P1: Prevention of cartilage degeneration associated with meniscal injury

在骨科创伤的背景下，本项目提出评估半月板的关系

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