《生命科学》 2026, 38(3): 540-559
Menin在骨代谢及相关疾病中的作用研究进展
摘 要：
骨代谢是一个动态平衡的过程，由成骨细胞介导的骨形成和破骨细胞介导的骨吸收相互调控。当破骨细胞活性增强导致骨吸收超过骨形成时，会导致骨质疏松、骨肿瘤等疾病，严重影响人的身体健康和生活质量。因此，深入探究骨代谢平衡失调的机制，并寻找有效的防治靶点备受关注。近期研究发现，多发性内分泌腺瘤病1型（multiple endocrine neoplasia type 1，MEN1）基因编码产物Menin在骨代谢中发挥重要调控作用：成骨细胞中Menin缺失可影响骨量，导致骨质流失，表明其在骨组织稳态中发挥重要作用。此外，运动作为改善骨代谢的有效方式，其潜在机制可能与Menin的功能密切相关。因此，本文将围绕Menin的分子结构及生物学功能，系统总结其在骨髓间充质干细胞、成骨细胞和破骨细胞等骨相关细胞中的作用机制，进一步探讨其在骨质疏松、骨肿瘤等疾病中的功能表现，及其在运动调控骨代谢中的潜在作用；并在此基础上，归纳其潜在干预靶点，为骨代谢相关疾病的防治提供理论依据。
通讯作者：高海宁 , Email:45208373@qq.com
Abstract:
Bone metabolism is a dynamically balanced process regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Dysregulation of this balance leads to various bone disorders, including osteoporosis and bone tumors. Menin, the protein product encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, has emerged as a critical regulator of bone metabolism. This review aims to comprehensively summarize the molecular structure and biological functions of Menin, systematically analyze its regulatory roles in bone cells and diseases, and explore its potential role in exercise-mediated bone metabolism. Structurally, Menin is a ~67 kDa nuclear protein containing multiple functional domains, including nuclear localization signals and interaction sites for transcription factors such as JunD, Smad3, and NF-κB. Functionally, Menin participates in transcriptional regulation, DNA damage repair, and cell cycle control. In mesenchymal stem cells, Menin promotes osteogenic lineage specification through BMP-2/Smad1/5 and Runx2 signaling pathways during early differentiation, while inhibiting late-stage osteogenic gene expression via TGF-β/Smad3 signaling to maintain osteoblast homeostasis. Notably, Menin exhibits stage-specific bidirectional regulatory effects: its deletion in osteoblast precursors stimulates osteoclastogenesis and bone resorption, whereas its deletion in mature osteoblasts impairs osteogenic capacity. Additionally, Menin indirectly modulates osteoclast activity through the RANKL/OPG axis and non-RANKLdependent mechanisms involving the CXCL10 pathway. In bone-related diseases, Menin dysfunction is closely associated with MEN1-related bone complications, osteoporosis, and bone tumors. In MEN1 syndrome, both PTH-dependent and PTHindependent mechanisms contribute to bone loss, with circulating miRNAs emerging as potential biomarkers for early screening. In osteoporosis, Men1 deletion in osteoblasts induces cellular senescence via the inhibition of AMPK/mTORC1 pathway and promotes bone resorption through RANKL upregulation. In bone tumors, Menin regulates serine biosynthetic pathway and oncogene expression through the Menin-KMT2A/KMT2B complex, rendering a promising therapeutic target. Furthermore, emerging evidence suggests that Menin may mediate the regulation of exercise on bone metabolism through Wnt/β-catenin, BMP, AMPK/mTORC1, and RANKL/OPG signaling pathways, as well as the hypothalamus-bone axis. However, direct evidence in mammalian models remains limited. Future research should focus on elucidating the role of Menin in mechanotransduction, developing cell-specific Men1 knockout animal models coupled with mechanical loading interventions, and exploring Menin-targeted therapeutic strategies for bone metabolic diseases. This review provides a theoretical foundation for understanding the multifaceted roles of Menin in bone metabolism and offers new perspectives for the precise prevention and treatment of bone-related disorders.
Communication Author：GAO Hai-Ning , Email:45208373@qq.com
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