Deciphering the skeletal interoceptive circuitry to control bone homeostasis

Abstract Bone tissue is richly innervated, and the influence of the nervous system on the physiological and pathological status of bone tissue has emerged as a significant research focus. The recent discovery of the skeletal interoceptive circuits further emphasizes the crucial role of the central nervous system in the control of bone homeostasis. Skeletal interoception represents one of the most intricate mechanisms in the human body for maintaining bone homeostasis, as it involves the orchestrated efforts of skeletal, nervous, immune, and endocrine systems. In this review, we comprehensively introduce the three primary components of the skeletal interoceptive circuitry, including the ascending pathways that perceive and convey signals to the central nervous system, the central neural pathways that process and interpret these signals, and the descending pathways that mediate the regulatory effects on bone tissue. We also discuss how innovative therapeutic strategies can be developed to modulate bone homeostasis by leveraging the most updated findings on skeletal interoceptive circuitry. We anticipate that the application of knowledge on skeletal interoception will lead to a paradigm shift in the field of orthopaedics and biomaterials.