EGFR signaling in growth plate development

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DESCRIPTION (provided by applicant): Growth plate development is critical for longitudinal bone growth. This process, including chondrocyte proliferation, maturation and hypertrophy, mineralization, matrix remodeling and transition from cartilage to bone, is tightly controlled by circulating systemic hormones and locally produced growth factors. However, the regulatory mechanisms have not been fully elucidated. Previous studies noticed that altering epidermal growth factor receptor (EGFR) activity resulted in abnormal growth plate structures but the detailed molecular mechanisms have not been studied yet. We recently found that young growing rats treated with EGFR-specific inhibitors developed profound defects in growth plate cartilage characterized by epiphyseal growth plate thickening and massive accumulation of hypertrophic chondrocytes. Further studies demonstrate that EGFR inhibitors suppressed the expression of matrix metalloproteinases (MMP9 and 13), increased the amount of collagen fibrils, and decreased cartilage ECM degradation in the growth plate. Consistently, TGF¿, an EGFR ligand, strongly stimulated the expression of MMP9 and 13 in primary chondrocytes. Hence, we hypothesize that EGFR signaling regulates ECM degradation and replacement of hypertrophic cartilage with bone by promoting MMP expression in the growth plate. We propose the following aims to test this hypothesis: 1) determine whether chondrogenic EGFR signaling is required for cartilage degradation and growth plate development~ 2) investigate the molecular mechanisms by which EGFR signaling stimulates chondrogenic expression of MMP9 and 13. In particular, we will utilize a pharmacological rat model, a chondrocyte-specific EGFR knockout mouse model, and primary chondrocyte cultures to examine the growth plate phenotypes and analyze the underlying mechanisms. Our long-term goal is to study the role of EGFR signaling in cartilage function. Findings from this project will suggest EGFR signaling as a novel pathway regulating endochondral ossification and a potential pharmaceutical target for skeletal disorders that have abnormal cartilage degradation, including childhood growth plate disorders and osteoarthritis. In addition, as a new investigator, I will be greatly benefited from this award by generating preliminary data to be used for competing future research supports. PUBLIC HEALTH RELEVANCE: Growth plate development is essential in formation and growth of the skeleton and this process is tightly controlled by growth factors. This proposal wil investigate the role of a novel growth factor signaling in regulating growth plate development and successfully accomplishing it will achieve a better management of diseases associated with growth defects, such as chondrodysplasia, retarded growth and reduced final height, fracture healing, and degenerative cartilage diseases, such as osteoarthritis.