Epidermal Growth Factor Receptor in Joint Health and Osteoarthritis

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases in the world. Our laboratory has shown that epidermal growth factor receptor (EGFR) signalling is involved in the process of cartilage degeneration in OA. Regulation of EGFR signalling by mitogen-inducible gene 6 (Mig-6) and dual specificity phosphatase 1 (DUSP-1) allows for signal modulation, and mouse models have linked these proteins to joint pathologies. Failure to control EGFR signalling may be involved in OA progression leading to my overarching hypothesis: regulation of EGFR signalling is essential for maintenance of joint health. I initially tested the role of Mig-6 in cartilage health using cartilage-specific deletion of Mig-6 in a mouse model. Using various histological and imaging techniques, we demonstrated that these animals show increased anabolic activity in articular cartilage, as well as the formation of chondro-osseous nodules in their knee joints within the first 3 months. These mice did not develop severe OA as I predicted, however, there were early signs of developing articular cartilage pathology. To assess the role of Mig-6 in elderly cartilage, we employed the same mouse model but aged these animals to 21 months, near the end of their life span. These KO animals exhibited similar knee phenotypes, however, no abnormal growths were observed in the ankle and elbow joints which showed enhanced cartilage thickness. Only minor signs of OA were noted. Using an inducible system to delete Mig-6 from cartilage of 3 week old mice, we found limited evidence of increased anabolic activity at 12 weeks. These studies demonstrate that Mig-6 may be playing an important role during development and that loss of Mig-6 may positively impact cartilage health. Finally, I examined the knee joints of whole body Dusp1 null mice at 21 months of age for signs of OA. Both Dusp1 null and control mice showed similar signs of OA, indicating that DUSP-1 mediated regulation of signalling downstream of EGFR is not essential to prevent spontaneous OA progression. Taken together, these data demonstrate that EGFR signalling regulated by both Mig-6 and DUSP-1 is important in joint homeostasis, and has revealed a potential target in Mig-6 for future cartilage regenerative treatments

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

© 2020 The Author(s). Background: 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. Methods: Utilizing knee joints from cartilage-specific Mig-6-overexpressing (Mig-6 over/over ) 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. Results: Our data show that cartilage-specific Mig-6 overexpression did not cause any major developmental abnormalities in the 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 was decreased relative to controls. Immunostaining for MMP13 appeared 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 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

Atoh1 \u3csup\u3e+\u3c/sup\u3e secretory progenitors possess renewal capacity independent of Lgr5 \u3csup\u3e+\u3c/sup\u3e cells during colonic regeneration

During homeostasis, the colonic epithelium is replenished every 3–5 days by rapidly cycling Lgr5 + stem cells. However, various insults can lead to depletion of Lgr5 + stem cells, and colonic epithelium can be regenerated from Lgr5-negative cells. While studies in the small intestine have addressed the lineage identity of the Lgr5-negative regenerative cell population, in the colon this question has remained unanswered. Here, we set out to identify which cell(s) contribute to colonic regeneration by performing genetic fate-mapping studies of progenitor populations in mice. First, using keratin-19 (Krt19) to mark a heterogeneous population of cells, we found that Lgr5-negative cells can regenerate colonic crypts and give rise to Lgr5 + stem cells. Notch1 + absorptive progenitor cells did not contribute to epithelial repair after injury, whereas Atoh1 + secretory progenitors did contribute to this process. Additionally, while colonic Atoh1 + cells contributed minimally to other lineages during homeostasis, they displayed plasticity and contributed to epithelial repair during injury, independent of Lgr5 + cells. Our findings suggest that promotion of secretory progenitor plasticity could enable gut healing in colitis

Evaluation of Force 2.25CS to control corn rootworm larvae (Diabrotica spp.) in Illinois, 2008

Annual summary of field crop insect management trials, Department of Crop Services, University of Illinois. Providing accurate and unbiased evaluations of insect control products and management strategies to assist growers in Illinois.University of Illinois Extension and Department of Crop Science

Evaluation of a seed-blend (Pioneer Optimum AcreMax) to control corn rootworm larvae (Diabrotica spp.) in Illinois, 2008

Annual summary of field crop insect management trials, Department of Crop Services, University of Illinois. Providing accurate and unbiased evaluations of insect control products and management strategies to assist growers in Illinois.University of Illinois Extension and Department of Crop Science

On Target: 2007 Annual Summary of Field Crop Insect Management Trials

Since its inception in 1984, the University of Illinois Insect Management and Insecticide Evaluation Program has provided the producers of Illinois complete and informative evaluations of registered insecticides and new chemical and transgenic tools for the management of insect pests in Illinois. It is our intention to provide scientifically sound efficacy data to aid the producers of Illinois in their insect pest management decision making.University of Illinois Extension and Department of Crop Science

Evaluation of transgenic hybrids and insecticidal seed treatments for control of black cutworm larvae (Agrotis ipsilon) in Illinois, 2008

Annual summary of field crop insect management trials, Department of Crop Services, University of Illinois. Providing accurate and unbiased evaluations of insect control products and management strategies to assist growers in Illinois.University of Illinois Extension and Department of Crop Science

Evaluation of products to control corn rootworm larvae (Diabrotica spp.) in Illinois, 2008

Annual summary of field crop insect management trials, Department of Crop Services, University of Illinois. Providing accurate and unbiased evaluations of insect control products and management strategies to assist growers in Illinois.University of Illinois Extension and Department of Crop Science

Comparison of experimental and commercially available granular insecticides to control corn rootworm larvae (Diabrotica spp.) in Illinois, 2008

Annual summary of field crop insect management trials, Department of Crop Services, University of Illinois. Providing accurate and unbiased evaluations of insect control products and management strategies to assist growers in Illinois.University of Illinois Extension and Department of Crop Science

Evaluation of foliar- and seed-applied insecticides to control soybean aphids (Aphis glycines) in Illinois, 2008

Annual summary of field crop insect management trials, Department of Crop Services, University of Illinois. Providing accurate and unbiased evaluations of insect control products and management strategies to assist growers in Illinois.University of Illinois Extension and Department of Crop Science