Mineralization: Integrins and Focal Adhesion Kinase

University Of Iowa, Iowa City IA

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Abstract

Osteogenesis involves the recruitment of multi-potential mesenchymal stem cells and the progressive differentiation of these cells into osteoblasts. Osteoblast differentiation and skeletal formation during embryonic development is mediated by an essential transcription factor protein core binding core binding factor-alpha1 (cbfa1). Integrin receptors are widely expressed and bind extracellular matrix proteins. They also regulate intracellular signaling pathways that contribute to the development of cranial-facial structures, wound healing, cell motility, cell growth and differentiation, and apoptosis. Signaling pathways and proteins mediated by integrins, such as the focal adhesion tyrosine kinase FAK, can regulate cell growth and differentiation, as well as cell fate. Yet the role of integrin receptor mediation of osteoblast differentiation and subsequent mineralization is not fully understood. Adhesion- mediated signaling transduced through osteoblast-extracellular matrix interactions during osteogenesis may represent essential pathways for processing environmental cues necessary for gene expression, as well as bone formation and remodeling during osteoblast differentiation. The goal of this proposal is to determine if the integrin associated protein tyrosine kinase FAK mediates osteogenic gene expression (Cbfa1, BSP, Collagen type I), and subsequent mineralization. We hypothesize that blocking the interaction of various osteoblast integrin receptors with their underlying extracellular matrix with specific antibodies will affect gene expression and minerization. We also predict that over-expressing the integrin associated protein tyrosine kinase FAK in a non- mineralizing. We also predict that over-expressing the integrin associated protein tyrosine kinase FAK in a non-mineralizing OB clones will lead to mineralization. We will use histological, biochemical, and molecular approaches to perform these studies. Data acquired from these studies will allow us to better understand how osteoblast differentiation and osteogenesis are mediated through integrin receptors and associated signaling proteins such as FAK. This will allow for development of new therapeutic approaches that in turn could lead to novel treatments and tissue-engineered biological applications to increase the quality of life for many patients.