Overexpression of MIG-6 in the cartilage induces an osteoarthritis-like phenotype in mice

• Published in: Arthritis research & therapy Vol. 22; no. 1; pp. 119 - 13
• Main Authors: Bellini, Melina, Pest, Michael A, Miranda-Rodrigues, Manuela, Qin, Ling, Jeong, Jae-Wook, Beier, Frank
• Format: Journal Article
• Language: English
• Published: England BioMed Central 19-05-2020; BMC
• Subjects: Animals; Articular cartilage; Cartilage, Articular - diagnostic imaging; Chondrocytes; Epidermal growth factor receptor; Male; Mice; Mice, Knockout; Mitogen inducible gene-6; Osteoarthritis; Osteoarthritis - genetics; Phenotype; Mitogen inducible gene-6; Articular cartilage; Osteoarthritis; Epidermal growth factor receptor
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-020-02213-z

Osteoarthritis (OA) is the most common form of arthritis and characterized by degeneration of the articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a negative regulator of the epidermal growth factor receptor (EGFR). Cartilage-specific Mig-6 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of the articular cartilage, and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network in the cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of Mig-6 in this study.
Utilizing knee joints from cartilage-specific Mig-6-overexpressing (Mig-6
) mice (at multiple time points), we evaluated the articular cartilage using histology, immunohistochemical staining, and semi-quantitative histopathological scoring (OARSI) at multiple ages. MicroCT analysis was employed to examine skeletal morphometry, body composition, and bone mineral density.
Our data show that cartilage-specific Mig-6 overexpression did not cause any major developmental abnormalities in the articular cartilage, although Mig-6
mice have slightly shorter long bones compared to the control group. Moreover, there was no significant difference in bone mineral density and body composition in any of the groups. However, our results indicate that Mig-6
male mice show accelerated cartilage degeneration at 12 and 18 months of age. Immunohistochemistry for SOX9 demonstrated that the number of positively stained cells in Mig-6
mice was decreased relative to controls. Immunostaining for MMP13 appeared increased in areas of cartilage degeneration in Mig-6
mice. Moreover, staining for phospho-EGFR (Tyr-1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6
mice.
Overexpression of Mig-6 in the articular cartilage causes no major developmental phenotype; however, these mice develop earlier OA during aging. These data demonstrate that Mig-6/EGFR pathways are critical for joint homeostasis and might present a promising therapeutic target for OA.