Alternative regulatory mechanism for the maintenance of bone homeostasis via STAT5-mediated regulation of the differentiation of BMSCs into adipocytes

Obesity and osteoporosis: a common therapeutic target A protein connected with bone maintenance and fat cell differentiation could provide a novel therapeutic target for both obesity and osteoporosis. The processes of healthy bone remodeling and fat cell (adipocyte) differentiation from bone marrow stem cells (BMSCs) are intrinsically connected. The transcription factor protein STAT5 plays roles in maintaining bone homeostasis and adipocyte differentiation, but its role in the latter is unclear. Nacksung Kim at Chonnam National University Medical School in Gwangju, South Korea, and co-workers examined the role of STAT5 in mice. Mice without the Stat5 gene had increased fat tissue in their bone marrow, suggesting increased BMSC differentiation into adipocytes. The mice also had reduced bone mass due to increased numbers of bone-degrading cells. Further investigations showed that STAT5 regulates the differentiation of BMSCs into adipocytes via activation of a regulatory gene. 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(fl/fl);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.

Automated summary

The study reveals that STAT5 negatively regulates the differentiation of bone marrow mesenchymal stem cells into adipocytes and plays a crucial role in bone homeostasis by directly and indirectly regulating osteoclast differentiation.