Jérôme Frenette
University of California, USA
Title: Targeting RANK/RANKL/OPG as a novel treatment for muscular dystrophy
Biography
Biography: Jérôme Frenette
Abstract
Receptor-activator of nuclear factor kB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology is still elusive. One key determinant of muscle contractility is the Ca2+ pump called sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) which transfers Ca2+ from the cytosol into the lumen of the SR, making Ca2+ available for the next contraction. Here we showed that daily injections of OPG-Fc for 10 days; the inhibitor of RANKL/RANK interactions, greatly increased force of dystrophic mice relative to PBS-treated mdx mice and prevented the loss of SERCA activity. To understand more precisely the contribution of muscle RANK in muscular dystrophy, we treated dystrophic mice with an anti-RANKL antibody or generated a RANK/dystrophin double-deficient mouse. These results showed that the genetic deletion of RANK or pharmacological blockade of RANKL preserved muscle force and reduced significantly muscle damage in dystrophic mice. RANK/RANKL/OPG triad is thus a new and key factor in muscular dystrophy and its inhibition represents a new therapeutic avenue for possibly several forms of muscular dystrophy.