Young Jong Ko 1 2 , Hong Moon Sohn 1 2 , Yuria Jang 1 2 , Mineon Park 1 2 , Bora Kim 1 2 , et al
Clin Transl Med. 2021 Mar;11(3):e368.doi: 10.1002/ctm2.368.
Background: The discovery of receptor activator of nuclear factor-ĸB ligand (RANKL) as the final effector in the pathogenesis of osteoporosis has led to a better understanding of bone remodeling. When RANKL binds to its receptor (RANK), osteoclastic differentiation and activation are initiated. Herein, we propose a strategy using a novel RANKL variant as a competitive inhibitor for RANKL. The RANKL variant activates LGR4 signaling, which competitively regulates RANK and acts as an immunogen that induces anti-RANKL antibody production.
Methods: We modified the RANK-binding site on RANKL using minimal amino acid changes in the RANKL complex and its counterpart receptor RANK and tried to evaluate the inhibitory effects on osteoclastogenesis.
Results: The novel RANKL variant did not bind RANK in osteoclast progenitor cells, but activated LGR4 through the GSK3-β signaling pathway, thereby suppressing activated T cell cytoplasmic nuclear factor calcineurin-dependent 1 (NFATc1) expression and activity during osteoclastogenesis. Our RANKL variant generated high levels of RANKL-specific antibodies, blocked osteoclastogenesis, and inhibited osteoporosis in ovariectomized mouse models. Generated anti-RANKL antibodies showed a high inhibitory effect on osteoclastogenesis in vivo and in vitro.
Conclusions: We observed that the novel RANKL indeed blocks RANKL via LGR4 signaling and generates anti-RANKL antibodies, demonstrating an innovative strategy in the development of general immunotherapy.