EGFR/ MIG-6 signalling in osteoarthritis

Purpose: Osteoarthritis (OA) is the most common form of arthritis and progresses by degeneration of articular cartilage, amongst others. Despite an increasing awareness of OA as a medical problem, there is a surprising absence of effective medical treatments beyond pain control and surgery. Our laboratory has identified several promising novel targets for therapeutic strategies in OA, such as transforming growth factor alpha (TGFα) and epidermal growth factor receptor (EGFR) in cartilage degeneration. Mitogen-inducible gene 6 (Mig-6) has been identified as negative regulator of receptor tyrosine kinases EGFR and c-Met. Importantly, our results (Pest et al. 2014) using ablation of Mig-6 in cartilage showed anabolic buildup of articular cartilage and formation of chondro-osseous nodules. It is possible that deregulation of other growth factors such as HGF/c-Met play an important role in tissue repair and may be partially responsible to the Mig-6 knockout (KO) phenotype. Methods: Genetically modified mice for cartilage-specific overexpression of Mig-6 were generated and harvested at 6 and 12 weeks of age. Micro-Computed Tomography (μCT) imaging was used to analyse changes in subchondral bone architecture and to investigate 3D joint. Immunohistochemistry (IHC) was performed on knee joint sections from 12-week old and 36-week old cartilage-specific Mig-6 (Mig-6fl/f; Col2-Cre+/-) knockout mice for detecting hepatocyte growth factor (HGF). Results: Our preliminary results show statistically significant shorter long bones (femur, tibia, humerus, radius, and ulna) in mice with cartilage-specific Mig-6 overexpression (Mig-6over/over; Col2-Cre+/-) at 6 and 12-weeks of age. These results suggest altered growth plate development when compared to control mice (Mig-6over/over; Col2-Cre-/-). Immunostaining for HGF in the articular cartilage was similar in both genotypes at 12 weeks of age, but increased in 36-week-old Mig6 KO animals compared to controls. Conclusions: Our findings show that decreased EGFR and/or HGF/c-Met signaling through Mig-6 overexpression may play a role in endochondral bone growth. Moreover, the increased HGF expression in Mig-6 KO mice may be involved in the formation of the calcified nodules in the knee. Therefore, further examination of the mechanisms of HGF and c-MET in cartilage is under way to help understand its function in the cartilage of Mig-6 KO and overexpressing animals.