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

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-beta 1 (TGF-beta 1) level, could be an important causative mechanism of traumatic HO formation.