Identification of the Bmp2 Chondrocyte Enhancer

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Arthritis is characterized by destruction of cartilage in the joint. Molecules involved in embryonic cartilage development have been investigated as possible therapies for cartilage repair. Bone Morphogenetic Protein 2 (Bmp2) is one such molecule. Local injections or adenoviral delivery of Bmp2 to the joint results in new cartilage synthesis, thus making it a promising candidate. Unfortunately, it also stimulates anabolic activity in the surrounding tissues, resulting in osteophytes and synovial fibrosis. The project described in this proposal would identify the cis-regulatory sequences required for expression of Bmp2 specifically in chondrocytes- the cells that synthesize cartilage. Tissue-specific Bmp2 expression during development is governed by multiple enhancers found within vast intergenic sequences that flank the gene on either side. We have evidence that Bmp2 expression in chondrocytes is governed by an enhancer located within the 5'intergenic sequence. Using BAC transgenesis we will map the location of this enhancer to a 40-kb interval. Within this interval, we will identify the sequences that have enhancer activity in chondrocytes. Locating these sequences is a key step to unraveling the mechanisms governing chondrocyte-specific expression of Bmp2. Gaining a better understanding of these mechanisms will, in turn, provide us with leverage over the potent anabolic activity of Bmp2 in the joint.