The goal of this project is to define how ion channels regulate osteoblast function. The hypothesis to be tested is that ion channels regulate osteoblast function and therefore bone remodeling. The mechanism by which 1,25-dihydroxyvitamin D3 and vitamin D3 metabolites affect channel activity and osteocalcin release will be investigated.
In Specific Aim #1, studies will attempt to define the mechanism of action of 1,25(OH)2D and vitamin D3 metabolites on voltage-gated calcium channels in osteoblast cells. The investigator will determine whether the effects of 1,25(OH)2D3 require binding to its cytosolic receptor and whether protein synthesis is involved in this regard. The role of second messengers, such as calcium and protein kinase C, in controlling of the activity of voltage-gated calcium channels will be explored. Furthermore, efforts will be made to elucidate whether there is direct activation of the channel by binding to the channel itself or whether this effect is mediated through G proteins. Experiments will determine whether vitamin D3 metabolites alter osteocalcin release by modulating calcium-mediated events.
In Specific Aim #2, the applicant will determine how calcium influx through voltage-dependent calcium channels controls osteocalcin release. The modulation of potassium conductances will be investigated and the control of potassium channels by signals which regulate osteocalcin release will be explored. The intent is to define how potassium channels in ROS cells are modulated by signals which affect osteocalcin release, including calcium, cAMP or protein kinase C. The applicant will also determine whether vitamin D3, estradiol, progesterone, or glucocorticoids modulate potassium conductances. Finally, the regulation of osteocalcin release by potassium depolarization will be determined.
|Li, Fangping; Wang, Wenwei; Gu, Ming et al. (2011) L-type calcium channel activity in osteoblast cells is regulated by the actin cytoskeleton independent of protein trafficking. J Bone Miner Metab 29:515-25|
|Silva, Ian V; Cebotaru, Valeriu; Wang, Hua et al. (2003) The ClC-5 knockout mouse model of Dent's disease has renal hypercalciuria and increased bone turnover. J Bone Miner Res 18:615-23|
|Zhao, Pei-Lin; Wang, Xi-Tao; Zhang, Xue-Mei et al. (2002) Tubular and cellular localization of the cardiac L-type calcium channel in rat kidney. Kidney Int 61:1393-406|
|Kadiyala, S; Nagaba, S; Takeuchi, K et al. (2001) Metabolites and analogs of 1alpha,25-dihydroxyvitamin D(3): evaluation of actions in bone. Steroids 66:347-55|
|Silva, I V; Blaisdell, C J; Guggino, S E et al. (2000) PTH regulates expression of ClC-5 chloride channel in the kidney. Am J Physiol Renal Physiol 278:F238-45|
|Wang, S S; Devuyst, O; Courtoy, P J et al. (2000) Mice lacking renal chloride channel, CLC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. Hum Mol Genet 9:2937-45|
|Lajeunesse, D; Delalandre, A; Guggino, S E (2000) Thiazide diuretics affect osteocalcin production in human osteoblasts at the transcription level without affecting vitamin D3 receptors. J Bone Miner Res 15:894-901|
|Wang, X T; Nagaba, S; Nagaba, Y et al. (2000) Cardiac L-type calcium channel alpha 1-subunit is increased by cyclic adenosine monophosphate: messenger RNA and protein expression in intact bone. J Bone Miner Res 15:1275-85|
|Wang, X T; Nagaba, Y; Cross, H S et al. (2000) The mRNA of L-type calcium channel elevated in colon cancer: protein distribution in normal and cancerous colon. Am J Pathol 157:1549-62|
|Lajeunesse, D; Moreau, R; Hobbs, W et al. (1998) Influence of aluminum on the regulation of PTH- and 1,25(OH)2D3-dependent pathways in the rat osteosarcoma cell line ROS 17/2.8. J Bone Miner Res 13:962-9|
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