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. Epub 2015 Jun 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density Conservation Agents / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects*
  • Denosumab / pharmacology*
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • NF-kappa B / metabolism*
  • Osteoprotegerin / metabolism*
  • RANK Ligand / antagonists & inhibitors
  • Rats
  • Signal Transduction / drug effects


  • Bone Density Conservation Agents
  • NF-kappa B
  • Osteoprotegerin
  • RANK Ligand
  • Denosumab