Substance P aggravates ligature-induced periodontitis in mice

Abstract

Periodontitis is one of the most common oral diseases in humans, affecting over 40% of adult Americans. Pain-sensing nerves, or nociceptors, sense local environmental changes and often contain neuropeptides. Recent studies have suggested that nociceptors magnify host response and regulate bone loss in the periodontium. A subset of nociceptors projected to periodontium contains neuropeptides, such as calcitonin gene-related peptide (CGRP) or substance P (SP). However, the specific roles of neuropeptides from nociceptive neural terminals in periodontitis remain to be determined. In this study, we investigated the roles of neuropeptides on host responses and bone loss in ligature-induced periodontitis. Deletion of tachykinin precursor 1 (Tac1), a gene that encodes SP, or treatment of gingiva with SP antagonist significantly reduced bone loss in ligature-induced periodontitis, whereas deletion of calcitonin related polypeptide alpha (Calca), a gene that encodes CGRP, showed a marginal role on bone loss. Ligature-induced recruitment of leukocytes, including neutrophils, and increase in cytokines leading to bone loss in periodontium was significantly less in Tac1 knockout mice. Furthermore, intra-gingival injection of SP, but not neurokinin A, induced a vigorous inflammatory response and osteoclast activation in alveolar bone and facilitated bone loss in ligature-induced periodontitis. Altogether, our data suggest that SP plays significant roles in regulating host responses and bone resorption in ligature-induced periodontitis.

Nociceptor mechanisms underlying pain and bone remodeling via orthodontic forces: toward no pain, big gain

“…Retrograde labeling by injecting a tracer into mouse gingiva has demonstrated that periodontal afferents are primarily small- and medium-diameter neurons ( 46 , 72 ). Among these, 23% are CGRP-positive and 28% are TRPV1-positive.…”

“…TRPV1-expressing nociceptors can also contribute to the development of orthodontic pain. As TRPV1 and neuropeptides are highly colocalized in periodontal afferents ( 46 , 72 ), and nerve terminals containing neuropeptides such as CGRP and substance P (SP) are projected into periodontal ligaments ( 77 , 78 ), the activation of TRPV1-expressing nerve terminals by orthodontic forces can induce the release of neuropeptides such as CGRP or SP into the periodontal tissues. These neuropeptides play crucial roles in vasodilation and the recruitment of immune cells to damaged tissue ( 79 ).…”

“…Interestingly, the deletion of tachykinin precursor 1, a gene that encodes SP, or the treatment of gingiva with an SP antagonist, significantly reduces bone loss in ligature-induced periodontitis. Whereas the deletion of calcitonin-related polypeptide alpha, a gene that encodes CGRP, has a marginal role in bone loss ( 72 ). Furthermore, exogenous SP, but not neurokinin A, induces a vigorous inflammatory response and osteoclast activation in alveolar bone and facilitates bone loss in ligature-induced periodontitis ( 72 ).…”

“…Whereas the deletion of calcitonin-related polypeptide alpha, a gene that encodes CGRP, has a marginal role in bone loss ( 72 ). Furthermore, exogenous SP, but not neurokinin A, induces a vigorous inflammatory response and osteoclast activation in alveolar bone and facilitates bone loss in ligature-induced periodontitis ( 72 ). SP knockouts show decreased immune cell infiltration and pro-inflammatory cytokines at the site of ligature, which recapitulates the findings from mice with nociceptor ablations ( 72 ).…”

“…Furthermore, exogenous SP, but not neurokinin A, induces a vigorous inflammatory response and osteoclast activation in alveolar bone and facilitates bone loss in ligature-induced periodontitis ( 72 ). SP knockouts show decreased immune cell infiltration and pro-inflammatory cytokines at the site of ligature, which recapitulates the findings from mice with nociceptor ablations ( 72 ). These findings suggest that SP plays significant roles in regulating host responses and bone resorption in ligature-induced periodontitis and that the resorptive effect of SP is sufficiently dominant to overcome the osteogenic activity of CGRP or SP.…”