Inhibition of bone resorption in vitro by antisense RNA and DNA molecules targeted against carbonic anhydrase II or two subunits of vacuolar H(+)-ATPase.

Laitala, Tuna; Väänänen, H. Kalervo

doi:10.1172/jci117235

Cited by 88 publications

(51 citation statements)

References 36 publications

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“…It has been shown that expression of the proton channel part of V-H + -ATPase is stimulated in resorbing osteoclasts (21) and that antisense RNA and DNA molecules targeted against two subunits of the V-H + -ATPase do indeed inhibit bone resorption by rat osteoclasts (22). This enzyme is therefore a major potential target for reducing osteoclast activity and, consequently, for designing novel agents useful for the treatment of osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

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

Visentin¹,

Dodds²,

Valente³

et al. 2000

J. Clin. Invest.

112

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IntroductionInhibitors of bone resorption can preserve bone mass and maintain normal bone architecture, thereby preventing fractures in later life (1).The bone-resorption process requires secretion of protons by the osteoclasts (2). This allows the dissolution of the bone mineral and the maintenance of the acidic environment required by proteolytic enzymes to degrade the bone matrix (3). Protons are extruded by a proton pump belonging to the class of vacuolar-type H + -ATPases (V-H + -ATPases (4) that is present in high concentration on the ruffled border (apical surface) of the resorbing osteoclast.The osteoclast V-H + -ATPase therefore represents a previously unexploited molecular target for the design of novel agents for reducing osteoclast activity. However, since V-H + -ATPase is an ubiquitous component of eukaryotic organisms and is the major electrogenic pump of endomembranes (5), the selective inhibition of the osteoclast V-H + -ATPase must be achieved in order to afford novel drugs that may constitute useful and safe agents for the treatment of osteoporosis and related osteopenic diseases.Bafilomycin A 1 , a potent and specific inhibitor of V-H + -ATPases (6), inhibits bone resorption both in vitro (7) and in vivo (8). However, since bafilomycin is not selective for any particular type of V-H + -ATPases, when administered to animals it inhibits all the essential V-H + -ATPases leading to systemic alteration of cellular physiology and to unacceptable toxicity (9). Recently, a novel class of small molecules endowed with potent osteoclast V-H + -ATPase inhibitory activity has been discovered (10), whose optimization resulted in (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB 242784; Figure 1) (11). The in vitro V-H + -ATPase inhibitory profile of SB 242784 has been reported previously (11). SB 242784 was a low-nanomolar inhibitor (IC 50 = 26.3 nM) of the bafilomycin-sensitive (vacuolar) Mg 2+ -ATPase in membrane preparations of osteoclasts obtained from egg-laying hens. In addition, SB 242784 was a very potent inhibitor of bone resorption (IC 50 = 3.4 nM) in an assay measuring the collagen fragments released from bone slices after a 48-hour incubation with human osteoclasts.In this paper we characterize further the biochemical and pharmacological actions of SB 242784 and demonstrate that it is highly selective for the V-H + -ATPase of human osteoclasts when compared with V-H + -ATPases from a number of other human tissues. Most importantly, we show that oral administration of SB 242784 reduces the retinoid-induced hypercalcemia in thyroparathyroidectomized (TPTX) rats and prevents the A potent and selective inhibitor of the osteoclastic V-H + -ATPase, (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pentadienamide (SB 242784), was evaluated in two animal models of bone resorption. SB 242784 completely prevented retinoid-induced hypercalcemia in thyroparathyroidectomized (TPTX) rats when administered orally ...

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Section: Discussionmentioning

confidence: 99%

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

Visentin¹,

Dodds²,

Valente³

et al. 2000

J. Clin. Invest.

112

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“…In resorbing osteoclasts, carbonic anhydrase II is highly expressed, whereas in nonresorbing osteoclasts only low basal expression is maintained. Antisense RNA targeted against carbonic anhydrase inhibits bone resorption in vitro [20].…”

Section: Osteoclast Physiologymentioning

confidence: 99%

Molecular Understanding of Osteoclast Differentiation and Physiology

Lee

2010

Endocrinol Metab

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“…For this process, carbonic anhydrase II (CA II), which is abundant in the osteoclast cytoplasm and on the inner surface of its ruffled border, catalyzes the hydration of CO 2 to bicarbonate and a proton, thereby contributing to the H + secretion acidifying the bone resorption compartment and to HCO 3 − secretion by the HCO 3 − /Cl − exchanger, which maintains pH homeostasis. (19) The blockage of CA II with antisense oligonucleotides or acetazolamide, a potent CA II inhibitor, has been reported to suppress bone resorption by osteoclasts, (20,21) and a CA II deficiency syndrome has been shown to exhibit nonfunctional osteoclasts and osteopetrosis. (22) In addition, CA II expression is stronger in actively resorbing mature osteoclasts than in nonresorbing osteoclasts.…”

mentioning

confidence: 99%

Suppression of Adjuvant-Induced Arthritic Bone Destruction by Cyclooxygenase-2 Selective Agents With and Without Inhibitory Potency Against Carbonic Anhydrase II

Katagiri

Ogasawara

Hoshi

et al. 2006

Journal of Bone and Mineral Research

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In vitro assays revealed that COX-2 inhibitors with CA II inhibitory potency suppressed both differentiation and activity of osteoclasts, whereas that without the potency reduced only osteoclast differentiation. However, all COX-2 inhibitors similarly suppressed bone destruction in adjuvant-induced arthritic rats, indicating that suppression of osteoclast differentiation is more effective than that of osteoclast activity for the treatment.Introduction: Cyclooxygenase (COX)-2 and carbonic anhydrase II (CA II) are known to play important roles in the differentiation of osteoclasts and the activity of mature osteoclasts, respectively. Because several COX-2 selective agents were recently found to possess an inhibitory potency against CA II, this study compared the bone sparing effects of COX-2 selective agents with and without the CA II inhibitory potency. Materials and Methods: Osteoclast differentiation was determined by the mouse co-culture system of osteoblasts and bone marrow cells, and mature osteoclast activity was measured by the pit area on a dentine slice resorbed by osteoclasts generated and isolated from bone marrow cells. In vivo effects on arthritic bone destruction were determined by radiological and histological analyses of hind-paws of adjuvant-induced arthritic (AIA) rats. Results: CA II was expressed predominantly in mature osteoclasts, but not in the precursors. CA II activity was inhibited by sulfonamide-type COX-2 selective agents celecoxib and JTE-522 similarly to a CA II inhibitor acetazolamide, but not by a methylsulfone-type COX-2 inhibitor rofecoxib. In vitro assays clearly revealed that celecoxib and JTE-522 suppressed both differentiation and activity of osteoclasts, whereas rofecoxib and acetazolamide suppressed only osteoclast differentiation and activation, respectively. However, bone destruction in AIA rats was potently and similarly suppressed by all COX-2 selective agents whether with or without CA II inhibitory potency, although only moderately by acetazolamide. Conclusions: Suppression of osteoclast differentiation by COX-2 inhibition is more effective than suppression of mature osteoclast activity by CA II inhibition for the treatment of arthritic bone destruction.

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Inhibition of bone resorption in vitro by antisense RNA and DNA molecules targeted against carbonic anhydrase II or two subunits of vacuolar H(+)-ATPase.

Cited by 88 publications

References 36 publications

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

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

Molecular Understanding of Osteoclast Differentiation and Physiology

Suppression of Adjuvant-Induced Arthritic Bone Destruction by Cyclooxygenase-2 Selective Agents With and Without Inhibitory Potency Against Carbonic Anhydrase II

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