Disturbed Cartilage and Joint Homeostasis Resulting From a Loss of Mitogen‐Inducible Gene 6 in a Mouse Model of Joint Dysfunction

Abstract

Objective Mitogen-inducible gene 6 (MIG-6) regulates epidermal growth factor receptor (EGFR) signaling in synovial joint tissues. Whole-body knockout of the Mig6 gene in mice has been shown to induce osteoarthritis and joint degeneration. To evaluate the role of chondrocytes in this process, Mig6 was conditionally deleted from Col2a1-expressing cell types in the cartilage of mice. Methods Bone and cartilage in the synovial joints of cartilage-specific Mig6-deleted (knockout [KO]) mice and control littermates were compared. Histologic staining and immunohistochemical analyses were used to evaluate joint pathology as well as the expression of key extracellular matrix and regulatory proteins. Calcified tissue in synovial joints was assessed by micro–computed tomography (micro-CT) and whole-skeleton staining. Results Formation of long bones was found to be normal in KO animals. Cartilage thickness and proteoglycan staining of articular cartilage in the knee joints of 12-week-old KO mice were increased as compared to controls, with higher cellularity throughout the tissue. Radiopaque chondro-osseous nodules appeared in the knees of KO animals by 12 weeks of age and progressed to calcified bone–like tissue by 36 weeks of age. Nodules were also observed in the spine of 36-week-old animals. Erosion of bone at ligament entheses was evident by 12 weeks of age, by both histologic and micro-CT assessment. Conclusion MIG-6 expression in chondrocytes is important for the maintenance of cartilage and joint homeostasis. Dysregulation of EGFR signaling in chondrocytes results in anabolic activity in cartilage, but erosion of ligament entheses and the formation of ectopic chondro-osseous nodules severely disturb joint physiology.

EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation

“…Previous studies of EGFR signaling in articular cartilage development and degeneration focused on an indirect approach analyzing mice lacking Mig-6, an EGFR inhibitor (9)(10)(11)(12). Because Mig-6 is not specific to EGFR, those results are too complicated to clearly interpret EGFR function.…”

“…Mig-6 null mice develop a severe OA-like joint degeneration phenotype at an early adult stage (9). However, mice with limb-(Prx1-Cre) or cartilage-(Col2-Cre) specific deletion of Mig-6 showed a much milder OA phenotype (10)(11)(12). Indeed, a…”

Reduction in Disease Progression by Inhibition of Transforming Growth Factor α–CCL2 Signaling in Experimental Posttraumatic Osteoarthritis

“…In the developmental context, EGFR activity stimulates increased cartilage thickness and chondrocyte proliferation (38). Indeed, we have reported increased chondrocyte proliferation in articular cartilage treated with exogenous TGFa (9), and cartilage-specific knockout of Mig-6 also leads to excessive articular chondrocyte proliferation (39,40). Thus, moderate suppression of EGFR activity likely abolishes protective anabolic effects in early OA development (e.g., in the DMM OA model), whereas excessive EGFR activity in later OA stages (represented in our more aggressive rat posttraumatic OA model) is deleterious.…”

Novel Insights into Osteoarthritis Joint Pathology from Studies in Mice

“…The first study to implicate Mig-6 in OA described OA-like pathology with cartilage degeneration, osteophyte formation, and subchondral cysts in mice harboring global Mig-6 deletion [70]. Further studies aimed to elucidate the tissue-specific role of Mig-6 within the joint and identified similar joint pathologies, in addition to aberrant proliferative activity in both the cartilage and joint periphery [71][72][73][74]. These data indicate a much more complex role of Mig-6, and possibly EGFR signaling, in joint homeostasis.…”