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Invivo role of S100A4 in OA pathophysiology

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Summary: This R03 pilot application is in response to PAR-09-031, NIAMS Small Grant Program for New Investigators. The purpose is to obtain pilot data on the role of S100A4 in the development of osteoarthritis. Osteoarthritis (OA) is the most common form of arthritis; it commonly affects the older populations and significantly impacts their normal daily activities. Currently, there are no effective treatments available to either improve or even slow down the disease process. Understanding the molecular mechanisms underlying cartilage degradation and the subsequent development of OA may lead to more targeted interventions that could better treat the symptoms of OA or inhibit its progression. The long-term objective of the current proposal is to understand the role of the calcium-binding protein S100A4 in chondrocytic function and in the development of OA. The chondrocyte is the sole cellular constituent of cartilage and its prime function is to synthesize and maintain an extracellular matrix (ECM) in response to various anabolic and catabolic signals. Imbalance in these signals results in altered chondrocytic function, leading to degradation of cartilage and development of OA. S100 proteins are low molecular weight, acidic, calcium-binding proteins that play an important role in various cellular functions. Uniquely, members of this family function both inside the cell and outside the cell. We have shown that chondrocytes express S100A4 and its expression is upregulated in OA cartilage; however, the function of S100A4 protein in chondrocytes is poorly understood. We recently found that intracellular S100A4 translocates into the nucleus upon IL-1 stimulation, and binds to the promoter region of the MMP-13 gene. In addition, knocking down S100A4 expression inhibited the expression of MMP-13. This suggests that S100A4 is a key regulator of MMP-13 expression in chondrocytes. The overall goal of this proposal is to determine the role of S100A4 in the pathophysiology of OA in vivo. This data is necessary in order to apply for an RO1 grant to support further mechanistic studies on S100A4 function in cartilage. We propose two specific aims: Aim 1: To determine role of S100A4 in the regulation of matrix metalloproteinase and ADAMTSs expression in vivo. Aim 2: To determine if deletion of S100A4 gene in mice reduces the severity of OA. The successful completion of our project will confirm the role of S100A4 in the cartilage biology in vivo and provide much needed rationale for future mechanistic studies to delineate a novel pathway for IL-1 regulation of MMP-13 expression that includes a new mechanism of transcriptional regulation by an S100A4 protein. The results from these studies will provide novel information needed to understand the role of the S100A4 protein in regulating chondrocyte function and its role in mediating cartilage degradation, and provide targets for improved therapeutic treatments for OA or interventions to halt its progression.
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