Novel techniques in the development of osteoporosis drug therapy: the osteoclast ruffled-border vacuolar H⁺-ATPase as an emerging target

Abstract

Introduction: Bone loss occurs in many diseases, including osteoporosis, rheumatoid arthritis and periodontal disease. For osteoporosis alone, it is estimated that 75 million people are afflicted worldwide, with high risks of fractures and increased morbidity and mortality. The demand for treatment consumes an ever-increasing share of healthcare resources. Successive generations of antiresorptive bisphosphonate drugs have reduced side effects, minimized frequency of dosing, and increased efficacy in halting osteoporotic bone loss, but their shortcomings have remained significant to the extent that a monoclonal antibody antiresorptive has recently taken a significant market share. Yet this latter, paradigm-shifting approach has its own drawbacks.

Areas covered: This review summarizes recent literature on bone-remodeling cell and molecular biology and the background for existing approaches and emerging therapeutics and targets for treating osteoporosis. The authors discuss vacuolar H⁺-ATPase (V-ATPase) molecular biology and the recent advances in targeting the osteoclast ruffled-border V-ATPase (ORV) for the development of novel antiresorptive drugs. They also cover examples from the V-ATPase-targeted drug discovery literature, including conventional molecular biology methods, in silico drug discovery, and gene therapy in more detail as proofs of concept.

Expert opinion: Existing therapeutic options for osteoporosis have limitations and inherent drawbacks. Thus, the search for novel approaches to osteoporosis drug discovery remains relevant. Targeting the ORV may be one of the more selective means of regulating bone resorption. Furthermore, this approach may be effective without removing active osteoclasts from the finely balanced osteoclast–osteoblast coupling required for normal bone remodeling.

Keywords::

• benzohydrazide
• bone loss pathology
• computer-aided drug discovery
• enoxacin
• gene therapy
• in silico drug design
• KM91104
• luteolin
• osteoporosis
• protein–protein interaction
• RNA interference
• vacuolar proton-translocating ATPase
• vacuolar H⁺-ATPase
• V-ATPase

Acknowledgments

The authors thank Dr Sean A.F. Peel of the University of Toronto Faculty of Dentistry for helpful discussion and critical reading of the manuscript.

Notes

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