Inferior alveolar nerve transection disturbs innate immune responses and bone healing after tooth extraction

Abstract

Coordination between the nervous and innate immune systems to maintain bone homeostasis is largely uncharacterized. The present study investigated the sensory–immune interaction in resting alveolar bone and healing socket by surgical sensory denervation. Bone histomorphometry and immunohistochemistry showed that sensory denervation resulted in moderate suppression of bone remodeling, with a proinflammatory milieu manifested by increased neutrophil recruitment and possible alternations in macrophage phenotypes along the resting bone surface. This denervation effect intensified when bone remodeling was triggered by tooth extraction, as revealed by disrupted temporospatial variations in macrophage subpopulations and neutrophil infiltration, which were closely associated with a dramatic decline in socket bone filling and residual ridge height. Antagonism of calcitonin gene‐related peptide (CGRP) brought about similar antianabolic and proinflammatory effects as sensory denervation, suggesting that sensory nerves may monitor the bony milieu by CGRP. Depletion of macrophages, rather than neutrophils, ruled out CGRP effects, illustrating that macrophages were the primary immune mechanism that linked sensory innervation, innate immunity, and bone. The data support that sensory innervation is required for control of innate immune responses and maintenance of bone homeostasis. Sensory neuropeptides, such as CGRP, are a possible target for the development of proanabolic treatments in bone disease by modulating innate immune responses.

Sensory denervation increases potential of bisphosphonates to induce osteonecrosis via disproportionate expression of calcitonin gene–related peptide and substance P

“…Previously, we transected the IAN outside the bony canal, which led to a breakdown of the distal nerve endings and a disturbed innate immune response along the resting bone surface 19,20 . In this study, IANI and IANT were performed in the intracanal region.…”

“…Among the neuropeptides, CGRP has been shown to play an important role in the growth, repair, and performance of the skeleton 21,22 . We found that local CGRP antagonism induced antianabolic and proinflammatory effects similar to those produced by sensory denervation, suggesting that sensory nerves may monitor the bony milieu by releasing CGRP 20 . CGRP can promote osteoblast differentiation and directly inhibit osteoclast formation by interacting with functional CGRP receptors expressed by these cells 21,22 .…”

“…Nerve endings of the IAN suffer from degradation after injury, causing a reduction in the release of sensory neurotransmitters, thus affecting the balance of bone metabolism 18,19 . Our previous study showed that inferior alveolar nerve transection (IANT) resulted in compromised bone remodeling and a proinflammatory innate immune response along the resting bone surface 18,20 . Sensory denervation led to a decline in socket bone filling and residual ridge height after tooth extraction, and these abnormalities were closely related to disrupted temporospatial variations in macrophage subpopulations and delayed neutrophil infiltration 20 …”

Simultaneous Regeneration of Bone and Nerves Through Materials and Architectural Design: Are We There Yet?

“…In addition, deficiencies in sensory or sympathetic nerves result in inferior bone healing. [56][57][58][59] Nerve-resident cells are also important for bone regeneration. [60] Fibroblast-like mesenchymal cells, which differentiate and proliferate in damaged nerves, adopt the features of bone or cartilage cells and migrate into the damaged site to participate in healing of murine bone scratch injury.…”

“…In addition, deficiencies in sensory or sympathetic nerves result in inferior bone healing. [ 56–59 ]…”