Published online before print July 9, 2009

This Article Full Text Full Text (PDF) Correction (v175,p2249) All Versions of this Article: ajpath.2009.080957v1 175/2/473    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Helas, S. Articles by Hofbauer, L. C. Search for Related Content PubMed PubMed Citation Articles by Helas, S. Articles by Hofbauer, L. C.

(American Journal of Pathology. 2009;175:473-478.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080957

Short Communication

Inhibition of Receptor Activator of NF-B Ligand by Denosumab Attenuates Vascular Calcium Deposition in Mice

Susann Helas^*, Claudia Goettsch^*, Michael Schoppet, Ute Zeitz, Ute Hempel^¶, Henning Morawietz^||, Paul J. Kostenuik^**, Reinhold G. Erben and Lorenz C. Hofbauer^*

From the Divisions of Endocrinology, Diabetes, and Bone Diseases,^* and Vascular Endothelium and Microcirculation,|| Department of Medicine III, the DFG Research Center, Center for Regenerative Therapies Dresden, and the Institute of Physiological Chemistry,^¶ Technical University, Dresden, Germany; the Department of Internal Medicine and Cardiology, Philipps-University, Marburg, Germany; the Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria; and Amgen Inc.,^** Thousand Oaks, California

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-B (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.

This article has been cited by other articles:

				S. Kiechl, J. Willeit, G. Schett, J. Blackwood, A. Kyrgidis, S. L. Blythe, M. R. Smith, S. R. Cummings, E. Siris, and A. Wang Denosumab, Osteoporosis, and Prevention of Fractures N. Engl. J. Med., November 26, 2009; 361(22): 2188 - 2191. [Full Text] [PDF]