Recent progress in PTH/PTHrP research

Abstract

Among many factors controlling secretion of PTH, Kimura [lJ observed the effect of dietary supplementation of calcium and vitamin D on vaious parameters related to bone and calcium metabolism including PTH in rats. In vitamin D deficient animals both dietary calcium and vitamin D are important for the controlling production and secretion of PTH as well as for the bone growth. Tsugawa E2J compared the effect of new vitamin D analogs, 22-oxa-1, 25 dihydroxyvitamin D3 (OCT) [3J and 2-(3-hydroxypropoxy)-1,25 dihydroxyvitamin D3 (ED-71) [4j with 1,25 dihydroxyvitamin D3 on intestinal calcium transport, bone mobilization and PTH secretion in vitamin D deficient rats. 1,25(OH)2D3 and ED-71 showed biphasic actions on the intestinal transport of calcium, but OCT showed only monophasic action. PTH was suppressed by 1,25(OH)2D3 and OCT at the first phase of action on the intestinal calcium transport, but not by ED-71, although PTH was suppressed at the second phase of action. PTH degrading system which was reviewed by Yamaguchi [5J is another pathway to control the level of PTH. Although PTH may be cleaved into N-terminal PTH in kupffer cells, the kidney is playing a role in eliminating and degrading PTH. Mechanism of ActionsAlthough many actions of PTH have been discovered in addition to so-called classical actions on bone and kidney, mechanisms of actions even on bone remain unclarified. PTH is playing the essential role in bone remodelling, first directly acting on osteoblast and then initiating the coupling phenomenon. In the early period of growth in rats of both sexes, Okano [6J showed decreased level of bone gla protein, 1,25(OH)2 D3 and alkaline phosphatase, but these parameters were normalized thereafter. 1,25(OH)2D3 level was consistently higher in male than in female animals. PTH showed steady rise with aging and it was concluded that 1,25(OH)2D3 was more important for the growth of animals. PTH has been shown to accelerate the bone resorption via some mechanism of action on osteoblast. However, it was also noted that small dosage of PTH is rather stimulating bone formation. Kawase [7J demonstrated that human PTH(l-34) stimulated bone formation dose dependently in vitarain D deficient rats in which PTH was increased. This fact implicates what is the boundary of dose stimulating bone formation and resorption. Or are there factors influencing the manner of action of PTH: for instance, basal PTH which may affect PTH receptor level by down regulation mechanism and/or vitamin D level which may influence on the action and secretion of PTH ? Yamauchi [8J studied expression and characterization of PTH receptors in rat calvaria cells, demonstrating that PTH receptor expression changes in the course of culture and that the highest number occurs before osteoblastic activity fully appears. Kano [9J showed the direct involvement of PKC as well as PKA in PTH-and PTHrP-induced c-fos gene expression in the regulation of osteoblast proliferation and osteoclast differentiation by PTH and PTHrP. Regarding the effect on the kidney, ...