Receptor activator of NF-[kappa]B ligand arrests bone growth and promotes cortical bone resorption in growing rats.
Receptor activator of NF-kappaB ligand (RANKL), produced by osteoblastic lineage cells and activated T cells, is an essential factor for osteoclast differentiation, activation, and survival. Therefore, RANKL is a focal point of therapies targeting bone diseases where there is an imbalance of bone metabolism in favor of bone resorption. The present study assesses the effects of exogenous RANKL on growing bone. RANKL (100 microg x kg-1x day-1 for 7 days) administered to Sprague-Dawley weanling rats caused major deficits in growth, appearance, and bone mineral densities (BMD). Urinary deoxypyridinoline crosslinks, a measure of bone turnover, were higher in the RANKL-treated rats (P = 0.031), and the bone mineral content was lower (P < 0.001). The final BMD in the RANKL-treated rats was lower (P = 0.039) than in the control rats (19 +/- 7 vs. 38 +/- 5 mg/cm3). Moreover, calculated cortical bone density in each bone slice (total BMD - trabecular BMD) indicated there was only 5% cortical bone remaining in RANKL-treated rats. We conclude that therapies targeting RANKL are likely to have effects on cortical as well as trabecular bone density.
McHugh
Nansie A
NA
Allergy Department, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. nansie.mchugh@spcorp.com
Vercesi
Haydee M
HM
Egan
Robert W
RW
Hey
John A
JA
D000596:Amino Acids / Q000737:chemistry / Q000652:urine; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects; D002352:Carrier Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D053245:RANK Ligand; D051381:Rats; D017207:Rats, Sprague-Dawley; D053246:Receptor Activator of Nuclear Factor-kappa B; D014057:Tomography, X-Ray Computed
D000596:Amino Acids; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C036020:deoxypyridinoline