Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Abstract

Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α 2 nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1ra Ast +/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1ra Ast +/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.autonomic nervous system | postnatal skeletal development

The Non-Neuronal Cholinergic System in Health and Disease

“…In this regard the nAChR subunit α 2 and the M3 mAChR appear to play important roles as nAChR subunit α 2 -deficient [186] and M3 mAChR-deficient mice [187,188] both show an osteoporosis-like phenotype.…”

Fat and Bone: Where are We Now?

“…Starting with leptin at the turn of the century [13], the number of central mediators of bone metabolism has grown significantly and their roles now extended to controlling bone homeostasis rather than simply exerting a positive or negative effect on bone. Our understanding of neuronal control has extended from the sympathetic nervous system [14] to the parasympathetic and sensory nervous systems [15,16]. Abnormalities in the central nervous system such as vestibular dysfunction may also indirectly affect bone mass [17].…”

Altered ultrastructure, density and cathepsin K expression in bone of female muscarinic acetylcholine receptor M3 knockout mice

“…It is supposed that acetylcholine and its widespread system of enzymes, transporters, and receptors participates in signaling pathways influenced by osteoporosis. Recently, cholinergic nerve fibers with an immunopositive staining for the vesicular acetylcholine transporter (VAChT) were found in bone [11]. In our previous work we showed that the amount of VAChT immunopositive nerve fibers was reduced in osteoporotic rats compared to sham operated animals [12].…”