The proper growth of the cranial base is essential for normal craniofacial development. Similar to long bones in the limbs, the cranial base is formed through endochondral ossification. The cranial base grows at the synchondrosis, a growth-plate-like cartilage that connects bones. Activating mutations in FGFR3 cause the most common forms of human dwarfisms, achondroplasia and thanatophoric dysplasias. The increased activity of FGFR3 causes hypoplasia of the cranial base, which results in malocclusion requiring orthodontic procedures and narrow foramen magnum that could cause sudden death of infants. Intracellular signaling pathways that mediate the actions of FGFR3 are of keen interest. Our recent genetic experiments have strongly suggested that the ERK1/ERK2 MARK pathway in chondrocytes controls growth and closure of the cranial base synchondroses. We hypothesize that ERK1 and ERK2 in chondrocytes coordinate chondrocyte differentiation and bone formation in the cranial base and long bones. We will examine the precise roles of ERK1 and ERK2 in chondrocytes by pursuing the following Specific Aims: 1) We will inactivate ERK2 in chondrocytes using the Cre-loxP system. We will further inactivate ERK2 in chondrocytes of ERK1-null mice to totally inactivate MARK in chondrocytes. These experiments will greatly advance our knowledge about the roles of ERK1 and ERK2 in endochondral ossification. The elucidation of the mechanisms of endochondral bone growth will eventually lead to the development of new therapies to control bone growth in the cranial base and long bones in various skeletal disorders. Relevance to public health: This study aims to identify the roles of ERK1 and ERK2 in the bone growth using genetically engineered mouse models. This study will provide insights that could be used to control growth of bones that are formed from cartilage. ? ? ?
