Approach to discovering novel therapeutic agents for osteoporosis based on integrin receptor blockade

On a global scale, osteoporosis is a major and growing public health problem. In the United States, osteoporosis is present in 24 million people (mostly women) and contributes to more than 1.3 million fractures/year. Serious morbidity and mortality result from these fractures. Current therapies for osteoporosis are few, efficacy is limited, and side effects problematic. Fundamental to the pathophysiology of osteoporosis is an imbalance between the tightly coupled processes of bone resorption and bone formation that characterize normal bone remodeling. Our laboratory is engaged in a research effort focused on elucidating the role of the osteoclast integrin in bone resorption, defining the nature of ligand–integrin interactions, and developing antagonists for cell surface adhesion molecules, particularly the α ν , β 3 vitronectin‐like integrin receptor present on the surface of human osteoclasts. Peptides containing the internal arginine‐glycine‐aspartic acid (RGD) motif have been shown to inhibit osteoclast‐mediated bone resorption in vivo. We are now designing more potent and selective inhibitors of bone resorption as a potential new mechanism‐based therapeutic approach to osteoporosis based on a novel mechanism. In an effort to rapidly identify the highest affinity ligands for the human α ν β 3 integrin, we have generated combinatorial peptide libraries containing substantial structural diversity. For instance, based on all possible sequence combinations of extracellular matrix proteins known to bind α ν β 3 , we recently synthesized and chemically analyzed a library of 360,000 peptides, all of which contain RGD. Human α ν β 3 receptors are now available in a clonal cell line that expresses high levels of recombinant receptor, these cells can serve as a very important research tool in this project because of the limited number of bone‐derived osteoclasts that can be harvested for experimentation. The library of peptides will be screened by “affinity selection”: the highest binding affinity peptide(s) will be isolated and microsequenced. Receptor‐favored sequences will be synthesized and evaluated in a battery of in vitro and in vivo bioassays. Through these investigations, insight will be gained into the role of integrins in bone biology and patho‐physiology, and new directions will be developed for the design of potent human α ν β 3 ‐selective antagonists for the treatment of osteoporosis. © 1994 John Wiley & Sons, Inc.