Metabolic acidosis, present during many clinical disorders, has significant effects on bone. The proposed studies are designed to test hypotheses relating to the effects of increases in proton concentration ([H+]), acidosis, on the ionic composition of bone mineral and on bone cell function. We propose to study how acidosis affects mass spectroscopy and to study how acidosis alters signal transduction pathways and bone cell expression. With the microprobe we obtain sensitive, mass resolved images and spectra of the ionic composition of bone mineral. We propose three Specific Aims: 1) To test the hypothesis that there are specific changes in bone ion composition with respect to time and location after exposure to acidosis. To pursue this aim we will test the hypothesis that in vivo acidosis initially causes a preferential loss of mid-cortical bicarbonate, Na and K due to physicochemical dissolution, with subsequent additional loss of phosphate due to cell-mediated resorption. We will test the hypothesis that the magnitude of H+ buffering by bone increases with age as the carbonate content increase and the phosphate content decreases and that there are labile pools of Ca and K preferentially released during in vivo acidosis. We will test the hypothesis that mice deficient in osteopontin (OP), matrix gla protein (MGP) or c-src have altered basal bone ion composition and an altered osseous response (Jca and JH) to acidosis. 2) To test the hypothesis that the mechanism of acid-induced cell-mediated bone resorption involves activation of signal transduction pathways such as protein kinase A (PKA), protein kinase C (PKC) and/or mitogen-activated protein kinase (MAPK) by using specific inhibitors of PKA and PKC and measurements of PKA, PKC and MAPK during acidosis. 3) To test the hypothesis that metabolic acidosis selectively inhibits osteoblastic extracellular matrix gene expression via distinct transcriptional mechanisms, by testing acidosis effects on OP and MGP RNA transcription initiation. We will identify sequences in the mouse OP and MGP genes which are capable of conferring pH dependence to a reporter gene.
These Specific Aims are interrelated as the effects of acidosis at the level of the gene lead to alterations in bone cell function which subsequently alter bone mineral. Our long term goal is to develop a model to describe how acidosis affects bone in order to devise therapy to preserve mineral while maintaining the H+ buffering properties of bone.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Sharrock, William J
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University of Rochester
Internal Medicine/Medicine
Schools of Dentistry
United States
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Krieger, Nancy S; Yao, Zhenqiang; Kyker-Snowman, Kelly et al. (2016) Increased bone density in mice lacking the proton receptor OGR1. Kidney Int 89:565-73
Krieger, Nancy S; Bushinsky, David A (2013) The relation between bone and stone formation. Calcif Tissue Int 93:374-81
Krieger, Nancy S; Culbertson, Christopher D; Kyker-Snowman, Kelly et al. (2012) Metabolic acidosis increases fibroblast growth factor 23 in neonatal mouse bone. Am J Physiol Renal Physiol 303:F431-6
Bushinsky, David A (2012) Clinical application of calcium modeling in patients with chronic kidney disease. Nephrol Dial Transplant 27:10-3
Krieger, Nancy S; Bushinsky, David A (2011) Pharmacological inhibition of intracellular calcium release blocks acid-induced bone resorption. Am J Physiol Renal Physiol 300:F91-7
Bushinsky, David A; Willett, Thomas; Asplin, John R et al. (2011) Chlorthalidone improves vertebral bone quality in genetic hypercalciuric stone-forming rats. J Bone Miner Res 26:1904-12
Monk, Rebeca D; Bushinsky, David A (2011) Making sense of the latest advice on vitamin D therapy. J Am Soc Nephrol 22:994-8
Frick, Kevin K; Bushinsky, David A (2010) Effect of metabolic and respiratory acidosis on intracellular calcium in osteoblasts. Am J Physiol Renal Physiol 299:F418-25
Bushinsky, David A (2010) Contribution of intestine, bone, kidney, and dialysis to extracellular fluid calcium content. Clin J Am Soc Nephrol 5 Suppl 1:S12-22
Asplin, John R; Donahue, Susan E; Lindeman, Christina et al. (2009) Thiosulfate reduces calcium phosphate nephrolithiasis. J Am Soc Nephrol 20:1246-53

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