Role of cyclooxygenase-2 in bone metabolism -analysis of cox-2 konckout mice-

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Studies on mice with disruption of the cyclooxygenase-2 (COX-2) gene have shown that prostaglandins produced by COX-2 are critical for the maximal stimulation of osteoclast differentiation. The current study examined the role of COX-2 in osteoblastic differentiation. Endogenous PGE_2 production was markedly decreased in marrow stromal cell (MSC) cultures from 5-6 wk old mice with disruption of both COX-2 alleles (COX-2^<-/->) compared to cultures from wild type littermates (COX-2^<+/+>). MSC cultures from COX-2^<-/-> mice had decreased alkaline phosphatase (ALP) staining and activity, osteocalcin mRNA expression, and von Kossa staining compared to COX-2^<+/+> cultures. Addition of PGE_2 to COX-2^<-/-> MSC cultures reversed differences in differentiation between COX-2^<+/+> and COX-2^<-/-> cultures. In MSC cultures from mice with only one COX-2 gene disrupted (COX-2^<+/-> mice), PGE_2 production and ALP staining were decreased compared to COX-2^<+/+> cultures. Hence, COX-2^<+/-> mice might be used as models to study COX-2 deficiency in adult mice, thereby avoiding potentially confounding effects of renal abnormalities in COX-2^<-/-> mice on bone metabolism. In vivo, there was a 9% decrease in tibial bone mineral content (BMC) in 3 mo old COX-2^<-/-> and COX-2^<+/-> mice compared to COX-2^<+/+> mice and a 10% decrease in femoral BMC in COX-2^<-/-> mice compared to COX-2^<+/+> mice. Dynamic histomorphometric analyses comparing COX-2^<+/-> mice with COX-2^<+/+> mice suggested decreased bone formation in COX-2^<+/-> mice. We conclude that the absence of COX-2 expression markedly impairs osteoblastic differentiation in vitro and may decrease bone formation more than resorption in vivo.