No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing

Abstract

Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their painpromoting effects. Finally, further examination of protein-sequestering antibodies and/or small *

Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion

“…Most notably, we find NGF and TrkA are localized predominantly at the chondro-osseous transition zone, where cartilage undergoes hypertrophy and transforms to bone adjacent to the invading vasculature 6,15 . Our genetic models of endogenous NGF and TrkA localization support previous studies observing peak expression of neurotrophins and their receptors during the hypertrophic cartilage phase of repair [47][48][49] . While our mRNA expression data show a peak at day 10, possible delays in mRNA-to-protein synthesis were considered when harvesting samples at day 14 for histological analysis.…”

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“…42 Not only NGF, but also BDNF, play a key regulatory part of pain in the periphery. 43 Ion channel genes such as TRPV1, Nav1.3 and Nav1.7, are also investigated in RA pain. Synthesized in DRGs, TRPV1 is linked to inflammatory pain and peripheral neuropathy.…”

No pain, no gain: Will migraine therapies increase bone loss and impair fracture healing?

“…With regard to fracture and CGRP, as recently summarized [6], several investigators have shown CGRP expression at the fracture site and reported correlative findings. Prior to the studies reported in this issue of EBioMedicine by Appelt et al [1] perhaps the best evidence Contents lists available at ScienceDirect EBioMedicine journal homepage: www.elsevier.com/locate/ebiom for a role of CGRP in fracture repair was a report that intraperitoneal injection with CGRP inhibitor significantly impaired fracture healing in a rat model, as demonstrated by a significant reduction in mineralized callus with an increase in cartilage [9].…”

“…With regard to fracture and CGRP, as recently summarized [6] , several investigators have shown CGRP expression at the fracture site and reported correlative findings. Prior to the studies reported in this issue of EBioMedicine by Appelt et al.…”

“…As we recently reviewed [6] , CGRP inhibits osteoclastogenesis and bone resorption, and αCGRP increases osteoblast proliferation and bone formation. Further, αCGRP global knockout mice (αCGRP −/− mice) were found to have reduced bone formation and low bone mass [7] .…”