{"doi":"10.1126/sciadv.adf5238","title":"RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes","abstract":"Treatment for type 1 diabetes (T1D) requires stimulation of functional β cell regeneration and survival under stress. Previously, we showed that inhibition of the RANKL/RANK [receptor activator of nuclear factor kappa Β (NF-κB) ligand] pathway, by osteoprotegerin and the anti-osteoporotic drug denosumab, induces rodent and human β cell proliferation. We demonstrate that the RANK pathway mediates cytokine-induced rodent and human β cell death through RANK-TRAF6 interaction and induction of NF-κB activation. Osteoprotegerin and denosumab protected β cells against this cytotoxicity. In human immune cells, osteoprotegerin and denosumab reduce proinflammatory cytokines in activated T-cells by inhibiting RANKL-induced activation of monocytes. In vivo, osteoprotegerin reversed recent-onset T1D in nonobese diabetic/Ltj mice, reduced insulitis, improved glucose homeostasis, and increased plasma insulin, β cell proliferation, and mass in these mice. Serum from T1D subjects induced human β cell death and dysfunction, but not α cell death. Osteoprotegerin and denosumab reduced T1D serum-induced β cell cytotoxicity and dysfunction. Inhibiting RANKL/RANK could have therapeutic potential.","journal":"Science Advances","year":2023,"id":329559,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":889599,"name":"Joanna Filipowska","orcid":"0000-0002-5721-5032","position":1,"is_corresponding":false},{"id":1052315,"name":"Jeong‐su Do","orcid":"0000-0002-2375-2585","position":2,"is_corresponding":false},{"id":782834,"name":"Nancy Leon-Rivera","orcid":"0000-0003-0231-492X","position":3,"is_corresponding":false},{"id":310882,"name":"Rosemary Li","orcid":"0000-0002-2605-634X","position":4,"is_corresponding":false},{"id":853218,"name":"Rollie F. Hampton","orcid":"0000-0003-3285-6957","position":5,"is_corresponding":false},{"id":1035090,"name":"Selassie Ogyaadu","orcid":null,"position":6,"is_corresponding":false},{"id":1035088,"name":"Camilla Levister","orcid":null,"position":7,"is_corresponding":false},{"id":55744,"name":"Josef Penninger","orcid":"0000-0002-8194-3777","position":8,"is_corresponding":false},{"id":1052316,"name":"Helena Reijonen","orcid":"0000-0002-9386-3918","position":9,"is_corresponding":false},{"id":231683,"name":"Carol J. Levy","orcid":"0000-0002-3492-2578","position":10,"is_corresponding":false},{"id":823636,"name":"Rupangi C. Vasavada","orcid":"0000-0003-3228-9235","position":11,"is_corresponding":false},{"id":1052314,"name":"Nagesha Guthalu Kondegowda","orcid":"0000-0003-1738-6176","position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-19T01:09:01.509601Z","pmid":"37910614","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}