Accelerated and increased joint damage in young mice with global inactivation of mitogen-inducible gene 6 after ligament and meniscus injury

Abstract

IntroductionLigament and meniscal damage can cause joint disease. Arthritic joints contain increased amounts of epidermal growth factor receptor (EGFR) protein, and polymorphisms in EGFR are associated with arthritis risk. The role of endogenous EGFR regulation during joint disease due to ligament and meniscal trauma is unknown. Mitogen-inducible gene 6 (MIG-6) can reduce EGFR phosphorylation and downstream signaling. We examined the effect of EGFR modulation by MIG-6 on joint disease development after ligament and meniscus injury.MethodsKnee ligament transection and meniscus removal were performed surgically on mice homozygous for a global inactivating mutation in MIG-6 (Mig-6−/−) and in wild-type (WT) animals.ResultsTwo weeks after surgery, Mig-6−/−mice had bone erosion as well as greater fibrous tissue area and serum RANKL concentration than WT mice. Four weeks after surgery, Mig-6−/−mice had less cartilage and increased cell proliferation relative to contralateral control and WT knees. Increased apoptotic cells and growth outside the articulating region occurred in Mig-6−/−mice. Tibia trabecular bone mineral density (BMD) and the number of trabeculae were lower in surgically treated knees relative to the respective control knees for both groups. BMD, as well as trabecular thickness and number, were lower in surgically treated knees from Mig-6−/−mice relative to WT surgically treated knees. Phosphorylated EGFR staining in surgically treated knees decreased for WT mice and increased for Mig-6−/−mice. Fewer inflammatory cells were present in the knees of WT mice.ConclusionMig-6−/−mice have rapid and increased joint damage after ligament and meniscal trauma. Mig-6 modification could lessen degenerative disease development after this type of injury.

RNA-binding protein SAMD4 regulates skeleton development through translational inhibition of Mig6 expression

“…RNA sequencing analysis revealed that 33 genes were enriched in anti-Flag samples compared with anti-IgG samples (Supplementary Table S2). Among those targets, we found that two genes, Mig6 [35, 36] and Tnfrsf12a [40, 41], had been reported to be involved in the regulation of bone development (Figure 5b and Supplementary Table S2). …”

“…Given that Samd4-deficient mice exhibited osteopenic phenotype and that Mig6-deficient mice displayed a subchondral bone phenotype [35, 36], we hypothesized that SAMD4 may regulate Mig6 by binding and inhibiting the translation of Mig6 mRNA. Indeed, upregulating the expression of SAMD4 resulted in a decrease in MIG6 protein level (Figure 5c).…”

“…Cartilage-specific deletion of Mig6 was shown to result in osteoarthritis-like disorder with excessive articular chondrocyte [35, 36]. The repression of MIG6 expression by SAMD4 implied that SAMD4 have effects on chondrocyte.…”

“…MIG6 is a non-kinase scaffolding adaptor [33, 34] that is highly expressed in both chondrocytes and osteoblasts [35]. Furthermore, Mig6 deficiency in mice lead to excessive articular chondrocyte proliferation following an osteoarthritis-like disorder [35, 36]. The higher MIG6 protein level in Samd4 PB/PB mice resulted in impaired skeletogenesis.…”

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.…”