A selective inhibitor of the osteoclastic V-H+-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats

Visentin, L.; Dodds, Robert A.; Valente, Maurizio; Misiano, Paola; Bradbeer, Jeremy N.; Oneta, S.; Liang, Xiaoguang; Gowen, Maxine; Farina, Carlo

doi:10.1172/jci6145

Cited by 111 publications

(75 citation statements)

References 40 publications

(29 reference statements)

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“…In the ADO patients, as well as other osteoclast-rich forms of osteopetrosis, it has been shown that bone formation is ongoing, despite the absence of bone resorption (11,17,41,42), a phenomenon that is also found in rodent models of osteoclast-rich osteopetrosis (70,71), and in animal models treated with inhibitors of osteoclastic acid secretion (63,72,73,74).…”

Section: Analysis Of Osteoclasts From Ado Patientsmentioning

confidence: 97%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Section: Analysis Of Osteoclasts From Ado Patientsmentioning

confidence: 97%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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“…Osteoclast-selective PPIs may therefore be used as antiresorptive agents 12 with the potential of preventing fractures. [13][14][15][16] Administration of a selective inhibitor of the osteoclastic vacuolar H+/ K+ ATPase prevents bone loss in ovariectomized rats, an animal model representative of postmenopausal osteoporosis. 15 As bone resorption is necessary for the development of normal bone microstructure, however, one may speculate that PPI-induced blockade of the osteoclast-associated vacuolar proton pump may actually increase fracture risk.…”

Section: Introductionmentioning

confidence: 99%

Use of Acid-Suppressive Drugs and Risk of Fracture: A Meta-analysis of Observational Studies

Eom¹,

Park

Myung

et al. 2011

The Annals of Family Medicine

102

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PURPOSE Previous studies have reported inconsistent fi ndings regarding the association between the use of acid-suppressive drugs such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H 2 RAs) and fracture risk. We investigated this association using meta-analysis. METHODSWe searched MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 using common key words. We included case-control, nested case-control, and cohort studies. Two evaluators independently reviewed and selected articles. We determined pooled effect estimates by using random-effects meta-analysis, because of heterogeneity.RESULTS Of 1,809 articles meeting our initial inclusion criteria, 5 case-control studies, 3 nested case-control studies, and 3 cohort studies were included in the fi nal analyses. The pooled odds ratio (OR) for fracture was 1.29 (95% confi dence interval [CI], 1.18-1.41) with use of PPIs and 1.10 (95% CI, 0.99-1.23) with use of H 2 RAs when compared with nonuse of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30; 95% CI, 1.15-1.48) and hip fracture risk (adjusted OR = 1.34; 95% CI, 1.09-1.66), whereas long-term H 2 RA use was not signifi cantly associated with fracture risk. CONCLUSIONSWe found possible evidence linking PPI use to an increased risk of fracture, but no association between H 2 RA use and fracture risk. Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors.

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“…(8) It has been reported that SB242784, a derivative of bafilomycin A1, had greater than 1000-fold selectivity for inhibition of osteoclast V-ATPase compared with V-ATPase measured in other tissues. (9) However, we could not confirm that SB242784 had any inhibitory selectivity for H + transport. The discrepancy may be attributed to a difference in the assay method.…”

Section: Discussionmentioning

confidence: 71%

“…The discrepancy may be attributed to a difference in the assay method. We measured H + transport activities of isolated membrane vesicles, whereas Visentin et al (9) measured total Mg + -dependent ATPase activities in individual cells using a histochemical technique. It is likely that their assay is inadequate to verify inhibitory selectivity.…”

Section: Discussionmentioning

confidence: 99%

“…(9) In addition, it has been reported that SB242784 prevented bone loss in ovariectomized rats without apparent adverse effects on renal function. (9) In this study, we examined a novel specific V-ATPase inhibitor, FR167356 (Fig. 1A), 2,6-dichloro-N-[3-(1-hydroxy-1-methylethyl)-2-methyl-7-benzofuranyl]benzamide, which was obtained from chemical modification of a parental compound discovered through random screening by monitoring H + transport activity of chicken osteoclast microsomes.…”

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confidence: 99%

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A Vacuolar ATPase Inhibitor, FR167356, Prevents Bone Resorption in Ovariectomized Rats With High Potency and Specificity: Potential for Clinical Application

Niikura

Takeshita

Takano

2005

Journal of Bone and Mineral Research

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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 Ca 2+ release from cultured calvariae. In vivo, hypercalcemia was induced by retinoic acid in thyroparathyroidectomized-ovariectomized rats, and the effect on serum Ca 2+ 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.

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A selective inhibitor of the osteoclastic V-H+-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats

Cited by 111 publications

References 40 publications

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Use of Acid-Suppressive Drugs and Risk of Fracture: A Meta-analysis of Observational Studies

A Vacuolar ATPase Inhibitor, FR167356, Prevents Bone Resorption in Ovariectomized Rats With High Potency and Specificity: Potential for Clinical Application

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