Parathyroid and other cell types sense extracellular calcium (Ca2+o) through a recently cloned, G-protein-coupled Ca2+o -sensing receptor (CaR). In parathyroid (PT) and calcitonin (CT)-secreting C cells, the CaR regulates hormone secretion, while in the kidney it regulates Ca2+ and magnesium reabsorption, thereby contributing to systemic mineral ion homeostasis. Preliminary studies indicate that osteoblastic (OB) cells also express the CaR, raising the possibility that the receptor also regulates systemic mineral ion homeostasis through direct actions on bone cells. The overall goal of this proposal is to test further the hypothesis that the CaR is a key regulator of Obs and their precursors, affecting them in ways that contribute to skeletal and overall mineral ion homeostasis.
The Specific Aims are fourfold: 1) To determine which OB cells express the CaR (i.e. CaR mRNA and protein), 2) To determine which signaling pathways mediate CaR signaling in OB (e.g. phospholipase C), 3) To examine the function of the CR in OB (e.g. Chemotaxis, proliferation, differentiation), and 4) To verify that Ca2+ modulates OB function via the PTCaR (e.g. by comparing the effects of CaR agonists on primary OB isolated from wild-type and CaR knock-out mice). These studies will provide potentially important insights into the role of the CaR in normal skeletal homeostasis and in the deranged bone turnover present in debilitating and mostly skeletal diseases such as osteoporosis. Moreover, these studies will provide an initial indication of the feasibility of CaR-based therapeutics as a means of preventing and/or treating metabolic bone disease.
| Sanders, J L; Chattopadhyay, N; Kifor, O et al. (2001) Ca(2+)-sensing receptor expression and PTHrP secretion in PC-3 human prostate cancer cells. Am J Physiol Endocrinol Metab 281:E1267-74 |
| Sanders, J L; Chattopadhyay, N; Kifor, O et al. (2000) Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human breast cancer cell lines. Endocrinology 141:4357-64 |
| Sanders, J L; Chattopadhyay, N; Kifor, O et al. (2000) Extracellular calcium-sensing receptor (CaR) expression and its potential role in parathyroid hormone-related peptide (PTHrP) secretion in the H-500 rat Leydig cell model of humoral hypercalcemia of malignancy. Biochem Biophys Res Commun 269:427-32 |
