A novel modified RANKL variant can prevent osteoporosis by acting as a vaccine and an inhibitor
Open accessAbstract
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.
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A variant of RANKL with changes in the RANK binding site still activates LGR4 signaling and inhibits osteoclastogenesis; it acts as an immunogen triggering anti-RANKL antibodies and might reduce risks linked to abrupt suspension of denosumab.
“This variant still activates LGR4 signaling and inhibits osteoclastogenesis. Moreover, it has been observed that this variant acts as an immunogen triggering the production of anti‐RANKL antibodies, and its use might reduce the risks linked to the abrupt suspension of denosumab use.173,70”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [173]
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- Authors
- Ko, Y. J., Sohn, H. M., Jang, Y., Park, M., Kim, B., Kim, B., Park, J., Hyun, H., Jeong, B., Hong, C., & Lim, W.
- Affiliations
- Chosun University Hospital (KR)
- Chonnam National University (KR)
- Chosun University (KR)
- Corresponding author
- Lim, Wonbong
- ORCID
- Venue
- Clinical and Translational Medicine
- Publisher
- Wiley
- Published
- 2021-03
- Volume
- 11
- Issue
- 3
- Pages
- e368-e368
- ISSN
- 2001-1326 (ISSN-L)
- PMC
- PMC7967917
- OpenAlex
- W3139176863
- Cited by
- 23
- References
- 44
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 3
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Clinical and Translational Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Research Foundation of Korea (NRF‐2018R1D1A1B07047024, NRF‐2017R1D1A1A02018589, NRF‐2020R1F1A1056573)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- osteoporosis, GSK3β, NFATc1, osteoclastogenesis, anti-RANKL antibody, immunotherapy, competitive inhibitors, ovariectomy, bone remodeling
- MeSH terms
- Animals, Bone Resorption, Cell Differentiation, Osteoclasts, Osteogenesis, Osteoporosis, Vaccines, Mice, RANK Ligand
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