In addition, three conditions are required for HO: (1) the presence of an osteoinductive factor, (2) chondrocyte progenitor and osteoblast progenitor cells, and (3) an environment permissive to osteogenesis [1]. Once these conditions are met, mesenchymal cells are recruited, RGFP966 mouse which then proliferate and differentiate into chondrocytes and/or osteoblasts, and ultimately induce ectopic bone formation [10]. In this review, we will summarize our current understanding of the pathology and mechanisms of HO, and in particular, endochondral HO. We will then discuss current and future therapies for the HO. Finally, we will explore how lessons learned from HO research can be applied to the dental field. The endochondral

HO process largely recapitulates the cellular events of endochondral Gefitinib supplier ossification in embryonic skeletal development and fracture healing. However, in HO, these cellular events are temporally and spatially unsynchronized. Therefore tissues of HO are disorganized and inhomogeneous. Mature heterotopic bone can also form bone marrow cavities and produce apparently normal bone marrow [11]. Histological evaluation of HO has shown that tissue destruction is followed by cell proliferation

and tissue formation (Fig. 1) [12]. To initiate the process of HO formation, inflammation first occurs in response to stimulations, including surgery, trauma, and viral illnesses [13]. Inflammatory cells such as lymphocytes, macrophages, and mast cells reside in the perivascular region of early HO lesions within skeletal muscle and connective tissue. The presence of inflammatory cells is associated with damage to skeletal muscle cells and tissue hypoxia, both Carbohydrate of which could trigger the proliferation of fibroblastic cells (undifferentiated

mesenchymal cells). This is the initial step of the anabolic phase in early HO lesions [14] and [15]. Tissue degeneration initiates local production, release, or delivery of skeletogenic-inducing factors that leads to recruitment and active proliferation of fibroblastic cells that differentiate into chondrocytes. Cartilaginous tissues are eventually replaced by bone through a normal sequence of endochondral ossification stages, and newly synthesized bone becomes mature and shows lamellar structure [16]. HO originates from several cell sources. These include hematopoietic stem cells, local resident mesenchymal stem cells (MSCs), circulating MSCs, muscle satellite cells, fibroblasts, progenitor cells derived from vessels [17], [18] and [19]. Cell lineage tracing studies were performed to determine the stem/progenitor cells responsible for HO in the BMP-induced HO mouse models [14] and [20]. In these studies, three possible candidates, skeletal muscle progenitor cells (MyoD+), endothelium and endothelial precursors (Tie2+), and vascular smooth muscle cells (SMMHC+) were examined.