Abstract
The vacuolar ATPase (V-ATPase) is a multisubunit enzyme that couples ATP hydrolysis to proton pumping across membranes. Recently, there is increasing evidence that V-ATPase may contribute to the pathogenesis of bone resorption disorders due to it is predominantly expressed in osteoclasts also function in bone resorption making it a good candidate in a therapeutic target for osteoporosis. Osteoclasts are capable of generating an acidic microenvironment necessary for bone resorption by utilizing V-ATPases to pump protons into the resorption lacuna. In addition, it has been shown that therapeutic interventions have been proposed that specifically target inhibition of the osteoclast proton pump. Modulation of osteoclastic V-ATPase activity has been considered to be a suitable therapy for the treatment of osteoporosis. All theses findings suggest that V-ATPase have important biological effects in bone resorption that might be a promising therapeutic target for osteoporosis. In this review, we will briefly discuss the biological features of osteoporosis and summarize recent advances on the role of V-ATPase in the pathogenesis and treatment of osteoporosis.
Similar content being viewed by others
References
Marie PJ (2009) Bone cell-matrix protein interactions. Osteoporos Int 20:1037–1042
Roodman GD (2009) Pathogenesis of myeloma bone disease. Leukemia 23:435–441
Zhao B, Takami M, Yamada A et al (2009) Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. Nat Med 15:1066–1071
Yao G, Feng H, Cai Y et al (2007) Characterization of vacuolar-ATPase and selective inhibition of vacuolar-H(+)-ATPase in osteoclasts. Biochem Biophys Res Commun 357:821–827
Xiao YT, Xiang LX, Shao JZ (2008) Vacuolar H(+)-ATPase. Int J Biochem Cell Biol 40:2002–2006
Su Y, Zhou A, Al-Lamki RS et al (2003) The a-subunit of the V-type H+-ATPase interacts with phosphofructokinase-1 in humans. J Biol Chem 278:20013–20018
Laitala-Leinonen T, Vaananen HK (1999) Decreased bone resorption, osteoclast differentiation, and expression of vacuolar H+-ATPase in antisense DNA-treated mouse metacarpal and calvaria cultures ex vivo. Antisense Nucleic Acid Drug Dev 9:155–169
Hu Y, Nyman J, Muhonen P et al (2005) Inhibition of the osteoclast V-ATPase by small interfering RNAs. FEBS Lett 579:4937–4942
Xu J, Feng HT, Wang C et al (2003) Effects of bafilomycin A1: an inhibitor of vacuolar H(+)-ATPases on endocytosis and apoptosis in RAW cells and RAW cell-derived osteoclasts. J Cell Biochem 88:1256–1264
Nadler G, Morvan M, Delimoge I et al (1998) (2Z, 4E)-5-(5, 6-dichloro-2-indolyl)-2-methoxy-N-(1, 2, 2, 6, 6- pentamethylpiperidin-4-yl)-2, 4-pentadienamide, a novel, potent and selective inhibitor of the osteoclast V-ATPase. Bioorg Med Chem Lett 8:3621–3626
Xu J, Cheng T, Feng HT et al (2007) Structure and function of V-ATPases in osteoclasts: potential therapeutic targets for the treatment of osteolysis. Histol Histopathol 22:443–454
Farina C, Gagliardi S (2002) Selective inhibition of osteoclast vacuolar H(+)-ATPase. Curr Pharm Des 8:2033–2048
Kornak U, Schulz A, Friedrich W et al (2000) Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 9:2059–2063
Jefferies KC, Cipriano DJ, Forgac M (2008) Function, structure and regulation of the vacuolar (H+)-ATPases. Arch Biochem Biophys 476:33–42
Blair HC, Teitelbaum SL, Ghiselli R et al (1989) Osteoclastic bone resorption by a polarized vacuolar proton pump. Science 245:855–857
Vaananen HK, Karhukorpi EK, Sundquist K et al (1990) Evidence for the presence of a proton pump of the vacuolar H(+)-ATPase type in the ruffled borders of osteoclasts. J Cell Biol 111:1305–1311
Sundquist K (1993) Characterization of ATP-dependent proton transport in medullary bone-derived microsomes. Bone Miner 20:17–29
Mattsson JP, Keeling DJ (1996) [3H]Bafilomycin as a probe for the transmembrane proton channel of the osteoclast vacuolar H(+)-ATPase. Biochim Biophys Acta 1280:98–106
Hall TJ (1994) Cytotoxicity of vacuolar H(+)-ATPase inhibitors to UMR-106 rat osteoblasts: an effect on iron uptake into cells? Cell Biol Int 18:189–193
Francis MJ, Lees RL, Trujillo E et al (2002) ATPase pumps in osteoclasts and osteoblasts. Int J Biochem Cell Biol 34:459–476
Inoue T, Wang Y, Jefferies K et al (2005) Structure and regulation of the V-ATPases. J Bioenergy Biomembr 37:393–398
Qi J, Wang Y, Forgac M (2007) The vacuolar (H +)-ATPase: subunit arrangement and in vivo regulation. J Bioenergy Biomembr 39:423–426
Drory O, Nelson N (2006) The emerging structure of vacuolar ATPases. Physiology (Bethesda) 21:317–325
Michigami T, Kageyama T, Satomura K et al (2002) Novel mutations in the a3 subunit of vacuolar H(+)-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis. Bone 30:436–439
Niikura K (2006) Vacuolar ATPase as a drug discovery target. Drug News Perspectives 19:139–144
Cipriano DJ, Wang Y, Bond S et al (2008) Structure and regulation of the vacuolar ATPases. Biochim Biophys Acta 1777:599–604
Wang Y, Inoue T, Forgac M (2004) TM2 but not TM4 of subunit c′′ interacts with TM7 of subunit a of the yeast V-ATPase as defined by disulfide-mediated cross-linking. J Biol Chem 279:44628–44638
Wang Y, Cipriano DJ, Forgac M (2007) Arrangement of subunits in the proteolipid ring of the V-ATPase. J Biol Chem 282:34058–34065
Blake-Palmer KG, Su Y, Smith AN et al (2007) Molecular cloning and characterization of a novel form of the human vacuolar H+-ATPase e-subunit: an essential proton pump component. Gene 393:94–100
Supek F, Supekova L, Mandiyan S et al (1994) A novel accessory subunit for vacuolar H(+)-ATPase from chromaffin granules. J Biol Chem 269:24102–24106
Schoonderwoert VT, Martens GJ (2002) Targeted disruption of the mouse gene encoding the V-ATPase accessory subunit Ac45. Mol Membr Biol 19:67–71
Demirci FY, White NJ, Rigatti BW et al (2001) Identification, genomic structure, and screening of the vacuolar proton-ATPase membrane sector-associated protein M8–9 gene within the COD1 critical region (Xp11.4). Mol Vis 7:234–239
Da Silva N, Shum WW, El-Annan J et al (2007) Relocalization of the V-ATPase B2 subunit to the apical membrane of epididymal clear cells of mice deficient in the B1 subunit. Am J Physiol Cell Physiol 293:C199–C210
Zhang Z, Zheng Y, Mazon H et al (2008) Structure of the yeast vacuolar ATPase. J Biol Chem 283:35983–35995
Perez-Sayans M, Garcia-Garcia A, Reboiras-Lopez MD et al (2009) Role of V-ATPases in solid tumors: importance of the subunit C (Review). Int J Oncol 34:1513–1520
Graham LA, Hill KJ, Stevens TH (1995) VMA8 encodes a 32-kDa V1 subunit of the Saccharomyces cerevisiae vacuolar H(+)-ATPase required for function and assembly of the enzyme complex. J Biol Chem 270:15037–15044
Nelson H, Mandiyan S, Nelson N (1995) A bovine cDNA and a yeast gene (VMA8) encoding the subunit D of the vacuolar H(+)-ATPase. Proc Natl Acad Sci USA 92:497–501
Hirsch S, Strauss A, Masood K et al (1988) Isolation and sequence of a cDNA clone encoding the 31-kDa subunit of bovine kidney vacuolar H+-ATPase. Proc Natl Acad Sci USA 85:3004–3008
Imai-Senga Y, Sun-Wada GH, Wada Y et al (2002) A human gene, ATP6E1, encoding a testis-specific isoform of H(+)-ATPase subunit E. Gene 289:7–12
Graf R, Lepier A, Harvey WR et al (1994) A novel 14-kDa V-ATPase subunit in the tobacco hornworm midgut. J Biol Chem 269:3767–3774
Muench SP, Huss M, Song CF et al (2009) Cryo-electron microscopy of the vacuolar ATPase motor reveals its mechanical and regulatory complexity. J Mol Biol 386:989–999
Supekova L, Sbia M, Supek F et al (1996) A novel subunit of vacuolar H(+)-ATPase related to the b subunit of F-ATPases. J Exp Biol 199:1147–1156
Geyer M, Fackler OT, Peterlin BM (2002) Subunit H of the V-ATPase involved in endocytosis shows homology to beta-adaptins. Mol Biol Cell 13:2045–2056
Baron R (1989) Molecular mechanisms of bone resorption by the osteoclast. Anat Rec 224:317–324
Baron R, Neff L, Louvard D et al (1985) Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border. J Cell Biol 101:2210–2222
Feng S, Deng L, Chen W et al (2009) Atp6v1c1 is an essential component of the osteoclast proton pump and in F-actin ring formation in osteoclasts. Biochem J 417:195–203
Laitala-Leinonen T, Lowik C, Papapoulos S et al (1999) Inhibition of intravacuolar acidification by antisense RNA decreases osteoclast differentiation and bone resorption in vitro. J Cell Sci 112(Pt 21):3657–3666
Lee BS, Holliday LS, Ojikutu B et al (1996) Osteoclasts express the B2 isoform of vacuolar H(+)-ATPase intracellularly and on their plasma membranes. Am J Physiol 270:C382–C388
Mattsson JP, Skyman C, Palokangas H et al (1997) Characterization and cellular distribution of the osteoclast ruffled membrane vacuolar H+-ATPase B-subunit using isoform-specific antibodies. J Bone Miner Res 12:753–760
Chen SH, Bubb MR, Yarmola EG et al (2004) Vacuolar H+-ATPase binding to microfilaments: regulation in response to phosphatidylinositol 3-kinase activity and detailed characterization of the actin-binding site in subunit B. J Biol Chem 279:7988–7998
Holliday LS, Lu M, Lee BS et al (2000) The amino-terminal domain of the B subunit of vacuolar H+-ATPase contains a filamentous actin binding site. J Biol Chem 275:32331–32337
Okumura S, Mizoguchi T, Sato N et al (2006) Coordination of microtubules and the actin cytoskeleton is important in osteoclast function, but calcitonin disrupts sealing zones without affecting microtubule networks. Bone 39:684–693
Li YP, Chen W, Liang Y et al (1999) Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet 23:447–451
Manolson MF, Yu H, Chen W et al (2003) The a3 isoform of the 100-kDa V-ATPase subunit is highly but differentially expressed in large (> or = 10 nuclei) and small (< or = nuclei) osteoclasts. J Biol Chem 278:49271–49278
Sobacchi C, Frattini A, Orchard P et al (2001) The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet 10:1767–1773
Smith AN, Jouret F, Bord S et al (2005) Vacuolar H+-ATPase d2 subunit: molecular characterization, developmental regulation, and localization to specialized proton pumps in kidney and bone. J Am Soc Nephrol 16:1245–1256
Visentin L, Dodds RA, Valente M et al (2000) A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. J Clin Invest 106:309–318
Sundquist K, Lakkakorpi P, Wallmark B et al (1990) Inhibition of osteoclast proton transport by bafilomycin A1 abolishes bone resorption. Biochem Biophys Res Commun 168:309–313
Niikura K, Takeshita N, Takano M (2005) A vacuolar ATPase inhibitor, FR167356, prevents bone resorption in ovariectomized rats with high potency and specificity: potential for clinical application. J Bone Miner Res 20:1579–1588
Sorensen MG, Henriksen K, Neutzsky-Wulff AV et al (2007) Diphyllin, a novel and naturally potent V-ATPase inhibitor, abrogates acidification of the osteoclastic resorption lacunae and bone resorption. J Bone Miner Res 22:1640–1648
Acknowledgments
This work was supported by the China National Science Foundation grants No. 30901526.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yuan, FL., Li, X., Lu, WG. et al. The vacuolar ATPase in bone cells: a potential therapeutic target in osteoporosis. Mol Biol Rep 37, 3561–3566 (2010). https://doi.org/10.1007/s11033-010-0004-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-010-0004-7