自噬诱导的成骨细胞衍生外泌体通过重塑肠道微生物群代谢来维持骨形成并预防骨质疏松症。
Autophagy-induced osteoblast-derived exosomes maintain bone formation and prevent osteoporosis by remodeling gut microbiota-metabolism.
作者信息
Chen Lin, Lu Liesheng, Fan Chunyi, Zhu Xiaonan, Pan Ling, Tang Shanshan, Wang Yufan, Peng Yongde, You Li
机构信息
Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Department of Endocrinology, Shanghai Tenth People`s Hospital, Tongji University, Shanghai, 200072, China.
出版信息
Biomed J. 2025 May 6:100870. doi: 10.1016/j.bj.2025.100870.
BACKGROUND
Osteoporosis is a chronic disease of bone metabolism with high incidence rates. Recently, exosome therapy has emerged as a promising avenue for the treatment of osteoporosis. However, the role of autophagy-induced osteoblast-derived exosomes (Auto-exo) in osteoporosis has yet to be elucidated.
METHODS
The effect of Auto-exo in bone formation was assessed in vivo. The composition of gut microbiota was determined through 16S rDNA sequencing, and metabolite profiles were analyzed using liquid chromatography-mass spectrometry (LC-MS). Cell experiments were conducted to explore the role of bilirubin in bone formation.
RESULTS
Auto-exo were successfully isolated and identified. Auto-exo promoted bone formation and alleviated osteoporosis progression in a mouse model of osteoporosis. 16S rDNA sequencing revealed that Auto-exo changed diversity and composition of gut microbiota in osteoporotic mice, with a notable increase in Lactobacillus and a decrease in Dubosiella and Faecalibaculum. LC-MS analysis indicated that Auto-exo treatment reduced the elevated levels of bilirubin in osteoporotic mice. Cell experiments uncovered that bilirubin remarkably inhibited osteoblast differentiation. Furthermore, Auto-exo promoted osteoblast differentiation via inhibiting bilirubin production.
CONCLUSIONS
Our findings demonstrated that Auto-exo promoted bone formation by modulating the gut microbiota-metabolites bilirubin axis, thereby alleviating osteoporosis progression. This discovery provides a novel perspective on the mechanisms underlying the therapeutic effects of Auto-exo in osteoporosis.
背景
骨质疏松症是一种发病率较高的慢性骨代谢疾病。近年来，外泌体疗法已成为治疗骨质疏松症的一个有前景的途径。然而，自噬诱导的成骨细胞衍生外泌体（自噬外泌体）在骨质疏松症中的作用尚未阐明。
方法
在体内评估自噬外泌体对骨形成的影响。通过16S rDNA测序确定肠道微生物群的组成，并使用液相色谱 - 质谱联用仪（LC-MS）分析代谢物谱。进行细胞实验以探讨胆红素在骨形成中的作用。
结果
成功分离并鉴定了自噬外泌体。自噬外泌体促进了骨质疏松症小鼠模型中的骨形成并减轻了骨质疏松症的进展。16S rDNA测序显示，自噬外泌体改变了骨质疏松症小鼠肠道微生物群的多样性和组成，乳酸杆菌显著增加，而杜波氏菌和粪杆菌减少。LC-MS分析表明，自噬外泌体治疗降低了骨质疏松症小鼠中升高的胆红素水平。细胞实验发现，胆红素显著抑制成骨细胞分化。此外，自噬外泌体通过抑制胆红素产生促进成骨细胞分化。
结论
我们的研究结果表明，自噬外泌体通过调节肠道微生物群 - 代谢物胆红素轴促进骨形成，从而减轻骨质疏松症的进展。这一发现为自噬外泌体治疗骨质疏松症的潜在机制提供了新的视角。
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