Elsevier

Biochemical Pharmacology

Volume 58, Issue 8, 15 October 1999, Pages 1237-1246
Biochemical Pharmacology

Commentaries
Cyclooxygenase knockout mice: Models for elucidating isoform-specific functions

https://doi.org/10.1016/S0006-2952(99)00158-6Get rights and content

Abstract

The development of cyclooxygenase (COX) deficient mice has allowed investigation into the individual physiological roles of the COX-1 and COX-2 isoforms. In the following article, the phenotypes of the two Ptgs (genes coding for COX-1 and COX-2) knockouts are summarized, and recent studies to investigate the effects of COX deficiency on cancer susceptibility, inflammatory response, gastric ulceration, and female reproductive processes are discussed. Also, the development and potential uses of mice deficient in both COX isoforms and mice containing only a single copy of one isoform are discussed. Additionally, when the data permit, the effects of genetic ablation of COX activity are compared with those of pharmacological inhibition of COX activity by nonsteroidal anti-inflammatory drugs. The data suggest that prostaglandins derived via the individual COX isoforms have separate as well as common functions. However, for the maintenance of normal physiology, it appears that deficiency of COX-2 has more profound effects than deficiency of COX-1.

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

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