Interoceptive regulation of bone homeostasis: The interplay between the nervous and skeletal systems in pathophysiology

Studies have demonstrated that the nervous system can perceive and respond to signaling from bone tissue, a process termed interoception, which plays a crucial role in the homeostasis of bone tissue. Sensory nerves extensively innervate bone tissue and transmit interoceptive signals to the central nervous system (CNS). The hypothalamus, located within the CNS, is instrumental in processing these interoceptive signals and regulating bone homeostasis through the autonomic nervous system, the release of neuropeptides, and neuroendocrine mechanisms. Although CNS regulation of bone has been recognized for decades, the specific interoceptive mechanisms governing skeletal homeostasis remain an emerging research focus. This review explores the latest advancements in interoceptive regulation of bone homeostasis, highlighting its role in skeletal diseases such as osteoporosis and osteoarthritis(OA). Furthermore, we discuss potential therapeutic strategies targeting interoceptive pathways, including biomaterials, pharmacological interventions, and non-pharmacological approaches. By elucidating the interplay between the nervous and skeletal systems, this review provides new insights into the regulation of bone health and its implications for future treatments of skeletal disorders. Interoceptive regulation of bone homeostasis involves: (1) peripheral interoceptors detecting microenvironmental changes; (2) ascending pathways (primarily DRG somatosensory neurons projecting via dorsal horn) transmitting mechanical/thermal/nociceptive signals to the CNS; (3) central integration and interpretation; and (4) efferent neuroendocrine responses modulating skeletal homeostasis. These pathways are modulated by signaling molecules like NGF, PGE2, and Netrin-1, and interact with bone tissue through receptors like TRPV1, EP4, and NPY1R, which influence osteoclast and osteoblast activity. The figure also highlights pharmacological interventions, such as ALN (alendronate), Diosmetin, and Celecoxib, which target these pathways to regulate bone homeostasis.