Research progress on the role of Menin in bone metabolism and related diseases

<p indent="0mm">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 (<italic>MEN1</italic>) 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-RANKL-dependent mechanisms involving the CXCL10 pathway. In bone-related diseases, Menin dysfunction is closely associated with <italic>MEN1</italic>-related bone complications, osteoporosis, and bone tumors. In MEN1 syndrome, both PTH-dependent and PTH-independent mechanisms contribute to bone loss, with circulating miRNAs emerging as potential biomarkers for early screening. In osteoporosis, <italic>Men1</italic> 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 <italic>Men1</italic> 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. <alternatives id="alt1"> <graphic specific-use="online" xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="./online/c1.png" href="./online/c1.png"/> <graphic specific-use="print" xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="./print/c1.pdf" href="./print/c1.pdf"/> </alternatives>