Investigations of osteopetrotic mutant animals provide valuable information regarding osteoclast ontogeny and function. For example, studies of the op/op osteopetrotic mouse have revealed that M-CSF is a critical cytokine involved in osteoclastogenesis, and osteopetrosis in c-fos knock-out mice demonstrates that this transcription factor facilitates differentiation of macrophage precursors to the osteoclast phenotype. Despite the fact that the osteoclast is of hematopoietic origin, the role of myeloid-specific transcription factors in osteoclast differentiation is unknown. The investigators have discovered a new osteopetrosis mutant in transgenic mice lacking the myeloid and B-lymphoid specific transcription factor, PU.1. PU.1 is found to be normally expressed during osteoclast differentiation. PU.1 -/- mice are devoid of both macrophages and osteoclasts and thus represent the earliest developmental lesion inducing osteopetrosis yet identified. They also find expression of PU.1 in osteoclastogenic cultures parallels the number of bone-resorbing cells and mRNA levels of the beta3 integrin subunit, which modulates appearance of the functional osteoclast integrin, alpha(v)beta3. Furthermore, an active promoter fragment of the beta3 integrin subunit contains three PU.1 consensus response elements, suggesting PU.1 may regulate expression of this resorption-modulating integrin. Based on these observations, the Specific Aims of this application are to determine if 1) PU.1 -/- mice can be rescued by transplantation of normal spleen cells, since PU.1 mutation is inherent to the osteoclast (myeloid) precursor; 2) PU.1 expression is required throughout the temporal spectrum of osteoclast differentiation; and 3) PU.1 regulates expression of the osteoclast beta3 integrin gene.
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