Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP

Abstract

The transient receptor potential vanilloid 1 (TRPV1) channel is abundantly expressed in peripheral sensory neurons where it acts as an important polymodal cellular sensor for heat, acidic pH, capsaicin, and other noxious stimuli. The oral cavity is densely innervated by afferent sensory neurons and is a highly specialized organ that protects against infections as well as physical, chemical, and thermal stresses in its capacity as the first part of the digestive system. While the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study we found that Trpv1−/− mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1−/− mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin gene-related peptide (CGRP), and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrate-resistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP.

A peptide derived from rice inhibits alveolar bone resorption via suppression of inflammatory cytokine production

“…To assess the ability of the Amyl‐1‐18 peptide to prevent periodontal diseases, a ligature‐induced murine model of periodontitis was used. Ligature‐induced periodontitis in vivo is widely used to analyze the pathogenesis of periodontitis and elucidate the effect of new therapies, as the model is similar to clinical periodontitis, manifesting as alveolar bone resorption and the infiltration of inflammatory cells induced by plaque accumulation around the ligature . In our observation, the decrease of TRAP‐positive cells in Amyl‐1‐18‐treated mice indicated that the administration of Amyl‐1‐18 prevented alveolar bone resorption by inactivating osteoclast activation in this experimental murine model of periodontitis.…”

Antimicrobial function of the polyunsaturated fatty acid KetoC in an experimental model of periodontitis

“…The maxillae were fixed, decalcified, embedded, and sectioned as previously reported . Serial sections 5‐µm thick were then cut in the sagittal direction along the long axis of the teeth and stained with hematoxylin and eosin (H‐E).…”

Nerves in Bone: Evolving Concepts in Pain and Anabolism

“…CGRP may also promote osteoblast differentiation indirectly by inducing osteogenic signals from endothelial cells . High concentrations of CGRP suppress osteoclast maturation and activity in vitro, and CGRP regulates osteoblast production of RANKL and osteoprotegerin (OPG) to indirectly modulate osteoclastogenesis …”

“…Conversely, mice overexpressing CGRP under the control of the osteocalcin promoter have increased trabecular bone formation and density; of interest, calvarial cultures from osteocalcin‐CGRP mice produced CGRP, whereas cultures from nontransgenic mice did not, suggesting an alternative endogenous source for this neuropeptide. Activation of cells expressing TRPV1 suppresses alveolar bone resorption by a mechanism including osteoclast suppression by CGRP . CGRP promotes bone accrual during fracture repair .…”

“…(83,88) CGRP may also promote osteoblast differentiation indirectly by inducing osteogenic signals from endothelial cells. (89) High concentrations of CGRP suppress osteoclast maturation and activity in vitro, (90)(91)(92) and CGRP regulates osteoblast production of RANKL and osteoprotegerin (OPG) to indirectly modulate osteoclastogenesis. (84,85,93,94) Of the sensory neuropeptides identified in bone, CGRP is the most well studied in vivo, with consistent osteoanabolic effects and some evidence for a neural origin.…”