Prevention of Cartilage Degeneration Associated with Meniscal Injury

University Of Rochester, Rochester NY

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Abstract

In the context of orthopaedic trauma, this project proposes to evaluate the relationship between meniscal[unreadable] injury and the development of osteoarthritis (OA). A significant clinical association has been documented[unreadable] between traumatic meniscal injury and OA, but the mechanism(s) behind how damage to the meniscus[unreadable] either directly or indirectly induces pathogenesis are not known. Recently, we have determined that articular[unreadable] chondrocyte loss of TGF-beta signaling induced by over-expression of the ubiquitin ligase Smurf2 leads to[unreadable] an OA-like phenotype in the mouse. Furthermore, we have identified up-regulation of Smurf2 in human[unreadable] articular cartilage shortly following meniscal trauma. Based on these findings, we hypothesize that Smurf2[unreadable] up-regulation is the seminal event in the arthritic process the follows meniscal injury. Furthermore, based on[unreadable] our findings that increased BMP signaling occurs in conjunction with inappropriate maturation of articular[unreadable] chondrocytes during OA, we also hypothesize that reduction of BMP signaling via genetic or gene therapy[unreadable] approaches will decelerate disease progression in murine OA induced by meniscal injury. To address these[unreadable] central hypotheses, we propose to address the following 3 Specific Aims: In Aim 1, we will comprehensively[unreadable] characterize the tissue and molecular events leading to cartilage degeneration in a model of murine OA[unreadable] induced by meniscal injury. In Aim 2, we will use genetic and gene therapy approaches to evaluate a[unreadable] candidate therapeutic intervention in this murine OA model that are based on reduction of BMP signaling.[unreadable] For these basic science aims, we will employ MRI and microCT imaging methods, histomorphometry and[unreadable] molecular analyses to evaluate disease phenotype. Then, in Aim 3, a human clinical study will be executed[unreadable] which will quantify articular cartilage structural changes following acute meniscal injury using a quantitative[unreadable] MRI approach. Molecular changes will also be assessed in discard cartilage and meniscus tissue to further[unreadable] evaluate the involvement of Smurf2 in the pathogenesis of OA disease following injury.