Embryonic expression of cyclooxygenase-2 causes malformations in axial skeleton.
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.
Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Minsub
M
Shim
Julie
J
Foley
Colleen
C
Anna
Yuji
Y
Mishina
Thomas
T
Eling
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002356:Cartilage / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D047108:Embryonic Development; D005333:Fetus / Q000002:abnormalities / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics; D013131:Spine / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D016159:Tumor Suppressor Protein p53; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human