Abstract
Cyclooxygenases (COXs) have important functions in various physiological and pathological processes. COX-2 expression is highly induced by a variety of stimuli and is observed during certain periods of embryonic development. In this report, the direct effect of COX-2 expression on embryonic development is examined in a novel COX-2 transgenic mouse model that ubiquitously expresses human COX-2 from the early stages of embryonic development. COX-2 transgenic fetuses exhibit severe skeletal malformations and die shortly after birth. Skeletal malformations are localized along the entire vertebral column and rib cage and are linked to defective formation of cartilage anlagen. The cartilage anlagen of axial skeleton fail to properly develop in transgenic embryos because of impaired precartilaginous sclerotomal condensation, which results from the reduction of cell number in the sclerotome. Despite the ubiquitous expression of COX-2, the number of apoptotic cells is highly increased in the sclerotome of transgenic embryos but not in other tissues, suggesting that it is a tissue-specific response. Therefore, the loss of sclerotomal cells due to an increased apoptosis is probably responsible for axial skeletal malformations in transgenic fetuses. In addition, the sclerotomal accumulation of p53 protein is observed in transgenic embryos, suggesting that COX-2 may induce apoptosis via the up-regulation of p53. Our results demonstrate that the aberrant COX-2 signaling during embryonic development is teratogenic and suggest a possible association of COX-2 with fetal malformations of unknown etiology.
Highlights
Cyclooxygenase (COX)2 is a rate-limiting enzyme in the arachidonic acid cascade and catalyzes the conversion of arachidonic acid to prostaglandin H2, which is converted to various prostaglandins by cell-specific prostaglandin synthases
Our results demonstrate that the aberrant COX-2 signaling during embryonic development is teratogenic and suggest a possible association of COX-2 with fetal malformations of unknown etiology
Because Cre recombicytomegalovirus early enhancer/chicken -actin (CAG) pro- nase is ubiquitously expressed from the Mox2 locus [6], a widemoter was used to direct the expression of the human COX-2 spread expression of COX-2 was expected in the COX-2 transgene in transgenic mice
Summary
Cyclooxygenase (COX)2 is a rate-limiting enzyme in the arachidonic acid cascade and catalyzes the conversion of arachidonic acid to prostaglandin H2, which is converted to various prostaglandins by cell-specific prostaglandin synthases. Despite the ubiquitous expression of COX-2, the number of apoptotic cells is highly increased in the sclerotome of transgenic embryos but not in other tissues, suggesting that it is a tissue-specific response.
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