David A. Bushinsky DHHS/PHS/NIH 5 R01 AR046289 Bushinsky PI Effects of Acid on Bone 07/01/06-05/31/11 DHHS/PHS/NIH 5 R01 DK075462 Bushinsky PI Contribution of Increased VDR and CaR to Hypercalciuria in the GHS Rat 02/15/08-01/31/12 Metabolic acidosis induces calcium efflux from bone and, in the process, buffers the additional hydrogen ions. Initially metabolic acidosis stimulates physicochemical mineral dissolution and subsequently cell-mediated bone resorption. Acidosis increases activity of the bone resorbing cells, the osteoclasts, and regulates activity of the bone forming cells, the osteoblasts. Osteoblastic immediate, early response genes are inhibited as are genes controlling matrix formation. Expression of the osteoclastic differentiation factor RANKL is up-regulated in osteoblasts. Both the regulation of RANKL and acid-induced calcium efflux are mediated by prostaglandins. In humans, idiopathic hypercalciuria is associated with stone formation. In order to study the mechanisms that are responsible for excess urine calcium excretion, in ways that are difficult or impossible in humans, we have developed a rat model of hypercalciuria. Spontaneously hypercalciuric rats have been successively inbred for over 65 generations to produce a strain in which urine calcium excretion is over 10 times greater than that of controls, and all rats from kidney stones. Analysis of the model has revealed that the rats not only exhibit increased intestinal calcium reabsorption but an independent defect in intestinal calcium renal tubular calcium resorption and an increased tendency for bone resorption. These findings closely parallel those in patients with idiopathic hypercalciuria. In the intestine, bone and kidney there is an increased number of vitamin D receptors where are hyper-responsive to 1,25 (OH)2D3. Whether the increased number of vitamin D receptors is directly responsible for the hypercalciuria and whether the same abnormality is present in humans with idiopathic hypercalciuria is under investigation. Hypercalciuric rats appear to be an excellent model to provide insights into the mechanisms causing hypercalciuria, and to delineate treatments for stone disease.