Skeletal interoception in osteoarthritis

Abstract

The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of the organism. Among its various forms, skeletal interoception specifically regulates the metabolic homeostasis of bones. Osteoarthritis (OA) is a complex joint disorder involving cartilage, subchondral bone, and synovium. The subchondral bone undergoes continuous remodeling to adapt to dynamic joint loads. Recent findings highlight that skeletal interoception mediated by aberrant mechanical loads contributes to pathological remodeling of the subchondral bone, resulting in subchondral bone sclerosis in OA. The skeletal interoception is also a potential mechanism for chronic synovial inflammation in OA. In this review, we offer a general overview of interoception, specifically skeletal interoception, subchondral bone microenviroment and the aberrant subchondral remedeling. We also discuss the role of skeletal interoception in abnormal subchondral bone remodeling and synovial inflammation in OA, as well as the potential prospects and challenges in exploring novel OA therapies that target skeletal interoception.

Fig. 1

Diagram of the interoception circuits. The interoceptors located at the peripheral sensory nerve terminals perceive interoceptive signals generated by peripheral organs. The spinal and vagal nerves are two major ascending/afferent pathways that transmit interoceptive signals to the brain. In spinal nerve pathway, the somatosensory neurons in DRG project to the brain via the SDH. The spinal nerves primarily transmit somatic sensations such as temperature, injury, and pain-related signals from the skin, muscle, and skeleton. The vagal nerves transmit mechanical and chemical signals originating from visceral organs through JG and NG. Upon receiving interoceptive signals, various barin regions, including the NTS, thalamus, hypothalamus, PBN, hippocampus, ACC, amygdala, SC, PIC, AIC, PFC, and OFC, partake in the integration and interpretation of these signals. Finally, the brain sends the regulatory signals back the origin organs of interoceptive signals through descending/efferent interoceptive pathways. The SG, receiving projection from preganglionic sympathetic neurons in the spinal IML, and the PSG are two interoceptive effectors to maintain the internal organ homeostasis. This figure is a modified version of Fig. 1 published in Cell Metab Dec 6;34(12):1914-1931. DRG dorsal root ganglia, SDH spinal dorsal horn, JG jugular ganglia, NG nodose ganglia, NTS nucleus tractus solitarius, PBN parabrachial nucleus, ACC anterior cingulate cortex, SC somatosensory cortex, PIC posterior insular cortex, AIC anterior insular cortex, PFC prefrontal cortex, OFC orbitofrontal cortex, SG sympathetic ganglia, IML intermediolateral nucleus, PSG parasympathetic ganglia

Fig. 2

Aberrant subchondral bone remodeling in OA. OB-derived PGE2 interacts with EP4 receptors on OCs, promoting bone resorption and inducing the secretion of PDGF-BB to enhance type H angiogenesis. Furthermore, PGE2 stimulates OCs to secrete netrin1, which interacts with the DCC receptor on CGRP⁺ sensory nerves, leading to increased innervation in subchondral bone. In the OA subchondral bone, CGRP⁺ nerves stimulate EC migration through the release of SP, NPY, and VIP, which promote type H angiogenesis. The ECs involved in angiogenesis recruit MSCs through chemotaxis, thereby facilitating bone formation. The VEGF derived from OBs stimulates angiogenesis. The NGF stimulates both vascular and neural growth. Generally, the activation of SNS leads to subchondral bone resorption while suppressing bone formation through NE. OB osteoblast, PGE2 prostaglandin E2, EP prostaglandin E, OC osteoclast, PDGF-BB platelet-derived BB growth factor, DCC deleted in colorectal cancer, CGRP calcitonin-gene-related peptide, EC endothelial cell, SP substance P, NPY neuropeptide Y, VIP vasoactive intestinal peptide, MSC mesenchymal stem cells, VEGF vascular endothelial growth factor, NGF nerve growth factor, SNS sympathetic nervous system, NE norepinephrine

Fig. 3

Skeletal interoception in the aberrant subchondral bone remodeling of OA. Mechanical load stimulates OB-derived PGE2 production in the subchondral bone. The elevated PGE2 levels acting on EP4 receptors of sensory nerves transmits interoceptive signals to the VMH, leading to the activation of CREB signaling pathway. The activation of CREB signaling downregulated the descending sympathetic tone, leading to the commitment of MSCs to an osteoblastic lineage and promoting osteogenesis. The downregulated SNS promotes OB proliferation and differentiation via β2-AR, suppresses OC proliferation via α2-AR, and inhibits bone resorption through the α2-AR on OBs and decreased RANKL expression. Moreover, decreased NE binding with β2-AR on osteocytes inhibits NPY production, the decreased NPY locally promotes OB proliferation as well. The skeletal interoceptive signaling induces the expression of hypothalamic SMILE. The SMILE forms a transcriptional heterodimer with phosphorylated CREB on Npy promoters to suppress NPY expression. The downregulated hypothalamic NPY stimulates the lipolysis of adipose tissue to supply energy for osteoblastic bone formation. OB osteoblast, PGE2 prostaglandin E2, EP prostaglandin E, VMH ventromedial nucleus of hypothalamus, cAMP cyclic adenosine monophosphate, CREB cAMP response element-binding protein, MSC mesenchymal stem cell, SNS sympathetic nervous system, AR adrenergic receptor, RANKL receptor activator of nuclear factor κB ligand, NE norepinephrine, NPY neuropeptide Y, SMILE small heterodimer partner-interacting leucine zipper protein

Fig. 4

The potential synovial interoception circuit in OA synovitis. The PGE2 level is increased in ST of OA. The elevated PGE2 may activate EP receptors on sensory nerves, thus transmitting the interoceptive signals to the brain (need verification). The brain, after integrating and interpreting interoceptive signals, downregulates sympathetic nerve activity. The SNS exhibits anti-inflammatory effects during the chronic inflammation phase of the synovium, while suppressed sympathetic activity promotes synovial inflammation and the release of pro-inflammatory cytokines such as TNF-α and IL-1β. Further verifying the existence of synovial interoception circuit is warranted, as well as a more comprehensive exploration of the cerebral nucleis involved in synovial interoception. PGE2 prostaglandin E2, ST synovial tissue, EP prostaglandin E, SNS sympathetic nervous system, TNF-α tumor necrosis factor α, IL-1β interleukin 1β, NE norepinephrine

Fig. 5

Two PGE2-mediated mechanisms of OA pain. During aberrant subchondral bone remodeling, OBs produced PGE2 binds to EP4 receptors on CGRP⁺ sensory nerves, sensitizing sensitize DRG neurons by modifying the voltage-gated sodium channel Nav1.8. PGE2 also stimulates OCs through EP4 receptors. Activated OCs release netrin1 to activated OCs release netrin1, which binds to the DCC receptors on sensory neurons, promoting the innervation of CGRP⁺ sensory nerves in the subchondral bone. OB osteoblast, PGE2 prostaglandin E2, EP prostaglandin E, CGRP calcitonin-gene-related peptide, DRG dorsal root ganglia, OC osteoclast, DCC deleted in colorectal cancer

Fig. 6

Skeletal interoception in OA and its pain. In advanced OA, there is a progressive deterioration of articular cartilage, along with the development of subchondral bone sclerosis, osteophyte, bone cysts, and synovial inflammation. Elevated PGE2 in subchondral bone transmits interoceptive signals to the brain, which downregulated SNS activity to promote subchondral bone formation and sclerosis. PGE2 also activates OCs to release netrin1, which promotes sensory nerve innervation in the subchondral bone. In the chronic inflammatory phase of OA synovium, PGE2 level is elevated accompanied by decreased sympathetic nerve innervation. This suggests that the skeletal interoception circuit may be involved. The PGE2 in ST can also be released into synovial fluid promoting cartilage destruction. PGE2 prostaglandin E2, SNS sympathetic nervous system, OC osteoclast, ST synovial tissue, NE norepinephrine