2. Academic Validation
  3. Mycl, activated by Sgk1-phosphorylated Stat3, mediates osteoclastogenesis via Ctsk transcriptional regulation

Mycl, activated by Sgk1-phosphorylated Stat3, mediates osteoclastogenesis via Ctsk transcriptional regulation

  • Sci Rep. 2025 Nov 20;15(1):40945. doi: 10.1038/s41598-025-24679-0.
Yiru Wang # 1,  Chensong Yang # 2,  Fuming Cao # 3,  Yuyuan Zhang 4,  Mingzhu Li 1,  Yumei Zhang 1,  Chunxiang Sheng 5 6,  Li Shao 7
Affiliations

Affiliations

  • 1 Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200025, China.
  • 2 Department of Traumatic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 3 Nanmatou Community Health Service Center, Shanghai, China.
  • 4 Shanghai Acabridge Academy, Shanghai, China.
  • 5 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • 6 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200023, China. [email protected].
  • 7 Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200025, China. [email protected].
  • # Contributed equally.
PMID: 41266497 DOI: 10.1038/s41598-025-24679-0
Abstract

Osteoclast differentiation is essential for bone homeostasis, yet its molecular regulation remains incompletely understood. Here, we identify serum/glucocorticoid-regulated kinase 1 (SGK1), an AGC kinase responsive to hormonal signals, as a key regulator of osteoclastogenesis. Mechanistically, inhibition of SGK1 reduces STAT3 phosphorylation at Tyr705, leading to the downregulation of Mycl, a less characterized member of the MYC family of transcription factors. We demonstrate that Mycl directly binds to the Ctsk promoter, and functional assays confirm its critical role; Mycl overexpression rescued the osteoclast differentiation impairment caused by SGK1 inhibition. In vivo, treatment with the SGK1 Inhibitor GSK650394 increased trabecular bone mass and enhanced mechanical strength without compromising osteoblast activity. Collectively, our findings define a novel Sgk1-Stat3-Mycl-Ctsk signaling axis that contributes to osteoclastogenesis and suggest that SGK1 inhibition represent a potential therapeutic strategy for osteoporosis.

Keywords

Bone remodeling; Mycl; Osteoclastogenesis; Sgk1; Stat3 signaling.

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