Skeletal deterioration induced by RANKL infusion: a model for high-turnover bone disease.
RANKL was administered continuously to rats for 28 days to investigate its potential as a disease model for the skeletal system. Bone turnover rates, bone material, structural and mechanical properties were evaluated. RANKL infusion caused overall skeletal complications comparable to those in high bone-turnover conditions, such as postmenopausal osteoporosis.


BACKGROUND
RANKL is an essential mediator for osteoclast development. No study has examined in detail the direct skeletal consequences of excess RANKL on bone turnover, mineralization, architecture, and vascular calcification. We, therefore, administrated soluble RANKL continuously into mature rats and created a bone-loss model.


METHODS
Six-month-old Sprague-Dawley (SD) rats were assigned to three groups (n = 12) receiving continuous administration of saline (VEH) or human RANKL (35 microg/kg/day, LOW or 175 microg/kg/day, HI) for 28 days. Blood was collected routinely during the study. At sacrifice, hind limbs and aorta were removed and samples were analyzed.


RESULTS
High dose RANKL markedly stimulated serum osteocalcin and TRAP-5b levels and reduced femur cortical bone volume (-7.6%) and trabecular volume fraction (BV/TV) at the proximal tibia (-64% vs. VEH). Bone quality was significantly degraded in HI, as evidenced by decreased femoral percent mineralization, trabecular connectivity, and increased endocortical bone resorption perimeters. Both cortical and trabecular bone mechanical properties were reduced by high dose RANKL. No differences were observed in the mineral content of the abdominal aorta.


CONCLUSIONS
Continuous RANKL infusion caused general detrimental effects on rat skeleton. These changes are comparable to those commonly observed in high-turnover bone diseases such as postmenopausal osteoporosis.
Department of Bioengineering, Clemson University, Clemson, SC 29634, USA.
Y Y
YY
Yuan
P J
PJ
Kostenuik
M S
MS
Ominsky
S
S
Morony
S
S
Adamu
D T
DT
Simionescu
D M
DM
Basalyga
F J
FJ
Asuncion
T A
TA
Bateman
D000818:Animals; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D004195:Disease Models, Animal; D008297:Male; D010024:Osteoporosis / Q000139:chemically induced* / Q000473:pathology; D053245:RANK Ligand / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015415:Biomarkers; D053245:RANK Ligand