CHAPTER 37 – RANKL (Receptor activator of NFκB ligand)

This chapter highlights the observation that demonstrates the pivotal role of the receptor activator of NFκB RANKL/RANK system in a number of biologic systems, including the development and function of mammary tissue and in the maintenance of calcium metabolism and bone mass. The discovery and elucidation of the RANKL/ RANK/OPG (osteoprotegerin) system relates to osteoclastogenesis that has proven to be a groundbreaking finding for the field of bone biology. There is substantial evidence implicating a dysregulation of this system in a number of bone pathologies including osteoporosis, rheumatoid arthritis, and metastatic bone disease. It is assumed that the therapeutic potential intervening with this system for the treatment of these diseases must be explored. The recent description of the crystal structure of RANKL, suggests exciting opportunities for pharmacological intervention in a number of disorders outlined in the chapter. Proof of concept for this approach has already been achieved with recombinant OPG, which was shown to significantly reduce bone turnover in markers in postmenopausal women. One may speculate that the rational drug design of small molecular weight inhibitors, or OPG itself, may be useful in the treatment of disorders associated with increased osteoclast activity.