Overexpression Of Mig-6 In Cartilage Induces An Osteoarthritis-like Phenotype In Mice CURRENT STATUS: REVIEW

Background: Osteoarthritis (OA) is the most common form of arthritis and characterized by degeneration of 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 articular cartilage and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network in cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of Mig-6 in this study. Methods : Utilizing knee joints from cartilage-specific Mig-6 overexpressing ( Mig- 6over/over ) mice (at multiple time points), we evaluated the articular cartilage using histology, immunohistochemical staining and semi-quantitative OARSI scoring at multiple ages. MicroCT analysis was employed to examine skeletal morphometry, body composition, and bone mineral density. Results: Our data show that cartilage-specific Mig-6 overexpression did not cause any major developmental abnormalities in articular cartilage, although Mig-6 over/over 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 over/over 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 over/over mice decreased relative to controls. Immunostaining for MMP13 staining is increased in areas of cartilage degeneration in Mig-6 over/over mice. Moreover, staining for phospho-EGFR (Tyr-1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6 over/over mice. Conclusion: Overexpression of Mig-6 in articular cartilage causes no major developmental phenotype; however these mice develop earlier OA during aging. These data demonstrate that Mig-6/EGFR Previous research demonstrates that Mig-6 overexpression acts as a regulator of EGFR-ERK signalling (41), however these studies did not yet analyze joint tissues. Since our studies suggest dosage- and/or context-specific roles of EGFR signaling in joint homeostasis and OA (34), we now examined whether overexpression of Mig-6 alters these processes. Here, we report that cartilage-specific constitutive overexpression of Mig-6 did not cause cartilage degeneration in young mice, but early onset OA in middle aged mice. While we observed some effects of Mig-6 overexpression on bone length and weight, these effects were subtle and not accompanied by major morphological or histological changes in growth plate cartilage, overall skeletal morphology, or body composition. A previous study showed that deletion of EGFR in bone tissue (Col1-Cre EgfrWa5/f ) resulted in shorter femurs compared to wild-type mice (64), consistent with our findings. The EGFR network is essential during long bone development, since previous studies have shown that EGFR- or TGFα-deficient mice exhibit a widened zone of hypertrophic chondrocytes (23,65). Moreover, Qin and colleagues have shown that administration of the EGFR inhibitor, gefitinib, into 1-monht-old rats results in an enlarged hypertrophic zone due down-regulation of MMP-9,-13 and − 14 (30). Together these data suggest a critical role of EGFR during endochondral ossification and elucidate downstream mechanism of EGFR (66). Further research is required to provide more evidence of EGFR/Mig-6over/over signalling during bone formation, but many of these effects are relatively subtle and transient, and likely unrelated to the much more severe phenotypes observed later. Histologically, our findings showed that mice with cartilage-specific Mig-6 overexpression showed healthy articular cartilage with no significant difference in articular cartilage thickness from control group at the ages of 6 weeks and 11 weeks. However, Mig-6over/over mice developed severe degeneration