Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice.
Osteoporosis and vascular calcification frequently coincide. A potential mediator of bone metabolism and vascular homeostasis is the triad cytokine system, which consists of receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL), its receptor RANK, and the decoy receptor osteoprotegerin. Unopposed RANKL activity in osteoprotegerin-deficient mice resulted in osteoporosis and vascular calcification. We therefore analyzed the effects of RANKL inhibition by denosumab, a human monoclonal antibody against RANKL, on vascular calcium deposition following glucocorticoid exposure. Prednisolone pellets were implanted into human RANKL knock-in (huRANKL-KI) mice, which unlike wild-type mice are responsive to denosumab. No histomorphological abnormalities or differences in aortic wall thickness were detected between wild-type and huRANKL-KI mice, regardless of treatment with prednisolone, denosumab, or both. However, concurrent treatment with denosumab reduced aortic calcium deposition of prednisolone-treated huRANKL-KI mice by up to 50%, based on calcium measurement. Of note, aortic calcium deposition in huRANKL-KI mice was correlated negatively with bone mineral density at the lumbar spine (P = 0.04) and positively with urinary excretion of deoxypyridinoline, a marker of bone resorption (P = 0.01). In summary, RANKL inhibition by denosumab reduced vascular calcium deposition in glucocorticoid-induced osteoporosis in mice, which is further evidence for the link between the bone and vascular systems. Therefore, the prevention of bone loss by denosumab might also be associated with reduced vascular calcification in certain conditions.
Helas
Susann
S
Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technical University of Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
Goettsch
Claudia
C
Schoppet
Michael
M
Zeitz
Ute
U
Hempel
Ute
U
Morawietz
Henning
H
Kostenuik
Paul J
PJ
Erben
Reinhold G
RG
Hofbauer
Lorenz C
LC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D000069448:Denosumab; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010024:Osteoporosis / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000069448:Denosumab; D002118:Calcium