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

Abstract

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.

Osteoclast Multinucleation: Review of Current Literature

“…It acts as a proton pump coupled with ATP hydrolysis to transport protons in the intracellular space or across the cell membrane. In osteoclasts, V-ATPases in the plasma membrane can extracellularly release protons to the resorption lacunae, thus preserving the acidic extracellular environment needed for bone resorption [ 78 , 79 , 80 ]. V-ATPase consists of an extracellular domain V1 and a membrane-bound V0 domain.…”

Calcium Supplement by Tetracycline guided amorphous Calcium Carbonate potentiates Osteoblast promotion for Synergetic Osteoporosis Therapy

“…Osteoporosis is a common bone disease which can occur in any age as well as sex 1 , 2 . It is characterized as the disruption of bone homeostasis and loss of bone tissue which result in fracture and skeletal pain 3 .…”

AMP‐activated protein kinase (AMPK) regulates autophagy, inflammation and immunity and contributes to osteoclast differentiation and functionabs

“…Lysosomal inhibitors (e.g., chloroquine [CQ] and bafilomycin A1 [BAFA1]) increase the acidic pH, resulting in an inactivation of lysosome activity (Xu et al, 2003;Al-Bari et al, 2012;Xiu et al, 2014;Newton et al, 2015). Moreover, osteoclastic lysosomal enzymes are transported to bone-resorbing zone, which requires the involvement of multi-subunit proton pump vacuolar H + -ATPase (V-ATPase), which co-localise with mTOR, switches the signalling of amino acid sufficiency, and is influenced by AMPK activation (Hu et al, 2016;Duan et al, 2018). Autophagy early stage inhibitor 3methyladenine (3-MA) and the lysosomal inhibitor, BAF1, both activate mTOR phosphorylation; however, BAF1 does not affect AMPK activity (Tong et al, 2019).…”