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

Semun Seong,Inyoung Kim,Nacksung Kim,Jeong-Tae Koh,Jung Ha Kim,Kabsun Kim

doi:10.1038/s12276-021-00616-9

Semun Seong, Inyoung Kim + Show 4 more

Open Access

https://doi.org/10.1038/s12276-021-00616-9

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Abstract

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) (Stat5fl/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.

Highlights

There are seven known members of the signal transducer and activator of transcription factor (STAT) protein family: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6
These results show that adipocyte-specific Stat[5] conditional knockout (cKO) mice exhibit increased bone marrow adiposity, Fig. 3 Bone marrow adiposity is increased in Stat[5] cKO mice. a, b Femurs isolated from Stat[5] cKO mice (n = 4) and their wild-type littermates (n = 3) were subjected to osmium/tetroxide staining. a Representative images of osmium/tetroxide-stained femurs isolated from Stat[5] cKO mice and their wild-type littermates. b Quantification of osmium tetroxide-stained bone marrow adipose tissue based on micro-CT analysis. *P < 0.05 vs. control
We revealed that STAT5 functions as a negative regulator of adipocyte differentiation, both in vitro and in vivo, using Stat5fl/fl;Mx1-cre and Stat5fl/fl; Apn-cre mice

Summary

Introduction

There are seven known members of the signal transducer and activator of transcription factor (STAT) protein family: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. Activation of STAT protein family members is usually associated with Janus kinase (JAK). Phosphorylated or activated STAT proteins form dimers and translocate to the nucleus, where they bind to specific sites called GAS elements (TTCNNNGAA) to regulate the transcription of target genes[7,8]. Among the many STAT protein family members is STAT5, which has two isoforms, STAT5A and STAT5B. These isoforms are encoded by separate genes, they have over 90% amino acid sequence similarity and Official journal of the Korean Society for Biochemistry and Molecular Biology

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