Anabolic phenotype in cartilage-specific Mitogen-inducible gene-6 knockout mice is independent of Transforming growth factor-α
Background/ObjectiveOsteoarthritis (OA) is a whole joint disorder with no disease modifying treatment currently available. The Epidermal Growth Factor Receptor (EGFR) signaling pathway plays an important role in cartilage/bone development and its ligand transforming growth factor- (TGl{middle dot}) is upregulated in OA. In contrast, Mitogen-inducible gene 6 (Mig6) is a negative regulator of EGFR, and our studies demonstrate that cartilage-specific Mig-6 deletion results in anabolic effects on cartilage and formation of chondro-osseus nodules (CON). We aimed to attenuate EGFR signaling by inhibiting TGF production in cartilage-specific Mig6 deficient mice, to test whether this would prevent the formation of CONs. MethodsWe generated double knockout mice by crossing cartilage-specific Mig-6fl/flCol2a1-Cre+/- and whole-body Tgfa+/- mice to generate experimental and control wild-type mice. Knee and elbow sections were stained with toluidine blue to examine articular cartilage thickness and cell density, and tartrate-resistant acid phosphatase for osteoclast activity. Additionally, immunohistochemistry was completed to analyze phospho-EGFR and SOX9. ResultsMig-6 deficient mice display cartilage thickening and CONs at 12 weeks in both the elbow and knee joints, which is independent of TGF ligand presence. Similarly, articular cartilage cell density is increased in Mig-6fl/flCol2a1-Cre+/-Tgfa-/- and Mig-6fl/flCol2al-Cre+/- mice, but not Tgfa-/- mice, and displays increased SOX9 and phospho-EGFR staining. ConclusionThe articular cartilage displays increased thickness, increased cell density, and CON formation independent of the presence of TGF, suggesting the anabolic phenotype in the Mig6-deficient mice is independent of TGF/EGFR binding. The anabolic phenotype may be due to an alternative EGFR ligand activation, or perhaps due to other non-EGFR specific mechanism. More research is required to elucidate the exact pathway responsible for the anabolic effects.