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

• Published in: Cell metabolism 2015-07, Vol.22 (1), p.77-85
• Main Authors: Kondegowda, Nagesha Guthalu, Fenutria, Rafael, Pollack, Ilana R., Orthofer, Michael, Garcia-Ocaña, Adolfo, Penninger, Josef M., Vasavada, Rupangi C.
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.05.021

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. [Display omitted] •RANKL/RANK is a brake for rodent and human β-cell proliferation•Osteoprotegerin induces human β-cell replication by inhibiting RANKL•FDA-approved osteoporosis drug Denosumab enhances human β-cell replication in vivo•Osteoprotegerin is required for lactogen-induced rodent β-cell proliferation Kondegowda et al. reveal how prolactin interacts with a bone-related pathway, Osteoprotegerin (OPG), to stimulate pancreatic β-cell proliferation via RANKL inhibition, even in aged mice. OPG and Denosumab, an anti-RANKL antibody approved for osteoporosis, enhance human β-cell replication in humanized mice.