Pathological Role of bFGF in Human Adult Articular Cartilage

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DESCRIPTION (provided by applicant): Chondrocyte activation that results in degradation of articular cartilage is a key event in the pathogenesis of arthritis. Paradoxically, chondrocytes in damaged cartilage are highly active as part of a repair mechanism. For example, Osteoarthritic (OA) cells highly express anabolic factors, such as TGFb and BMPs compared to normal human adult articular chondrocytes (HACs). Unfortunately, in most cases, these attempts for repair fail, and eventually develop OA. Why? In the current proposal, we address this question and try to understand the potential mechanisms by which OA cells fail to repair. Recently, we reported the striking antagonistic effect of bFGF on the well-known cartilage anabolic activity of IGF-1 & BMP7 alone and in combination of these two anabolic factors in alginate and within cartilage explants. Surprisingly, this anti-combinatorial effect of bFGF does not inhibit cellular proliferation mediated by IGF-1 & BMP7. bFGF alone increases proliferation and even further promotes it when combined with other growth factors. We consider that this is the main reason why people still report bFGF as an anabolic factor for cartilage in vivo. Based on our data, we believe that bFGF promotes fibrocartilage formation which is a poor substitute of hyaline cartilage. The importance of the quality of repaired cartilage can not be overstressed. Multiple factors work in concert to control the overall metabolism of cartilage in vivo. bFGF is expressed by chondrocytes, is stored in the cartilage ECM, and is released from the cartilage matrix upon cartilage damage. More recent data revealed that the expression of bFGF and FGFR1 are highly upregulated in OA compared to normal HACs. Significant inhibitory action of bFGF on BMP/IGF-1 suggests that excessive expression/release of bFGF from the cartilage matrix during injury/trauma, with loading or in arthritis could substantially contribute to reduced anabolic activity in articular cartilage. Defining the precise inhibitory cellular/molecular mechanisms mediated by bFGF on Smad signaling pathway, which represents the cellular response to TGFb/BMP, will shed light on the therapeutic benefit by inhibition of excessive bFGF activity in cartilage in conditions characterized by loss of the normal anabolic-catabolic balance such as OA. Better understanding of the regulation and function of the posttranslational modifier SUMO in traumatic/arthritic cartilage may provide new targets for therapeutic intervention in cartilage-associated joint diseases such as OA.