Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclast

Abstract It has been well-validated that chronic psychological stress leads to bone loss, but the underlying mechanism remains unclarified. In this study, we established and analyzed the chronic unpredictable mild stress (CUMS) mice to investigate the miRNA-related pathogenic mechanism involved in psychological stress induced osteoporosis. Our result found that these CUMS mice exhibited osteoporosis phenotype that mainly attributed to the abnormal activities of osteoclasts. Subsequently, miRNA sequencing and other analysis showed that miR-335-3p, which is normally highly expressed in the brain, was significantly down-regulated in the nucleus ambiguous (NAC), serum, and bone of the CUMS mice. Additionally, in vitro studies detected that miR-335-3p is important for osteoclast differentiation, with its direct targeting site in FOS. Further studies demonstrated FOS was upregulated in CUMS osteoclast, and the inhibition of FOS suppressed the accelerated osteoclastic differentiation, as well as the expression of osteoclastic genes, such as Nfatc1, Acp5, Mmp9 , in miR-335-3p restrained osteoclasts. In conclusion, this work indicated that psychological stress may down-regulate the miR-335-3p expression, which resulted in the accumulation of FOS and the up-regulation of NFACT1 signaling pathway in osteoclasts, leading to its accelerated differentiation and abnormal activity. These results decipher a previously unrecognized paradigm that miRNA can act as a link between psychological stress and bone metabolism. Impact statement miR-335-3p, which targets FOS and inhibits its activation of NFATC1 signaling, is an important regulator for osteoclast function and responsible for the psychological stress induced osteoporosis