RANK/NF-KappaB signaling in chondrogenesis

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DESCRIPTION (provided by applicant): Most of the skeleton forms by endochondral ossification in a highly regulated process in which skeletal elements are first laid down during embryogenesis in a cartilaginous framework. These cartilage elements are invaded by blood vessels and partly replaced by bone, laid down by bone forming osteoblasts and remodeled by bone destroying osteoclasts at epiphyseal growth plates, which form near the ends of the growing bones and control skeletal growth. Many genes have been identified during the past decade as regulators of this process, and mutation or deletion of them can result in various chondrodysplasias, including dwarfism. RANKL/RANK/NF- B signaling was shown to regulate osteoclastogenesis after deletion of these genes in mice led to osteopetrosis due to failure of osteoclast formation. Surprisingly, these knockout mice also have short limbs, but the role of this signaling pathway in endochondral ossification has not been studied in detail. In this proposal, we plan to obtain preliminary data that will provide definitive evidence of a role for this pathway in chondrogenesis and to develop an assay that will permit in vitro morphologic assessment of manipulation of this and other signaling pathways. Our Specific Aims are: 1) To determine the role of RANKL/RANK/NF- B signaling in chondrogenesis; 2) To determine the effects of absent RANK/NF- B signaling on chondrocyte gene expression. NF- B transcription factors regulate the expression of a variety of genes involved in numerous cell processes, including the early stages of limb development. Delineation of a specific role for these factors in endochondral ossification should open up a new field of investigation into the pathogenesis of the many forms of chondrodysplasia that to date do not yet have an identified molecular basis.