Insulin-like growth factor-I (IGF-I), a conserved 70-residue secreted protein, plays a fundamental role in somatic growth in mammals and other vertebrate species. Although much evidence has accumulated supporting IGF-I as a major postnatal growth factor, regulated at least in part by growth hormone, many studies have suggested a broader range of functions for this peptide, including actions on local tissue growth, maintenance, and repair throughout the life span. These observations in turn imply that control of IGF-I synthesis may be multi-factorial, responding not only to systemic hormonal signals but also to tissue-specific factors. IGF-I is produced by many cells including osteoblasts, and can act as a growth and differentiation factor within the skeleton as well as in other tissues. Recent studies implicating IGF-I as a key component of the anabolic effects of parathyroid hormone (PTH) on bone and establishing a role for PTH in increasing bone mass and preventing osteoporosis only underscore the importance of IGF-I in maintaining skeletal integrity. Since osteoporosis is a disorder of remodeling in which bone resorption outstrips formation, any insights into pathways that enhance bone mass have potential therapeutic implications. As part of a long-term effort to understand the mechanisms by which IGF-I synthesis is controUed under different physiological conditions, the focus of this application will be on regulation of IGF-I gene transcription in bone cells. Key goals will be to define the signal transduction pathways and molecular mechanisms by which PTH through cyclic AMP and protein kinase A controls IGF-I expression via the transcription factor, C/EBPdelta. Toward this end the following four Specific Aims are proposed:1. To determine how PKA activates C/EBPdelta and stimulates its nuclear expression in osteoblasts.2. To establish how PKA promotes the transcriptional activity of C/EBPdelta in bone cells.3. To define mechanisms of termination of hormone-activated IGF-I transcription and down regulation of C/EBPdelta activity in osteoblasts.4. To evaluate by gene profiling the role of C/EBPdelta in osteoblast biology.
