Immune-neural regulatory mechanism of osteoporosis induced by androgen deficiency.

This article explores the pathophysiology of osteoporosis associated with androgen deficiency, a metabolic disorder characterized by inadequate levels of androgens or disruptions in androgen signaling. A focus is placed on the collaborative regulation of bone health by the immune and nervous systems. Notably, androgens are identified as critical modulators of immune responses, significantly influencing the development and progression of osteoporosis. The review highlights that androgens enhance erythropoietin (EPO) signaling, which exhibits dose-dependent effects on bone metabolism-physiological EPO levels promote osteoblast differentiation, while excessive EPO can induce osteoclastogenesis through the Janus kinase 2/Signal transducer and activator of transcription 5 (JAK2/STAT5) pathway. Importantly, the expression of EPO receptors (EPOR) is not confined to osteoblasts and osteoclasts but is also found on numerous immune cells, which suggests the potential for androgens to affect the EPO/EPOR signaling system and its implications for bone homeostasis. Additionally, androgens contribute to the management of osteoporosis by inhibiting osteoclastogenesis mediated by immune cells, promoting M2 macrophage polarization, decreasing Th17 cell differentiation, and lowering the Th1/Th2 ratio, ultimately leading to reduced Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) expression. Furthermore, the central nervous system plays a pivotal role by mitigating the overactivation of the hypothalamic-pituitary-adrenal (HPA) axis, thereby lessening glucocorticoid-induced osteoblast apoptosis. In peripheral contexts, neuropeptides such as calcitonin gene-related peptide (CGRP) and Semaphorin 3A (Sema3A) promote osteogenesis. Moreover, androgens are shown to enhance neuromuscular junction functionality, providing additional mechanical stress that contributes to the maintenance of bone mass. This review aims to elucidate the intricate mechanisms governing bone homeostasis and proposes a novel therapeutic framework for the management of osteoporosis induced by androgen deficiency. By emphasizing the regulatory roles of androgens within the context of immune-neural interactions, this work provides valuable insights that may inform future treatment strategies. The target audience includes endocrinologists, rheumatologists, osteoporosis researchers, and clinicians involved in metabolic bone disease management.