Mechanism of traumatic heterotopic ossification: In search of injury-induced osteogenic factors

Abstract

Heterotopic ossification (HO) is a pathological condition of abnormal bone formation in soft tissue. Three factors have been proposed as required to induce HO: (a) osteogenic precursor cells, (b) osteoinductive agents and (c) an osteoconductive environment. Since Urist's landmark discovery of bone induction in skeletal muscle tissue by demineralized bone matrix, it is generally believed that skeletal muscle itself is a conductive environment for osteogenesis and that resident progenitor cells in skeletal muscle are capable of differentiating into osteoblast to form bone. However, little is known about the naturally occurring osteoinductive agents that triggered this osteogenic response in the first place. This article provides a review of the emerging findings regarding distinct types of HO to summarize the current understanding of HO mechanisms, with special attention to the osteogenic factors that are induced following injury. Specifically, we hypothesize that muscle injury-induced up-regulation of local bone morphogenetic protein-7 (BMP-7) level, combined with glucocorticoid excess-induced down-regulation of circulating transforming growth factor-β1 (TGF-β1) level, could be an important causative mechanism of traumatic HO formation.

Keywords: bone morphogenetic protein; dystrophic calcification; glucocorticoid; heterotopic ossification; muscle injury; transforming growth factor-β1.

FIGURE 1

BMP‐7 expression in mouse blast‐traumatized muscle. (A‐C, G&H) H&E staining illustrating muscle tissue morphology at different time points following blast injury: (A) uninjured muscle tissue; (B) 3 days after injury; (C) 7 days after injury; (G) 14 days after injury; and (H) 28 day after injury. Scale bar = 200 µm (D, E, F) Immunofluorescence staining showing the expression of BMP‐7 (green) at early time points following blast injury: (D) uninjured muscle tissue; (E) 3 days after injury; and (F) 7 days after injury. Scale bar = 200 µm (I&J) Alizarin Red staining showing calcium deposition and mature bone formation: (I) 14 days after injury; and (J) 28 days after injury. Scale bar = 200 µm

FIGURE 2

Increased glucocorticoid level promotes ectopic mineralization. (Left) Representative microCT images showing ectopic mineralization in the combined blunt amputation and cardiotoxin injection group. (Right) At 4 weeks after amputation, endogenous plasma corticosterone level remains higher in amputated animals compared with unamputated control animals. (n = 4)

FIGURE 3

TGF‐β signalling antagonizes BMP signalling by competing for downstream co‐Smad4 for nuclear signal transduction. Under normal physiological conditions, circulating TGF‐β1 acts to maintain the osteoblastic differentiation threshold to control aberrant osteogenesis, whereas under pathological conditions resulting from severe trauma, the level or activity of TGF‐β1 is reduced or blunted, resulting in aberrant osteogenesis

FIGURE 4

Schematic of a two‐hit model for trauma‐induced HO. Muscle injury‐induced up‐regulation of local BMP‐7 level, and in combination with glucocorticoid excess‐induced down‐regulation of circulating TGF‐β1 level, represents a candidate causative mechanism of post‐traumatic HO formation