CommentariesCyclooxygenase knockout mice: Models for elucidating isoform-specific functions
Section snippets
General characteristics of COX-1 and COX-2 null mice
The DNA manipulations used to disrupt the genes coding for COX-1 and COX-2 have been reported 38, 39, 40. Both COX-1 and COX-2 deficient mice lacked the respective normal size message and immunoreactive protein. Mice heterozygous for Ptgs-1 or Ptgs-2 expressed the respective messages and proteins at about 50% of the levels observed in wild-type mice. In the tissues examined (stomach, colon, kidney, testes), COX-1 null mice did not compensate by up-regulating the expression of COX-2, nor did
Effects of COX deficiency on carcinogenesis
One of our original goals for making the COX null mice was to investigate the roles of COX-1 and COX-2 in carcinogenesis. Two types of cancers, colon cancer and skin cancer, had been chosen for study. The rationales for the COXs having roles in colon cancer development are based on both rodent and human epidemologic data. Reddy and colleagues [56 and references therein] had conducted many studies indicating that NSAIDs reduce carcinogen-induced intestinal cancer in rodents. Furthermore,
Effects of COX deficiency on female reproductive processes
Prostaglandins are known to have important roles in the female reproductive processes, and understanding of the contributions of the individual COX isoforms in female reproduction has been facilitated by the development of COX deficient mice 82, 83, 84, 85.
In initial studies, we observed that COX-1 null female mice produced litters of normal size, but had difficulty with parturition, and most pups were born dead or died shortly after birth [38]. Other aspects of the female reproductive
Effects of COX deficiency on the inflammatory response
Inflammation is a complex biological response modulated by various chemical mediators with which prostaglandins have a synergistic role 45, 88. Since the recent discovery of COX-2, a significant number of studies have associated this isoform with the inflammatory process, and, therefore, considerable effort has gone into developing NSAIDs that selectively inhibit this isoform 22, 23, 24, 25, 26, 27, 28, 29. To better understand the relative contributions of the COX isoforms in the inflammatory
Effects of COX deficiency on spontaneous and induced gastric ulceration
The current hypothesis about the medicinal usage of NSAIDs is that inhibition of COX-2 is responsible for their beneficial effects, whereas the inhibition of COX-1 is responsible for their adverse effects, the most common of which is gastric ulceration. Therefore, it was surprising that COX-1 deficient mice did not spontaneously develop gastric ulcers [38]. Measurement of gastric PG levels in the COX-1 null mice indicated a greater than 99% reduction, and this reduction in gastric PGs was
Development of mice deficient in both COX isoforms
Because both COX-1 and COX-2 null mice independently showed reasonable survival 38, 39, 40, we thought that it might be possible to develop a mouse line deficient in both isoforms, i.e. COX-1(−/−)-COX-2(−/−). A COX-1 and COX-2 double null mouse could offer a model to elucidate the essential physiological functions of PGs. In the course of generating double null mice, COX-1(+/−)-COX-2(+/−), COX-1(+/−)-COX-2(−/−), and COX-1(−/−)-COX-2(+/−) mice also would be produced. As gene dosage effects have
Relevance of COX-deficient mice to humans
Humans with platelets deficient in COX-1 activity have been identified [105]. Western analyses of three human cases have indicated two distinct types of defects. In two cases, no detectable COX-1 protein was observed, similar to the targeted disruption of the Ptgs-1 gene in mice [38]. In the second defect type, COX-1 protein was present, but the protein lacked catalytic activity. The characteristics of the three patients were: mild bleeding disorders, reduced platelet aggregation, and reduced
Conclusion
Data obtained with the COX-1 and COX-2 null mice have contributed to a clearer understanding of the physiological roles of the two COX isoforms. A summary of the phenotypes of the COX null mice is shown in Table 1. Based on pathologies observed in the null mice, it appears that deficiency of COX-2 has more severe effects than does deficiency of COX-1. No doubt, additional effects of COX deficiency will be obtained as these mice are studied further.
The mechanisms by which PGs originating from
References (108)
- et al.
Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase)
J Biol Chem
(1988) - et al.
A serum- and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein
J Biol Chem
(1991) - et al.
TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue
J Biol Chem
(1991) - et al.
Hormonal regulation of messenger ribonucleic acid encoding a novel isoform of prostaglandin endoperoxide H synthase in rat preovulatory follicles. Induction in vivo and in vitro
J Biol Chem
(1992) - et al.
Prostaglandin endoperoxide H synthases-1 and -2
Adv Immunol
(1996) - et al.
Differentiation of monocytoid THP-1 cells with phorbol ester induces expression of prostaglandin endoperoxide synthase-1 (COX-1)
Biochem Biophys Res Commun
(1993) - et al.
Effects of transforming growth factor-β and interleukin-1 β on expression of cyclooxygenase 1 and 2 and phospholipase A2 mRNA in lung fibroblasts and endothelial cells in culture
Biochem Biophys Res Commun
(1993) - et al.
Selective induction of prostaglandin G/H synthase I by stem cell factor and dexamethasone in mast cells
J Biol Chem
(1995) - et al.
Expression of a mitogen-inducible cyclooxygenase in brain neuronsRegulation by synaptic activity and glucocorticoids
Neuron
(1993) - et al.
Constitutive expression of prostaglandin endoperoxide G/H synthetase (PGHS)-2 but not PGHS-1 in human tracheal epithelial cells in vitro
Prostaglandins
(1996)