RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes.

Autor:	Kondegowda NG; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA.; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Filipowska J; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA.; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Do JS; Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA., Leon-Rivera N; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA., Li R; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Hampton R; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Ogyaadu S; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Division of Endocrinology and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Levister C; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Division of Endocrinology and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Penninger JM; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada., Reijonen H; Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA., Levy CJ; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Division of Endocrinology and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Vasavada RC; Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA.; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2023 Nov 03; Vol. 9 (44), pp. eadf5238. Date of Electronic Publication: 2023 Nov 01.
DOI:	10.1126/sciadv.adf5238
Abstrakt:	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.
Databáze:	MEDLINE
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