Defining the developmental origin of osteoclasts in vivo.

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A major limitation preventing effective treatment of infantile osteopetrosis is the lack of understanding how osteoclast differentiation is regulated during development and in the adult organism. Osteoclasts are bone-resorbing cells that are crucial for tooth eruption and bone integrity that is important for upright walk and the formation of a bone cavity. Tooth eruption and bone integrity is severely impaired in mice lacking the growth factors colony stimulating factor 1 (CSF1, M-CSF) and receptor activator of nuclear factor kb ligand (RANKL), or their corresponding receptors CSF1R (M-CSFR, CD115) and Rank, respectively. Deficiency of either of those factors results in impaired differentiation of macrophages and osteoclasts resulting in an osteopetrotic phenotype. According to prevalent assumption, osteoclasts are continuously generated from hematopoietic stem cells and progenitor populations in the bone marrow of adult mice were identified. However, we provide evidence here that the osteoclasts that are crucial for tooth eruption and bone cavity formation are of embryonic origin, challenging the current concept of osteoclast differentiation and regeneration and also the therapeutic treatment of osteopetrosis in patients. We present experiments in this proposal that will address mechanisms of osteoclast formation and regeneration in the embryo and in juvenile mice, characterize the spatiotemporal relevance for CSF1R-mediated signals in osteoclast differentiation, and test novel therapeutic options for the treatment of osteopetrosis in vivo.