In the context of orthopaedic trauma, this project proposes to evaluate the relationship between meniscalinjury and the development of osteoarthritis (OA). A significant clinical association has been documentedbetween traumatic meniscal injury and OA, but the mechanism(s) behind how damage to the meniscuseither directly or indirectly induces pathogenesis are not known. Recently, we have determined that articularchondrocyte loss of TGF-beta signaling induced by over-expression of the ubiquitin ligase Smurf2 leads toan OA-like phenotype in the mouse. Furthermore, we have identified up-regulation of Smurf2 in humanarticular cartilage shortly following meniscal trauma. Based on these findings, we hypothesize that Smurf2up-regulation is the seminal event in the arthritic process the follows meniscal injury. Furthermore, based onour findings that increased BMP signaling occurs in conjunction with inappropriate maturation of articularchondrocytes during OA, we also hypothesize that reduction of BMP signaling via genetic or gene therapyapproaches will decelerate disease progression in murine OA induced by meniscal injury. To address thesecentral hypotheses, we propose to address the following 3 Specific Aims:
In Aim 1, we will comprehensivelycharacterize the tissue and molecular events leading to cartilage degeneration in a model of murine OAinduced by meniscal injury.
In Aim 2, we will use genetic and gene therapy approaches to evaluate acandidate therapeutic intervention in this murine OA model that are based on reduction of BMP signaling.For these basic science aims, we will employ MRI and microCT imaging methods, histomorphometry andmolecular analyses to evaluate disease phenotype. Then, in Aim 3, a human clinical study will be executedwhich will quantify articular cartilage structural changes following acute meniscal injury using a quantitativeMRI approach. Molecular changes will also be assessed in discard cartilage and meniscus tissue to furtherevaluate the involvement of Smurf2 in the pathogenesis of OA disease following injury.
Showing the most recent 10 out of 133 publications