Crosstalk between substance P and calcitonin gene‐related peptide during heterotopic ossification in murine Achilles tendon

Abstract

Heterotopic ossification (HO) is abnormal bone formation within soft tissue, usually predisposed by neurogenic or musculoskeletal trauma. Inflammation resulting from trauma is considered to be the main trigger for HO by eliciting changes within the injury site, including elevation of bone morphogenetic proteins (BMPs). Recent research, however, has also associated changes in sensory neuropeptide expression with HO. Substance P (SP) and calcitonin gene-related peptide (CGRP) are two of those neuropeptides that have been implicated with various aspects of HO, including regulation of inflammation and BMP signaling. Despite discoveries associating SP and CGRP with soft tissue HO, it remains unclear whether SP and CGRP have a direct role in the induction of HO. Here, we investigated the effect of SP and CGRP in vivo with the aid of inkjet-based biopatterning technology to controllably deliver these neuropeptides onto a murine Achilles tendon. While we did not observe any significant effect with CGRP, SP alone promoted HO in vivo with increased expression of BMP2. Remarkably, when SP and CGRP were delivered together, CGRP counteracted the effect of SP and essentially blocked SP-induced HO. This report contributes to the understanding of the complex problem of HO pathophysiology and warrants more study to better elucidate the interplay between SP and CGRP in the induction of HO. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1444-1455, 2018.

Heterotopic Ossification: A Comprehensive Review

“…In a murine model of Achilles tendon HO formation, substance P delivery alone promoted HO formation and increased expression of BMP2; the addition of calcitonin gene‐related peptide (CGRP) in conjunction with substance P mitigated this effect. CGRP alone had little effect . Mast cells are recruited by sensory neurons by signaling factors such as substance P and have been strongly implicated in HO formation.…”

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

“…In fibrodysplasia ossificans progressive disease, mTOR ( Agarwal et al, 2016 ) and NF-κB/MAPK ( Barruet et al, 2018 ) were related with the formation of muscle heterotopic ossification under crosstalk with BMP signaling, and BMPs together with SMAD, AKT, and mTOR/S6K signaling could prevent heterotopic ossification progress when the activity of PI3Kα was inhibited ( Valer et al, 2019 ). RhoA-BMPs ( Mu et al, 2013 ) and CGRP-SP-BMP-2 ( Tuzmen et al, 2018 ) signaling also regulated heterotopic ossification progress in dystrophic muscle and Achilles tendon of mice, respectively. Additionally, BMP signaling pathway has crosstalk with Notch, FGF, and JAK/STAT signaling pathways in cell osteogenic differentiation potential and tissue ossification formation ( Chen et al, 2012 ; Zhang et al, 2019 , 2020 ).…”

Crosstalk between Bone and Nerves within Bone

“…[ 41 ] After activation by BMP2, a cascade of events occurs within the peripheral nerves to cause neuroinflammation, with elevated the level of SP and CGRP released by sensory nerves. [ 304 ] Neuroinflammation is necessary for opening the blood‐nerve barrier. [ 305 ] Nerve‐derived osteoprogenitors express Claudin‐5 when they cross the blood‐nerve barrier to the ossification site.…”