The skeletal connectome: From molecular circuitry to systemic network medicine.

Although classically viewed as a mechanical scaffold, the skeleton is increasingly recognized as a dynamic endocrine and sensory hub that integrates systemic biophysical and biochemical cues. In this review, we rethink skeletal physiology by proposing the 'skeletal connectome,' a network medicine framework that links circuit-level remodeling programs to multiorgan homeostasis. Structurally, we first distill the cellular logic of bone remodeling, emphasizing how osteoblasts, osteoclasts, and osteocytes act as plastic network nodes whose state transitions are constrained by topology, compartmentalization, and metabolic/biophysical gating. We subsequently map macroscopic connectome architecture, detailing bidirectional axes coupling bone to the immune, metabolic, neural, and muscular systems. Within this framework, we systematically re-evaluate diverse skeletal disorders, spanning mechanometabolic degeneration, autoimmune disease, endocrine-metabolic fragility, and bone metastasis. We conceptualize these conditions as resulting from specific disruptions in systemic communication networks. From a translational perspective, this connectome paradigm guides the evaluation of precision therapeutics, such as targeted protein degradation and mRNA-based drugs, designed to rewire dysfunctional circuits. Finally, we discuss emerging concepts like digital skeletal twins and in silico clinical trials, highlighting their promising conceptual/translational status-rather than as established clinical tools-to eventually complement real-world evidence in future personalized regimen design. SIGNIFICANCE STATEMENT: This review proposes the 'skeletal connectome' framework, redefining bone as a dynamic sensory and endocrine hub that integrates mechanical, metabolic, and immune circuits to sustain systemic homeostasis. By mapping diverse pathologies as characteristic network failure modes rather than isolated defects, this study outlines a translational roadmap for rewiring dysfunctional circuitry through precision perturbations-including mRNA therapeutics and targeted protein degradation-guided by digital skeletal twins.