Osteoprotegerin and Denosumab Stimulate Human Beta Cell Proliferation through Inhibition of the Receptor Activator of NF-κB Ligand Pathway

  • Cell Metab. 2015 Jul 7;22(1):77-85. doi: 10.1016/j.cmet.2015.05.021.
Nagesha Guthalu Kondegowda  1 ,  Rafael Fenutria  1 ,  Ilana R Pollack  1 ,  Michael Orthofer  2 ,  Adolfo Garcia-Ocaña  3 ,  Josef M Penninger  2 ,  Rupangi C Vasavada  4
Affiliations
  • 1. 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.
  • 2. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3,1030 Vienna, Austria.
  • 3. 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; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4. 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; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].
PMID: 26094891 DOI: 10.1016/j.cmet.2015.05.021
Abstract

Diabetes results from a reduction of pancreatic β-cells. Stimulating replication could normalize β-cell mass. However, adult human β-cells are recalcitrant to proliferation. We identified Osteoprotegerin, a bone-related decoy receptor, as a β-cell mitogen. Osteoprotegerin was induced by and required for lactogen-mediated rodent β-cell replication. Osteoprotegerin enhanced β-cell proliferation in young, aged, and diabetic mice. This resulted in increased β-cell mass in young mice and significantly delayed hyperglycemia in diabetic mice. Osteoprotegerin stimulated replication of adult human β-cells, without causing dedifferentiation. Mechanistically, Osteoprotegerin induced human and rodent β-cell replication by modulating CREB and GSK3 pathways, through binding Receptor Activator of NF-κB (RANK) Ligand (RANKL), a brake in β-cell proliferation. Denosumab, an FDA-approved osteoporosis drug, and RANKL-specific antibody induced human β-cell proliferation in vitro, and in vivo, in humanized mice. Thus, Osteoprotegerin and Denosumab prevent RANKL/RANK interaction to stimulate β-cell replication, highlighting the potential for repurposing an osteoporosis drug to treat diabetes.

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