Demystifying the Paradox of Biomineralization: Mechanisms Regulating Simultaneous Physiology and Pathologic Bone Formation

Abstract

Calcium and phosphate are essential elements in many biological processes, such as basic cellular function and signaling, yet they also combined to make biological crystals, most notably hydroxyapatite found in bone. Calcification within the body is a tightly regulated process, both during development and repair, allowing for the simultaneous formation of soft tissues (such as skeletal muscle), and calcified tissues within the skeleton. However, as you age or following a traumatic injury, these tightly regulated processes can become distorted, resulting in both the loss of mineral from bone, yet the simultaneous gain of mineralization in soft tissue. Through my dissertations, I have investigated the processes by which physiologic bone forms during fracture repair in aims of identifying the mechanisms of pathologic calcification of soft tissues following injury. While calcificaiton of the skeleton is essential for proper function, calcification of soft tissues such as the skeletal muscle results in pain, tissue deformation, chronic inflammation, loss of mobility, and in severe cases may necessitate the surgical excision of the affected tissue; thus, greatly impacting patient morbidity and mortality. Yet, the molecular pathogenesis of trauma-induced calcification remains unknown, and as a result current therapeutics remain limited, ineffective, or plagued by undesirable side effects. Through our work, by building upon the mechanisms of physiologic bone formation, we determined that the formation of dystrophic calcification within soft tissues, if persistent, is sufficient drive heterotopic ossificaiton, or bone formation. Furthermore, through these studies we demonstrated that the body possesses a second line of defense in the macrophage, responsible for regressing dystrophic calcification from soft tissue to prevent the maturation to heterotopic ossification. Together, these findings revealed a new paradigm by suggesting that persistent dystrophic calcification and heterotopic ossificaiton may be stages of a pathologic continuum. As such, these findings support further investigations into the application of early therapeutic interventions aimed at preventing dystrophic calcificaiton as a strategy to evade heterotopic ossificaiton formation. While current therapeutics aimed at inhibiting heterotopic ossificaiton simultaneously target the skeleton, future compounds targeting dystrophic calcification, in addition to preventing heterotopic ossificaiton, may also reduce the undesirable side effects on physiologic bone.