast number, and coculture of bone marrow-derived macrophages with Stat5 cKO adipocytes resulted in enhanced osteoclastogenesis, suggesting that an increase in the adipocyte number may contribute to bone loss. In summary, this study shows that STAT5 is a negative regulator of BMSC adipogenesis and contributes to bone homeostasis via direct and indirect regulation of osteoclast differentiation; therefore, it may be a leading target for the treatment of both obesity and bone loss-related diseases.
STAT5 是一种转录因子，可被各种细胞因子、激素和生长因子激活。激活的 STAT5 随后被转运到细胞核内，调节靶基因的转录，从而影响多个生物学过程。已有多项研究调查了 STAT5 在脂肪生成中的作用，但遗憾的是，其在脂肪生成中的作用仍存在争议。在本研究中，我们生成了脂肪细胞特异性 Stat5 条件性敲除（cKO）（Stat5;Apn-cre）小鼠，以研究 STAT5 在骨髓间充质干细胞（BMSC）脂肪生成中的作用。过表达组成性激活的 STAT5A 可显著抑制 BMSC 脂肪生成，而在体外缺乏 Stat5 则增强了脂肪生成。体内脂肪染色和组织学分析显示，Stat5 cKO 小鼠骨髓中的脂肪体积增加。ATF3 是 STAT5 介导的脂肪生成抑制过程中的 STAT5 靶标，其转录受 STAT5 与 Atf3 启动子结合的调节。ATF3 的过表达足以抑制 Stat5 缺陷脂肪细胞中增强的脂肪生成，而 Atf3 沉默则消除了 STAT5 介导的脂肪生成抑制。Stat5 cKO 小鼠由于破骨细胞数量增加而导致骨量减少，并且骨髓源性巨噬细胞与 Stat5 cKO 脂肪细胞共培养导致破骨细胞生成增强，这表明脂肪细胞数量的增加可能导致骨丢失。总之，本研究表明 STAT5 是 BMSC 脂肪生成的负调节剂，通过直接和间接调节破骨细胞分化来参与骨稳态；因此，它可能是治疗肥胖症和与骨丢失相关疾病的主要靶标。
