Defining the developmental origin of osteoclasts in vivo.

阻碍婴儿石骨症有效治疗的一个主要限制是缺乏对破骨细胞分化在发育过程中和成年机体中是如何调节的理解。破骨细胞是骨吸收细胞，对牙齿萌出和骨完整性至关重要，骨完整性对直立行走和骨腔的形成至关重要。在缺乏生长因子集落刺激因子1（CSF 1，M-CSF）和核因子kb配体受体激活剂（RANKL）或其相应受体CSF 1 R（M-CSFR，CD 115）和Rank的小鼠中，牙齿萌出和骨完整性严重受损。这些因子中的任一种的缺乏导致巨噬细胞和破骨细胞的分化受损，从而导致骨硬化表型。根据普遍的假设，破骨细胞是由造血干细胞连续产生的，并且在成年小鼠的骨髓中鉴定出祖细胞群。然而，我们在这里提供的证据表明，破骨细胞是至关重要的牙齿萌出和骨腔形成的胚胎起源，挑战破骨细胞分化和再生，也在患者的骨硬化症的治疗治疗目前的概念。我们目前的实验在这个建议，将解决破骨细胞的形成和再生的机制在胚胎和幼年小鼠，表征的时空相关性CSF 1 R介导的信号在破骨细胞分化，并测试新的治疗选择在体内治疗骨硬化症。

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.