Rescue of Female Infertility from the Loss of Cyclooxygenase-2 by Compensatory Up-regulation of Cyclooxygenase-1 Is a Function of Genetic Makeup

Abstract

Cyclooxygenase-2 (COX-2), an inducible rate-limiting enzyme in prostaglandin biosynthesis, is implicated in various physiological and pathological processes including female fertility, renal function, angiogenesis, inflammation, and tumorigenesis. We showed previously that targeted deletion of Ptgs2 encoding COX-2, but not Ptgs1 encoding COX-1, in C57BL/6J/129 mice produces complete female infertility resulting from multiple reproductive failures spanning ovulation, fertilization, and implantation. Here we show that Ptgs2 null mice on a CD1 background have dramatically improved female fertility including ovulation, fertilization, and implantation, giving rise to live births. We provide evidence that this improved fertility in CD1 Ptgs2 null mice is the result of a compensatory up-regulation of Ptgs1 which does not occur in C57BL/6J/129 mice missing Ptgs2. These results clearly demonstrate for the first time that COX-1 can replace specific functions of COX-2 in vivo in the context of genetic disparity. In light of this finding, the therapeutic use and efficacy of COX-2-specific inhibitors among human populations without regard for genetic and ethnic diversities should be revisited.

Autotaxin–lysophosphatidic acid– LPA 3 signaling at the embryo‐epithelial boundary controls decidualization pathways

“…Several tens of genes were up‐regulated 2 h after the T13 injection (Table 1). Among the genes, we focused on Hbegf and Ptgs2 (encoding COX‐2), because they are responsible for decidualization and knockout of these genes interfered with implantation (Lim et al , 1997; Song et al , 2002; Wang et al , 2004; Xie et al , 2007; Large et al , 2014), as was observed in Lpar3 KO mice (Ye et al , 2005). Both Hbegf and Ptgs2 were transiently induced, peaking at 2–9 h after the T13 injection (Fig 3A).…”

“…Maternal factors such as heparin‐binding epidermal growth factor (HB‐EGF) and cyclooxygenase‐2 (COX‐2) are induced in the epithelium surrounding the embryos (embryo‐epithelial interaction) and then act on the stroma to induce the expression of bone morphogenic protein 2 (Bmp2) and wingless‐related MMTV integration site 4 (Wnt4) in stroma (epithelial–stromal interaction; Lim et al , 1997; Paria et al , 2001; Song et al , 2002; Wang et al , 2004; Xie et al , 2007; Large et al , 2014). Mice in which these maternal factors (HB‐EGF, COX‐2, Bmp2, and Wnt4) are knocked out showed obvious defects in decidual reactions (Lim et al , 1997; Wang et al , 2004; Lee et al , 2007; Xie et al , 2007; Franco et al , 2011; Li et al , 2013; Large et al , 2014). Based on these observations, it has been proposed that some factor(s) are present in the embryo‐epithelial boundary and induce the expression of HB‐EGF and COX‐2 in the epithelium, which in turn facilitate the following decidual reactions through up‐regulation of Bmp2 and Wnt4 (Paria et al , 2001; Cha et al , 2012).…”

Loss of TNF-α-regulated COX-2 expression in ovarian cancer cells

“…It was found that, in contrast to the initial finding (Lim et al, 1997), the COX-2 knockout is reproductively adequate in females in certain genetic backgrounds due to a compensatory upregulation of COX-1 (Wang et al, 2004). Although COX-1 and COX-2 expression in ovaries is predominately in follicles and granulosa cells, rather than surface epithelial cells (Wang et al, 2004), it is possible that the loss of COX-2 expression in cancer cells leads to a compensatory expression of COX-1. Nevertheless, we did not observe the induction by TNF-a of COX-1 in cancer or noncancer ovarian surface epithelial cells.…”

Prostaglandin E2 Is a Product of Induced Prostaglandin-endoperoxide Synthase 2 and Microsomal-type Prostaglandin E Synthase at the Implantation Site of the Hamster

“…Both Ptgs1 and Ptgs2 are expressed in the uterine luminal epithelial, but not in stromal, cells during peri-implantation phases in the human endometrium (63). Thus, in the uterus, Ptgs1 and Ptgs2 functions are not also mutually exclusive because one isoform can also compensate for the lack of another isoform (64,65). In the current study, we demonstrated that PGE 2 is the preferential product of Ptgs2 and mPtges at the implantation site, and inhibition of Ptgs2 activity by using Ptgs2-selective inhibitor causes both the reduction in the number and the size of the implantation sites on day 5 of pregnancy in hamsters.…”