Inhibitors of cyclo-oxygenase-2 and secretory phospholipase A2 preserve bone architecture following ovariectomy in adult rats.
Epidemiological evidence and in vitro data suggest that COX-2 is a key regulator of accelerated remodeling. Accelerated states of osteoblast and osteoclast activity are regulated by prostaglandins in vitro, but experimental evidence for specific roles of cyclooxygenase-2 (COX-2) and secretory phospholipase A2 (sPLA2) in activated states of remodeling in vivo is lacking. The aim of this study was to determine the effect of specific inhibitors of sPLA2-IIa and COX-2 on bone remodeling activated by estrogen deficiency in adult female rats. One hundred and twenty-four adult female Wistar rats were ovariectomized (OVX) or sham-operated. Rats commenced treatment 14 days after surgery with either vehicle, a COX-2 inhibitor (DFU at 0.02 mg/kg/day and 2.0 mg/kg/day) or a sPLA2-group-IIa inhibitor (KH064 at 0.4 mg/kg/day and 4.0 mg/kg/day). Treatment continued daily until rats were sacrificed at 70 days or 98 days post-OVX. The right tibiae were harvested, fixed and embedded in methylmethacrylate for structural histomorphometric bone analysis at the proximal tibial metaphysis. The specific COX-2 or sPLA2 inhibitors prevented ovariectomy-induced (OVX-induced) decreases in trabecular connectivity (P<0.05); suppressed the acceleration of bone resorption; and maintained bone turnover at SHAM levels following OVX in the rat. The sPLA2 inhibitor significantly suppressed increases in osteoclast surface induced by OVX (P<0.05), while the effect of COX-2 inhibition was less marked. These findings demonstrate that inhibitors of COX-2 and sPLA2-IIa can effectively suppress OVX-induced bone loss in the adult rat by conserving trabecular bone mass and architecture through reduced bone remodeling and decreased resorptive activity. Moreover, we report an important role of sPLA2-IIa in osteoclastogenesis that may be independent of the COX-2 metabolic pathway in the OVX rat in vivo.
Department of Anatomy and Developmental Biology, School of Biomedical Sciences, The University of Queensland, Brisbane Qld 4072, Australia. l.gregory@qut.edu.au
Laura S
LS
Gregory
Wendy L
WL
Kelly
Robert C
RC
Reid
David P
DP
Fairlie
Mark R
MR
Forwood
D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control; D001842:Bone and Bones / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000172:deficiency; D005260:Female; D005663:Furans / Q000494:pharmacology*; D054501:Group II Phospholipases A2; D010052:Ovariectomy; D010421:Pentanoic Acids / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; C503211:5-(4-benzyloxyphenyl)-4S-(7-phenylheptanoylamino)pentanoic acid; D052246:Cyclooxygenase 2 Inhibitors; D004967:Estrogens; D005663:Furans; D010421:Pentanoic Acids; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2