Skeletal interoception in bone homeostasis and pain

Abstract

Accumulating evidence indicates that interoception maintains proper physiological status and orchestrates metabolic homeostasis by regulating feeding behaviors, glucose balance, and lipid metabolism. Continuous skeletal remodeling consumes a tremendous amount of energy to provide skeletal scaffolding, support muscle movement, store vital minerals, and maintain a niche for hematopoiesis, which are processes that also contribute to overall metabolic balance. Although skeletal innervation has been described for centuries, recent work has shown that skeletal metabolism is tightly regulated by the nervous system and that skeletal interoception regulates bone homeostasis. Here, we provide a general discussion of interoception and its effects on the skeleton and whole-body metabolism. We also discuss skeletal interoception-mediated regulation in the context of pathological conditions and skeletal pain as well as future challenges to our understanding of these process and how they can be leveraged for more effective therapy.

Keywords: central nervous system; energy metabolism; interoception; pain; skeleton.

Figure 1.. Diagram of current known interoception circuits.

Biochemical, mechanical, thermal and electromagnetic signals are the three major types of interoceptive signals. Interoceptors, located at peripheral sensory nerve endings, can detect interoceptive signals generated by the peripheral organs. Interoceptive signals are transmitted to the CNS via the ascending (afferent) interoceptive pathways. The vagal and spinal nerves are the two arms of the ascending interoceptive pathways, with cell bodies in the nodose ganglion (NG) and dorsal root ganglion (DRG), respectively. The vagal nerve transmits afferent inputs to neurons of the nucleus of the solitary tract (NTS). The DRG neurons send projections into the brain through the dorsal column of the spinal cord. Various brain regions are involved in central interpretation, integration, and regulation of interoceptive information, including the NTS, the parabrachial nucleus (PB), thalamus, hypothalamus, hippocampus, amygdala (AMY) and prefrontal cortex (PFC). The regulatory signals generated by the CNS, in turn, are sent back to the peripheral organs via descending (efferent) interoceptive pathways. The sympathetic ganglia and parasympathetic chain ganglia, receiving signals from the sympathetic preganglionic neurons in the intermediolateral nucleus (IML) act as effector neurons of interoception to maintain the peripheral organ homeostasis.

Figure 2.. Skeleton interoception maintains bone homeostasis.

PGE2 secreted by osteoblasts activates EP4 in sensory nerves as the ascending skeletal interoceptive pathway. Activation of CREB signaling by the PGE2/EP4 ascending interoceptive activity in the ventromedial nucleus of the hypothalamus (VMH) downregulates sympathetic nerve activity as the descending interoceptive pathway. The descending sympathetic tone is downregulated via skeleton interoceptive circuit to induce a commitment of mesenchymal stem/stromal cells (MSCs) to an osteoblastic lineage and bone formation.

Figure 3.. Skeleton intreoception regulates neuroendocrine factor NPY to balance metabolism between bone and fat.

The skeleton interoceptive signal PGE2 activates the interoceptor EP4 in sensory nerves to induce the heterodimerization of phosphorylated cAMP-response element binding protein (pCREB) and transcriptional suppressor small heterodimer partner interacting leucine zipper protein (SMILE) to downregulate the expression of neuroendocrine factor NPY in the arcuate nucleus (ARC). Decreased NPY concentration in the blood circulation secreted from ARC mediates the neuroendocrine descending interoceptive signal to balance metabolism between bone and fat. Downregulation of hypothalamic NPY expression induces adipose tissue lipolysis to supply enough free fatty acids (FFAs) for energy-consuming osteoblastic bone formation, as well as the differentiation from pre-osteoblasts to osteoblasts.

Figure 4.. Interoception-mediated regulation of feeding and fat and glucose metabolism.

Mammalian energy needs, appetite, and fat and glucose metabolism are regulated by interoception. The vagal and spinal nerve communicate the energy status from the energy centers to the brain, which induce the integration of interoceptive signals to regulate whole-body metabolic homeostasis through descending sympathetic nerve. The adipose tissue, gut and pancreas are richly innervated by sensory nerve fibers, and distinct afferent sensory neurons have been identified to control appetite and fat and glucose metabolism through different interoception circuits. Bone remodeling consumes tremendous amounts of energy and interoception regulates whole-body energy metabolic homeostasis to balance the necessary energy flow between the bone and different organs to meet these osteogenic needs.

Figure 5.. Skeleton interoception in bone homeostasis and disorders.

Metal divalent cations released from implants induce the production of the interoceptive signal PGE2 from macrophages, and this molecule activates the ascending interoceptive pathway to reduce sympathetic tone in the hypothalamus, resulting in increased osteogenesis and decreased osteoclastogenesis in the periosteum. Abnormal concentrations of PGE2 in the endplate and in subchondral bone induce hypersensitivity of sensory nerves by activating EP4, which leads to LBP and osteoarthritis pain. Netrin1 secreted by osteoclasts in subchondral bone induces sensory nerves innervation in subchondral bone, which also contribute to OA pain. Restoration of physiological PGE2 concentrations in the endplate activates skeleton interoception to induce osteoblastic bone formation in porous endplates, thus relieving LBP, reducing vertebral endplate porosity and modifying disease progression.