V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis

Theranostics. 2018 Oct 26;8(19):5379-5399. doi: 10.7150/thno.28391. eCollection 2018.


Vacuolar ATPases (V-ATPases) play a critical role in regulating extracellular acidification of osteoclasts and bone resorption. The deficiencies of subunit a3 and d2 of V-ATPases result in increased bone density in humans and mice. One of the traditional drug design strategies in treating osteoporosis is the use of subunit a3 inhibitor. Recent findings connect subunits H and G1 with decreased bone density. Given the controversial effects of ATPase subunits on bone density, there is a critical need to review the subunits of V-ATPase in osteoclasts and their functions in regulating osteoclasts and bone remodeling. In this review, we comprehensively address the following areas: information about all V-ATPase subunits and their isoforms; summary of V-ATPase subunits associated with human genetic diseases; V-ATPase subunits and osteopetrosis/osteoporosis; screening of all V-ATPase subunits variants in GEFOS data and in-house data; spectrum of V-ATPase subunits during osteoclastogenesis; direct and indirect roles of subunits of V-ATPases in osteoclasts; V-ATPase-associated signaling pathways in osteoclasts; interactions among V-ATPase subunits in osteoclasts; osteoclast-specific V-ATPase inhibitors; perspective of future inhibitors or activators targeting V-ATPase subunits in the treatment of osteoporosis.

Keywords: V-ATPase; inhibitor; osteoclasts; osteopetrosis; osteoporosis; pH; signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Osteoclasts / enzymology*
  • Osteoclasts / physiology*
  • Osteoporosis / genetics
  • Osteoporosis / physiopathology*
  • Osteoporosis / therapy
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / metabolism*
  • Vacuolar Proton-Translocating ATPases / antagonists & inhibitors
  • Vacuolar Proton-Translocating ATPases / metabolism*


  • Enzyme Inhibitors
  • Protein Isoforms
  • Protein Subunits
  • Vacuolar Proton-Translocating ATPases