A novel modified RANKL variant can prevent osteoporosis by acting as a vaccine and an inhibitor. Issue 3 (17th March 2021)

• Record Type: Journal Article
• Authors: Ko, Young Jong; Sohn, Hong Moon; Jang, Yuria; Park, Mineon; Kim, Bora; Kim, Beomchang; Park, Jae‐Il; Hyun, Hoon; Jeong, Byeongseok; Hong, Chansik; Lim, Wonbong
• Is Part Of: Clinical and translational medicine. Volume 11:Issue 3(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-17
• Subjects: immunotherapy -- LGR4 -- osteoclastogenesis -- RANK; Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.368
• Languages: English
• ISSNs: 2001-1326

Abstract

Abstract: 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. Abstract : Schematic diagram of mRANKL‐MT3 in dual inhibitory effect against RANKL during osteoclastogenesis. The first effect of mRANKL‐MT3 is induced to RANKL‐LGR4 modulation of the RANKL–NFATc1 signaling cascade by a negative‐feedback mechanism, which controls osteoclast activity. The second effect is induced to anti‐RANKL generation by mutant RANKL, which inhibits osteoclastogenesis and bone erosion.