Heterotopic ossification has some nerve

Abstract

Heterotopic ossification, defined as the formation of bone in abnormal anatomic locations, can be clinically insignificant or devastating and debilitating, depending on the site and duration of new bone formation. There are many causes of heterotopic ossification (HO), including soft tissue trauma, central nervous system injury, vasculopathies, arthropathies, and inheritance. One of the least understood components of HO is the interaction of the peripheral nervous system with the induction of this process. Recent work has shown that, upon traumatic injury, a cascade of events termed neurogenic inflammation is initiated, which involves the release of neuropeptides, such as substance P and calcitonin gene related peptide. Release of these peptides ultimately leads to the recruitment of activated platelets, mast cells, and neutrophils to the injury site. These cells appear to be involved with both remodeling of the nerve, as well as potentially recruiting additional cells from the bone marrow to the injury site. Further, sensory neurons stimulated at the injury site relay local information to the brain, which can then redirect neuroendocrine signaling in the hypothalamus towards repair of the injured site. While numerous studies have highlighted the important role of nerve-derived signals, both central and peripheral, in the regulation of normal bone remodeling of the skeleton,1 this review focuses on the role of the local, peripheral nerves in the formation of heterotopic bone. We concentrate on the manner in which local changes in bone morphogenetic protein (BMP) expression contribute to a cascade of events within the peripheral nerves, both sensory and sympathetic, in the immediate area of HO formation.

Figure 1

Schematic representation of the tentative neuroinflammatory mechanism and its relationship to heterotopic ossification. BMP2 can induce recruitment of mast cells and nerve tissue remodeling, through activation of sensory neurons and release of Substance P (SP) and calcitonin gene-related peptide (CGRP).

Figure 2

Schematic representation of the tentative interaction of the sympathetic nervous system and heterotopic ossification. Activation of the sympathetic nervous system, through sensory stimulation, leads to regulation of adipose, particularly the rapid appearance of brown adipose within the area of HO. The brown adipose appears to be critical to bone patterning and formation.