Zhang Jiayao, Li Juan, Huang Jiehong, Xiang Xuerui, Li Ruoyu, Zhai Yun, Lin Shuxian, Liu Weicai
Shanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Prosthodontics, Shanghai Tongji Stomatological Hospital and Dental School, Tongji University, Shanghai, China.
Department of Neurology and Neurological Rehabilitation, Shanghai Disabled Persons' Federation Key Laboratory of Intelligent Rehabilitation Assistive Devices and Technologies, Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China.
Elife. 2025 Jan 8;13:RP95944. doi: 10.7554/eLife.95944.
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 is 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 downregulated in the nucleus ambiguous, 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 . 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 and , in miR-335-3p-restrained osteoclasts. In conclusion, this work indicated that psychological stress may downregulate the miR-335-3p expression, which resulted in the accumulation of FOS and the upregulation 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.
慢性心理应激会导致骨质流失，这一点已得到充分验证，但其潜在机制仍不清楚。在本研究中，我们建立并分析了慢性不可预测轻度应激（CUMS）小鼠，以探究心理应激诱导骨质疏松症所涉及的与miRNA相关的致病机制。我们的结果发现，这些CUMS小鼠表现出骨质疏松表型，这主要归因于破骨细胞的异常活动。随后，miRNA测序和其他分析表明，通常在大脑中高表达的miR-335-3p在CUMS小鼠的疑核、血清和骨骼中显著下调。此外，体外研究检测到miR-335-3p对破骨细胞分化很重要，其直接靶向位点在……进一步研究表明，FOS在CUMS破骨细胞中上调，抑制FOS可抑制miR-335-3p抑制的破骨细胞中加速的破骨细胞分化以及破骨细胞基因（如……和……）的表达。总之，这项工作表明，心理应激可能会下调miR-335-3p的表达，导致FOS积累和破骨细胞中NFACT1信号通路的上调，从而导致其加速分化和异常活动。这些结果揭示了一种以前未被认识的模式，即miRNA可以作为心理应激和骨代谢之间的联系。
