The RANK Ligand pathway is “home” to several proteins that interact to regulate the production of osteoclasts, the cells that break down bone. The proteins include RANK, RANK Ligand, and OPG. RANK Ligand binds to its receptor RANK, triggering all stages of osteoclast formation, function, and survival. OPG is the protein that intercepts RANK Ligand before it can bind to RANK, thereby keeping the development and activity of the “bone-eating” osteoclasts in check.
Amgen’s quest to develop a potentially pioneering medicine for the treatment for bone loss and destruction began in the mid-1990s when Amgen scientists looking for other gene sequences in its genome discovery program fortuitously discovered OPG. This natural antagonist to RANK Ligand is produced by the human body and was picked out of gene sequence from a library because it appeared to be an example of a soluble protein.
Amgen was not looking for a potential bone drug. The Company’s genomics program was designed to screen interesting-looking but uncharacterized genes whose functions had not yet been defined. Scientists knew that the human genome contained more secreted proteins whose biology had not yet been uncovered but could offer the potential for novel therapies for numerous diseases.
In keeping with the Company’s philosophy – go where the science takes you – Amgen scientists continued to study OPG and the RANK Ligand pathway. One definitive x-ray demonstrated that bone density increased when OPG levels were increased in mice. Scientists found that mice overexpressing OPG exhibited profound osteopetrosis (abnormally dense bones) accompanied by a dramatic reduction in osteoclasts, whereas the mice that lacked OPG developed osteoporosis, resulting in spontaneous fractures. Based on these findings, three key discoveries were made: 1.) RANK Ligand is the long-sought regulator of osteoclasts; 2.) The only clear physiologic role of OPG is to bind to and inhibit RANK Ligand; 3.) The RANK Ligand pathway is essential in bone biology1.
References
1. Simonet, WS, et al. Cell. 1997; 89: 309-319
