Woo J-T et al. (2006) Reveromycin A, an agent for osteoporosis, inhibits bone resorption by inducing apoptosis specifically in osteoclasts. Proc Natl Acad Sci USA 12: 4729–4734

Researchers from Japan and the US have developed a novel antiresorptive drug, reveromycin A, which inhibits bone resorption by inducing apoptosis in OSTEOCLASTS. In osteoporosis, excessive bone resorption and bone loss is mediated by osteoclasts. The two main classes of antiresorptive drugs that are currently available, bisphosphonates and calcitonin, either cannot be used in combination with other common agents or decrease in effectiveness over time.

In a rodent model, Woo et al. showed that reveromycin A caused cell death only in mature, bone-resorbing osteoclasts, and not in osteoclast progenitors, osteoblasts or inactive osteoclasts. Reveromycin A caused apoptosis by blocking the aminoacylation activity of isoleucyl-transfer-RNA synthetase (thereby blocking protein synthesis), and by inducing cytochrome c release and caspase 3 activation. Apoptosis and inhibition of bone resorption were demonstrated both in vivo and in vitro.

The authors suggest that reveromycin A's specificity for osteoclasts might be the result of the acidic extracellular microenvironment of osteoclasts, which increased the ability of reveromycin A to permeate these cells. Their results indicate that reveromycin A has a very different mechanism of action to bisphosphonates or calcitonin, and will not have the same limitations on its use.