Vascular smooth muscle cells also did not contribute to any stages of HO [14]. In contrast, vascular endothelial precursors robustly contributed to all stages of BMP-induced HO, constituting approximately 50% of cells in the HO lesion of fibroproliferative, chondrogenic,

and osteogenic stages [14]. Consistently, Medici et al. reported that in both human and mouse FOP models, Tie2+ endothelial cells transdifferentiate into MSCs through a mechanism called endothelial-to-mesenchymal transition (EndMT) in ALK2 receptor signaling dependent manner, subsequently contributing to HO formation [20]. Circulating Selleckchem BEZ235 osteoprogenitor cells are also considered to be involved in HO formation. A study by Suda et al. showed that bone marrow-derived type I collagen+/CD45+ mononuclear cells are present in early HO lesions in patients with FOP. In blood samples from patients with FOP with active episodes of HO, they found significantly higher numbers of these cells compared to patients with stable disease or unaffected individuals [19]. These findings suggest that this population of cells in HO lesions is possibly recruited from remote bone marrow reservoirs after local inflammation. In addition CB-839 ic50 to the causative cells, adipocytes deserve much attention in order to understand the pathogenesis of HO [17]. Several studies have demonstrated that the low-oxygen tension accelerates growth of mesenchymal cells and their commitment

to a chondrocyte lineage [21] and [22]. Olmsted-Davis et al. [17] have demonstrated that adipocytes play a key role in establishing the hypoxic microenvironment necessary for ectopic bone formation medroxyprogesterone to occur via endochondral ossification. The underlying mechanism is thought to be related with the hypoxia-inducible factor 1 (HIF-1) pathway. Indeed, a recent study by Zimmermann et al. demonstrated that an inhibitor of HIF-1-alpha, Echinomycin effectively blocked HO formation in the mouse model of tenotomy-induced HO [23]. Thus, it is indicated that several cell populations appearing in the affected sites are able to induce HO and other types of cells indirectly contribute to enhance this condition.

Molecular mechanisms of HO have not been fully elucidated. Inflammatory and skeletogenic signaling pathways are speculated to play critical roles in HO formation. In FOP patients, ectopic ossification progresses episodically and in response to minor trauma beginning in childhood [24] and [25]. FOP can affect all fibrous connective tissues, in addition to all joints of the axial and appendicular skeleton. The genetic linkage analysis has revealed that all individuals with classic clinical features of FOP have the same heterozygous single nucleotide mutation (R206H) in the gene encoding ACVR1 (ALK2), a BMP type I receptor [26]. This mutation causes constitutive activation of BMP receptor serine-threonine kinase even in the absence of BMP ligand. Yu et al.