Is heterotopic ossification getting nervous?: The role of the peripheral nervous system in heterotopic ossification

Heterotopic ossification (HO), or de novo bone formation in soft tissue, is often observed following traumatic injury. Recent studies suggest that peripheral nerves may play a key functional role in this process. The results supporting a neurological basis for HO are examined in this article. Evidence supports the fact that BMPs released from bone matrix possess the capacity to induce HO. However, the process cannot be recapitulated using recombinant proteins without extremely high doses suggesting other components are required for this process. Study of injuries that increase risk for HO, i.e. amputation, hip replacement, elbow fracture, burn, and CNS injury suggests that a likely candidate is traumatic injury of adjacent peripheral nerves. Recent studies suggest neuroinflammation may play a key functional role, by its ability to open the blood-nerve barrier (BNB). Barrier opening is characterized by a change in permeability and is experimentally assessed by the ability of Evans blue dye to enter the endoneurium of peripheral nerves. A combination of BMP and barrier opening is required to activate bone progenitors in the endoneurial compartment. This process is referred to as “neurogenic HO”. Overview of neurogenic heterotopic ossification (HO). Induction of HO is thought to occur from the release of BMPs in bone matrix that enter through the blood nerve barrier, presumably due to selective permeability associated with specific injuries. Once inside, BMP2 induces neuroinflammation through activation of the TRVP1 receptor leading to the release of substance P and CGRP. This leads to the recruitment and degranulation of mast cells outside the barrier that can eventually activate MMP9 and other proteins involved in matrix remodeling, which open the barrier and allow cells to exit through the circulation. Parallel to this process, cells within the endoneurium undergo early osteogenic differentiation and express factors necessary for extravasation to the site of HO. As they exit the barrier to be deposited, cells within the perineurium have been activated through the release of noradrenaline and subsequent binding to the β3-adrenergic receptor. These cells have an immediate expansion of their mitochondria and undergo robust uncoupled aerobic respiration similar to brown adipose. These cells start to migrate towards the site of HO, where their elevated oxygen consumption leads to both localized tissue hypoxia potentially necessary to support not only chondrogen