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  • Chaperonin 60 sustains osteoblast autophagy and counteracts glucocorticoid aggravation of osteoporosis by chaperoning RPTOR.

Chaperonin 60 sustains osteoblast autophagy and counteracts glucocorticoid aggravation of osteoporosis by chaperoning RPTOR.

Cell death & disease (2018-09-19)
Wei-Shiung Lian, Jih-Yang Ko, Yu-Shan Chen, Huei-Jing Ke, Shin-Long Wu, Chung-Wen Kuo, Feng-Sheng Wang
ABSTRACT

Glucocorticoid excess medication interrupts osteoblast homeostasis and exacerbates bone mass and microstructure loss ramping up the pathogenesis of osteoporotic disorders. Heat shock protein 60 (HSP60) is found to maintain protein function within cellular microenvironment upon encountering detrimental stress. In this study, we revealed that supraphysiological dexamethasone decreased HSP60 expression along with deregulated autophagy in osteoblasts cultures. This chaperonin is required to sustain autophagic markers Atg4, and Atg12 expression, LC3-II conversion, and autophagic puncta formation, and alleviated the glucocorticoid-induced loss of osteogenic gene expression and mineralized matrix accumulation. Regulator-associated protein of mTOR complex 1 (RPTOR) existed in HSP60 immunoprecipitate contributing to the HSP60-promoted autophagy and osteogenesis because knocking down RPTOR impaired autophagic influx and osteogenic activity. HSP60 shielded from RPTOR dysfunction by reducing the glucocorticoid-induced RPTOR de-phosphorylation, aggregation, and ubiquitination. In vivo, forced RPTOR expression attenuated the methylprednisolone-induced loss of osteoblast autophagy, bone mass, and trabecular microstructure in mice. HSP60 transgenic mice displayed increased cortical bone, mineral acquisition, and osteoblast proliferation along with higher osteogenesis of bone marrow mesenchymal cells than those of wild-type mice. HSP60 overexpression retained RPTOR signaling, sustained osteoblast autophagy, and compromised the severity of glucocorticoid-induced bone loss and sparse trabecular histopathology. Taken together, HSP60 is essential to maintain osteoblast autophagy, which facilitates mineralized matrix production. It fends off glucocorticoid-induced osteoblast apoptosis and bone loss by stabilizing RPTOR action to autophagy. This study offers a new insight into the mechanistic by which chaperonin protects against the glucocorticoid-induced osteoblast dysfunction and bone loss.

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