Teresa Nesbitt

Coordinated maturational regulation of PHEX and renal phosphate transport inhibitory activity : evidence for the pathophysiological role of PHEX in X-linked hypophosphatemia

The mechanism by which inactivating mutations of PHEX (phosphate‐regulating gene with homologies to endopeptidases on the X chromosome) cause X‐linked hypophosphatemia remains unknown. However, recent reports suggest errant PHEX activity in osteoblasts may fail to inactivate a phosphaturic factor produced by these cells. To test this possibility, we examined coordinated maturational expression of PHEX and production of phosphate transport inhibitory activity in osteoblasts from normal and hyp‐mice. We assessed the inhibitory activity in conditioned medium by examining the effects on opossum kidney cell phosphate transport and osteoblast PHEX expression by reverse transcriptase‐polymerase chain reaction during a 17‐day maturational period. Inhibitory activity increased as a function of osteoblast maturational stage, with no activity after 3 days and persistent activity by 6 days of culture. More significantly, equal phosphate transport inhibitory activity in conditioned medium from normal and hyp‐mouse osteoblasts (control 1.90 ± 0.12, normal 1.48 ± 0.10, hyp 1.45 ± 0.04 nmol/mg of protein/minute) was observed at 6 days. However, by 10 days hyp‐mouse osteoblasts exhibited greater inhibitory activity than controls, and by 17 days the difference in phosphate transport inhibition maximized (control 2.08 ± 0.09, normal 1.88 ± 0.06, hyp 1.58 ± 0.06 nmol/mg of protein/minute). Concurrently, we observed absent PHEX expression in normal osteoblasts after 3 days, limited production at 6 days, and significant production by day 10 of culture, while hyp‐mouse osteoblasts exhibited limited PHEX activity secondary to an inactivating mutation. The data suggest that the presence of inactivating PHEX mutations results in the enhanced renal phosphate transport inhibitory activity exhibited by hyp‐mouse osteoblasts.

Role of calcitriol in prevention of osteoporosis: Part I

Prevention of postmenopausal osteoporosis is an alternative to the currently problematic goal of reversing the trabecular plate thinning and perforation that constitute the major pathologic defects in patients with established osteoporosis. 1,25(OH)2D3 (calcitriol) has been suggested as a drug that may decrease bone resorption sufficiently to preserve trabecular structure in perimenopausal women. In the present study, we compared the effects of calcitriol and an investigational analog, 1,25,26-(OH)3delta22-D3 (Ro-23-8525), to those of an inert vehicle in maintaining the bone mass of oophorectomized adult beagles. In these studies, we used dual-energy radiography to serially quantitate the bone density of control and treated animals. Treatment for 1 year with either agent resulted in no evidence of hypercalcemia or decreased renal function. Moreover, calcitriol and Ro-23-8525 effectively abolished the loss of bone mass observed in untreated oophorectomized controls. Indeed, treated animals displayed variations in bone density similar to that observed in sham-operated untreated animals. These data suggest that calcitriol and Ro-23-8525 may be potentially effective agents for prophylaxis of postmenopausal osteoporosis.