Jiahao Dong, Zhongyu Peng, Tao Chen
The traditional Chinese medicine (TCM) theory of "Kidney Governs Bone' has been progressively validated in modern medical research. However, a purely endocrinological perspective cannot fully explain its regulatory implications under complex conditions such as stress, inflammation, and nerve injury. As bone metabolism research shifts toward a systemic regulatory paradigm, the "brain-bone axis' provides a new framework for reinterpreting "Kidney Governs Bone.' Based on current evidence, the core scientific proposition of this article is that we propose the hypothesis that the therapeutic effects of TCM's "Kidney Governs Bone' theory can be partially explained by systemic regulation of the neuro-endocrine-immune network, and that the therapeutic efficacy of TCM interventions may be related to their ability for layered, multi-target regulation within this network. This proposition requires further validation in diverse pathological contexts. Based on this proposition, we propose three conceptual frameworks: ① extending "Kidney Governs Bone' from the traditional "kidney-bone' endocrine axis to a systemic regulatory framework centered on the "brain-bone axis'; ② constructing a three-level "central-peripheral-local' regulatory model that systematically integrates the hierarchical interactions within the neuro-endocrine-immune network; and ③ proposing a "stratified intervention' strategy for TCM, clarifying the target differences among different therapeutic principles across the three network levels. Using this framework, we systematically evaluate the mechanisms of TCM interventions: kidney-tonifying herbs regulate the hypothalamic-pituitary axis to maintain endocrine homeostasis; kidney-tonifying and blood-activating methods, as well as acupuncture and other external therapies, achieve "neuro-vascular-osteogenic' synergy by modulating sympathetic tone and upregulating neuropeptides such as CGRP; acupuncture and moxibustion remodel the bone immune microenvironment by activating the cholinergic anti-inflammatory pathway, promoting M2 macrophage polarization, and inhibiting NLRP3 inflammasome activation. Current challenges include spatiotemporal heterogeneity, network complexity, and clinical translation gaps. Future studies should employ technologies such as optogenetics, multi-omics integration, and organoid-on-a-chip platforms. The modern scientific connotation of "Kidney Governs Bone' is deeply reflected in the systemic regulation of the neuro-endocrine-immune network, and this interdisciplinary direction provides a crucial theoretical breakthrough for transforming TCM orthopedics from empirical medicine toward systems medicine.