WHERE NO BONE HAS GONE BEFORE: SUBSTANCE P MEDIATES HETEROTROPIC OSSIFICATION

By René A. Azeez, Honours BSc. Developmental Biology, University of Toronto. July 23, 2011.

            In the field of Developmental Biology one of the most fundamental principles is that of contextual determination, i.e. a cell goes along it’s particular lineage to become what it is destined to become based on a number of complex contextual factors. A condition known as Heterotopic Ossification (HO) in which patients have incurred soft tissue damage leading to the formation of extraskeletal bone is a common and serious reflection of the contextual principle. Although researchers have had advances in understanding the genetics of HO, the cellular and molecular triggers of HO have long remained unclear. That is, until recently when researchers from Northwestern University Feinberg School of Medicine and the Perelman School of Medicine at the University of Pennsylvania have managed to shed some light on the molecular mechanism of HO.

            In a previous study researchers were able to conclude that all forms of HO had something in common; the requirement of an inflammatory trigger. However, acknowledging that inflammation triggers are regulated by multiple cytokines (small cell signaling molecules that are secreted by the glial cells of the nervous system) and multiple complex neuro-endocrine controls, they conceded that identifying specific regulatory loci (specific gene or DNA sequences) that control these inflammatory triggers was difficult. Researchers were able to deduce that a pro-inflammatory neuropeptide known as Substance P (SP) was present in active areas of bone regeneration following a fracture.  Moreover, the receptor for SP had been found on cells and tissues associated with bone tissue formation and degradation. SP had also been shown to mediate immune modulation and injury-induced mobilization of CD29⁺, a cell involved in HO formation.

In this study, researchers lead by Lixin Kan studied the role of SP in patients with multiple forms of HO including sporadic, post-traumatic, neurologically associated HO, and fibrodysplasia ossificans progressiva or FOP (the genetic form of HO). They were able to show that SP expression intensified in early sporadic HO and FOP lesions. Moreover they were able to show that blocking SP prevented HO in these cases. Additionally, they were able to determine that cells that robustly express the SP receptor are required to mediate BMP-dependant (bone morphogenic protein) HO.

These results allowed researchers to determine that SP is seemingly critical in HO induction, and they go on to suggest that blocking SP or SP mediated HO pathways can be a potentially viable therapeutic approach in preventing HO.

REFERENCE: Lixin Kan, Vitali Y Lounev, Robert J Pignolo, Lishu Duan, Yijie Liu, Stuart R Stock, Tammy L McGuire, Bao Lu, Norma P Gerard, Eileen M Shore, Frederick S Kaplan, and John A Kessler. Substance P signaling mediates BMP dependent heterotopic ossification. Journal of Cellular Biochemistry, 2011.