Anabolic phenotype in cartilage-specific Mitogen-inducible gene-6 knockout mice is independent of Transforming growth factor-α

Background/Objective Osteoarthritis (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- α (TGl· α ) 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 α production in cartilage-specific Mig6 deficient mice, to test whether this would prevent the formation of CONs. Methods We generated double knockout mice by crossing cartilage-specific Mig-6 fl/fl Col2a1-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. Results Mig-6 deficient mice display cartilage thickening and CONs at 12 weeks in both the elbow and knee joints, which is independent of TGF α ligand presence. Similarly, articular cartilage cell density is increased in Mig-6 fl/fl Col2a1-Cre +/- Tgfa -/- and Mig-6 fl/fl Col2al-Cre +/- mice, but not Tgfa -/- mice, and displays increased SOX9 and phospho-EGFR staining. Conclusion The articular cartilage displays increased thickness, increased cell density, and CON formation independent of the presence of TGF α , suggesting the anabolic phenotype in the Mig6-deficient mice is independent of TGF α /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.