Exploring the Role of Peripheral Nerves in Trauma-Induced Heterotopic Ossification

Abstract Recent studies have linked pain and the resultant nociception induced neural inflammation (NINI) to trauma-induced heterotopic ossification (THO). It is postulated that nociception at the injury site stimulates the TRPV1 (the transient receptor potential cation channel subfamily V member 1) receptors on sensory nerves within the injured tissues resulting in the expression of neuroinflammatory peptides, Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP). Additionally, BMP-2 released from fractured bones and soft tissue injury also selectively in sensory nerves and activates TRVP1 receptors once within the nerve also resulting in the release of SP and CGRP and causing neuroinflammation and degranulation of mast cells causing the breakdown the blood-nerve barrier (BNB), leading to release of Neural Crest Derived Progenitor Cells (NCDPC) into the injured tissue. Parallel to this process BMP-2 initiates the NCDPCs towards osteogenic differentiation. CGRP has direct osteogenic effects on osteoprogenitor cells/ mesenchymal stem cells, by activating Bone Morphogenic Protein-2 (BMP-2) via canonical Wnt/β-catenin signaling and cAMP-CREB signaling. BMP-2 binds to Transforming Growth Factor–β receptor I (TGF-βRI) and activates TGF-β-activated kinase 1 (TAK1) leading to phosphorylation of SMAD1/5/8, which binds to the co-activator SMAD4 and translocates to the nucleus to serve as transcription factor for BMP responsive genes critical in osteogenesis such as Runx2 and others. Thus, NINI phenotypes and specifically CGRP induction, plays a crucial role in tHO initiation and progression through the activation of the BMP pathway, breakdown of the BNB, leading to the escape of NCDPCs, and the osteogenic differentiation of the latter.