RRC ID 77502
Author Niikura K, Takeshita N, Takano M.
Title A vacuolar ATPase inhibitor, FR167356, prevents bone resorption in ovariectomized rats with high potency and specificity: potential for clinical application.
Journal J Bone Miner Res
Abstract UNLABELLED:FR167356, a novel inhibitor of vacuolar ATPase, has high potency against osteoclast V-ATPase and low potency against lysosomal V-ATPase. FR167356 is the first compound of this nature to be tested. It has the potential to be useful for clinical application.
INTRODUCTION:It has been suggested that the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is their selectivity.
MATERIALS AND METHODS:In in vitro and in vivo studies, we compared FR167356 with other vacuolar ATPase (V-ATPase) inhibitors, bafilomycin A1 and SB242784. H+ transport by various membrane vesicles was assayed by measuring uptake of acridine orange. Inhibitory activity against in vitro bone resorption was examined by measuring the Ca2+ release from cultured calvariae. In vivo, hypercalcemia was induced by retinoic acid in thyroparathyroidectomized-ovariectomized rats, and the effect on serum Ca2+ level was assessed. Ovariectomized rats were treated with FR167356 or SB242784. One week after surgery, free deoxypyridinoline levels in 24-h urine samples, which were collected from 6 h after administration of FR167356, were measured by ELISA. After 4 weeks of treatment, plasma biochemical parameters were analyzed. BMD of the distal femur metaphysis was measured with pQCT. Histomorphometric analysis of the proximal tibias was performed. Blood gases of rats treated with FR167356 were measured with a blood gas analyzer for estimating the effect of FR167356 on in vivo function of renal V-ATPase.
RESULTS:FR167356, which is distinctly different from other V-ATPase inhibitors, has a high potency against osteoclast V-ATPase and low potency against lysosomal V-ATPase. Similarly, FR167356 inhibited bone resorption in vitro when stimulated by PTH, IL-1, and IL-6. FR167356 reduced retinoic acid-induced hypercalcemia in thyroparathyroidectomized-ovariectomized rats in a dose-dependent manner. Moreover, FR167356 was shown to restore BMD of ovariectomized rats caused by the inhibition of bone resorption. Ovariectomized rats treated with FR167356 did not show adverse symptoms, whereas SB242784 caused a decrease in body weight gain and significant changes in two plasma biochemical parameters. Interestingly, FR167356 treatment did not affect blood acid-base balance; however, FR167356 inhibited renal V-ATPase with a similar potency as for osteoclast V-ATPase inhibition.
CONCLUSION:Comparison of FR167356 with SB242784 implies that the characteristics of FR167356 may be more appropriate for clinical application as a V-ATPase inhibitor.
Volume 20(9)
Pages 1579-88
Published 2005-9-1
DOI 10.1359/JBMR.050517
PMID 16059630
MeSH Animals Benzamides / pharmacology* Benzofurans / pharmacology* Biological Transport Bone Density Bone Resorption* Bone and Bones / drug effects* Calcium / metabolism Cell Membrane / metabolism Drug Evaluation, Preclinical Enzyme-Linked Immunosorbent Assay Female Femur / pathology Inhibitory Concentration 50 Kidney / pathology Lysosomes / metabolism Macrolides / pharmacology Male Mice Models, Chemical Osteoclasts / metabolism Osteoporosis / pathology Protons Rabbits Rats Rats, Wistar Time Factors Vacuolar Proton-Translocating ATPases / antagonists & inhibitors* Vacuolar Proton-Translocating ATPases / metabolism
IF 5.854
Human and Animal Cells ST2(RCB0224)