The studies in this proposal are designed to analyze the role of the integrin, alpha(v)beta(3), in the organization of the osteoclasts associated with bone resorption. This integrin on the osteoclast cell membrane recognizes specific protein ligands in the bone matrix. Its binding to these ligands promotes osteoclast adhesion and is associated with the organization of the cell into specific regions necessary for the resorptive process, the clear zone and the ruffled membrane. We will analyze the pathways leading to osteoclast organization stimulated by matrix protein occupancy of the integrin. We will also analyze the synthesis of the integrin during hormone, 1,25(OH)(2)D(3), stimulated differentiation of osteoclast precursors. We hypothesize that the stimulatory effects of 1,25(OH)(2)D(3) on transcription of the integrin, alpha(v)beta(3), are opposed by a second steroid hormone, estrogen. The studies will test two hypotheses. First, we propose that integrin based cell signalling participates in the organization of the cell necessary for bone resorption, and that determination of the nature of these signals will provide tools with which osteoclast function can be controlled. Secondly, we propose that estrogens control osteoclast function, in part through their regulatory effects on expression of the integrin, alpha(v)beta(3).
The specific aims of the application are: 1) to determine the mechanisms of signal transduction stimulated by ligand binding to the osteoclast integrin, alpha(v)beta(3), and 2) to determine the mechanisms by which estrogens regulate expression of the integrin. Studies will be performed using pure preparation of osteoclast precursors generated from cultures of marrow mononuclear cells. The analysis of the effects of matrix protein binding to alpha(v)beta(3) on osteoclast [Ca+2](i) will be used as a framework from which the signals generated by integrin occupancy by ligands can be detected. Identification of these signals will then be used to formulate strategies demonstrating the role of individual signals in the organization of the osteoclast necessary for bone resorption. We will clone the promoter region of the alpha(v)beta(3) gene and analyze transcriptional regulation of the gene by steroid hormones. Successful completion of these studies should provide us major insights into the control of osteoclast function necessary to manipulate bone resorption in diseases such as osteoporosis and renal osteodystrophy.
| Hruska, Keith A; Mathew, Suresh (2011) The roles of the skeleton and phosphorus in the CKD mineral bone disorder. Adv Chronic Kidney Dis 18:98-104 |
| Hruska, Keith A; Choi, Eric T; Memon, Imran et al. (2010) Cardiovascular risk in chronic kidney disease (CKD): the CKD-mineral bone disorder (CKD-MBD). Pediatr Nephrol 25:769-78 |
| Hruska, Keith A (2009) Vascular smooth muscle cells in the pathogenesis of vascular calcification. Circ Res 104:710-1 |
| Sugatani, Toshifumi; Hruska, Keith A (2009) Impaired micro-RNA pathways diminish osteoclast differentiation and function. J Biol Chem 284:4667-78 |
| Hruska, Keith A; Mathew, Suresh; Lund, Richard J et al. (2009) The pathogenesis of vascular calcification in the chronic kidney disease mineral bone disorder: the links between bone and the vasculature. Semin Nephrol 29:156-65 |
| Mathew, Suresh; Lund, Richard J; Chaudhary, Lala R et al. (2008) Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol 19:1509-19 |
| Hruska, Keith A; Mathew, Suresh; Lund, Richard et al. (2008) Hyperphosphatemia of chronic kidney disease. Kidney Int 74:148-57 |
| Mathew, Suresh; Tustison, Kimberly S; Sugatani, Toshifumi et al. (2008) The mechanism of phosphorus as a cardiovascular risk factor in CKD. J Am Soc Nephrol 19:1092-105 |
| Hruska, Keith A; Saab, Georges; Mathew, Suresh et al. (2007) Renal osteodystrophy, phosphate homeostasis, and vascular calcification. Semin Dial 20:309-15 |
| Sugatani, T; Hruska, K A (2007) MicroRNA-223 is a key factor in osteoclast differentiation. J Cell Biochem 101:996-9 |
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