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

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