Mechanisms controlling vacuolar H+-adenosine triphosphatase activity: targets for the development of new therapeutic agents for the management of osteoporosis

L Shannon Holliday,^1,2 Nancy Huynh,¹ Jian Zuo,¹ Edgardo J Toro<sup>1,3

1</sup>Department of Orthodontics, University of Florida College of Dentistry, Gainesville, FL, USA; ²Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA; ³Department of Advanced Graduate Dental Education, University of Puerto Rico School of Dental Medicine, San Juan, Puerto Rico

Abstract: Recent genetic studies show that mutations in vacuolar H⁺-adenosine triphosphatase (V-ATPase) subunit isoforms that are selectively expressed in osteoclasts (a3 and d2) lead to both reduced bone resorption and increased bone formation. This implies that pharmaceuticals targeting these subunits or activities that are linked to these subunits might prove to be bone anabolic. The fact that V-ATPase is a ubiquitous "housekeeping" enzyme has made it challenging to directly target the enzymatic activity of the subset of V-ATPases involved in bone resorption; however, the unique mechanisms that control the V-ATPases involved in bone resorption have begun to emerge. These include binding interactions with the cytoskeleton and with proteins involved in regulating the cytoskeleton and membrane trafficking, links to glycolysis, and surprising ties to the renin–angiotensin signaling network. Links between controlling mechanisms and subunit a3 have been identified, suggesting that it may be possible to develop agents that disrupt bone resorptive V-ATPase activity while leaving the housekeeping activities unhindered. The first steps toward using this new information to rationally design novel classes of therapeutic agents have been taken. Such agents might selectively act against osteoclasts both to prevent the initiation of osteoporosis and to restore already-compromised bone.

Keywords: vacuolar H⁺-ATPase, enoxacin, luteolin, computational chemistry, microfilaments, ARF6