Fig. 4.

The “Two Hit” mechanism of HO formation: taken together with previous studies [36], our results suggest that nanohydroxyapatite can deposit with in skeletal muscle following injury if one of the skeletal muscle protection mechanisms (i.e., ABCC6 or plasmin) are insufficient. Fortunately, the body possesses a secondary macrophage-mediated clean-up crew to regress nanohydroxyapatite from damaged tissues, thereby resolving the predisposing factors to HO formation. Together, these two lines of defense are critical for preventing nanohydroxyapatite deposition within damaged tissues and its subsequent maturation to HO. These findings suggest a new paradigm for HO formation in which HO can result from insufficient protection against nanohydroxyapatite with a failure of macrophage-mediated regression