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The Receptor Activator of Nuclear Factor-κB Ligand Inhibitor Osteoprotegerin Is a Bone-Protective Agent in a Rat Model of Chronic Renal Insufficiency and Hyperparathyroidism.

Authors :
Padagas, J.
Colloton, M.
Shalhoub, V.
Kostenuik, P.
Morony, S.
Munyakazi, L.
Guo, M.
Gianneschi, D.
Shatzen, E.
Geng, Z.
Tan, H.-L.
Dunstan, C.
Lacey, D.
Martin, D.
Source :
Calcified Tissue International. Jan2006, Vol. 78 Issue 1, p35-44. 10p. 1 Diagram, 5 Charts, 1 Graph.
Publication Year :
2006

Abstract

Osteoprotegerin (OPG) acts by neutralizing the receptor activator of nuclear factor-κB ligand (RANKL), the primary mediator of osteoclast differentiation, function, and survival. We examined whether OPG could affect the bone loss associated with chronic kidney disease (CKD) in a rodent model of CKD and secondary hyperparathyroidism (SHPT). SHPT was induced in rats by 5/6 nephrectomy (5/6 Nx) and a 1.2% P/0.6% Ca2+ diet. Starting 1 week after 5/6 Nx, rats were treated with vehicle (veh) or OPG-Fc (3 mg/kg, intravenously) every 2 weeks for 9 weeks. At baseline, 3, 6, and 9 weeks, blood was taken and bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry. Serum parathyroid hormone (sPTH) levels reached 912 pg/ml in 5/6 Nx rats vs. 97 pg/ml in shams at 9 weeks. OPG-Fc had no effect on sPTH or Ca2+ levels throughout the 9-week study, indicating that SHPT was a renal effect independent of bone changes. At 3 weeks, 5/6 Nx-veh rats had osteopenia compared with sham-veh rats and 5/6 Nx-OPG-Fc rats had significantly higher percent changes in whole-body BMC, leg BMD, and lumbar BMD versus 5/6 Nx-veh rats. By 6–9 weeks, elevated sPTH was associated with reversal of bone loss and osteitis fibrosa in the proximal tibial metaphysis. OPG-Fc decreased this sPTH-driven high bone turnover, resulting in augmented thickness of proximal tibial trabeculae in 5/6 Nx rats. Thus, RANKL inhibition with OPG-Fc can block the deleterious effects of continuously elevated sPTH on bone, suggesting that RANKL may be an important therapeutic target for protecting bone in patients with CKD and SHPT. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
0171967X
Volume :
78
Issue :
1
Database :
Academic Search Index
Journal :
Calcified Tissue International
Publication Type :
Academic Journal
Accession number :
19433059
Full Text :
https://doi.org/10.1007/s00223-005-0161-1