TY - JOUR
T1 - Osteoprotegerin and Denosumab Stimulate Human Beta Cell Proliferation through Inhibition of the Receptor Activator of NF-κB Ligand Pathway
AU - Kondegowda, Nagesha Guthalu
AU - Fenutria, Rafael
AU - Pollack, Ilana R.
AU - Orthofer, Michael
AU - Garcia-Ocaña, Adolfo
AU - Penninger, Josef M.
AU - Vasavada, Rupangi C.
N1 - Funding Information:
We are grateful to Drs. A. Stewart, D. Scott, and N. Fiaschi-Taesch for their critical input; to Dr. D. Scott for manuscript editing; to C. Chin, T. Buch, A. Amlani, A. Otero, and Dr. J.F. López Acosta for experimental assistance; to the NIDDK-supported Integrated Islet Distribution Program (IIDP) for providing human islets; and to the microscopy cores at the University of Pittsburgh and the Icahn School of Medicine at Mount Sinai for their assistance and use of their facilities. J.P. is supported by advanced ERC grant and Innovator award by Era of Hope/DoD. This work was supported by grants from the National Institutes of Health (R01DK072264; DK102893) and the Juvenile Diabetes Research Foundation (17-2012-37) to R.C.V.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/7
Y1 - 2015/7/7
N2 - Summary 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.
AB - Summary 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.
UR - http://www.scopus.com/inward/record.url?scp=84937420517&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2015.05.021
DO - 10.1016/j.cmet.2015.05.021
M3 - Article
C2 - 26094891
AN - SCOPUS:84937420517
VL - 22
SP - 77
EP - 85
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 1
ER -