Mae. Rageh et al., Steroidal regulation of connective tissue growth factor (CCN2; CTGF) synthesis in the mouse uterus, J CL PATH-M, 54(5), 2001, pp. 338-346
Citations number
48
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Aims-To determine mechanisms regulating the production of connective tissue
growth factor (CCN2; CTGF) and transforming growth factor beta1 (TGF-beta1
) in the mouse uterus.
Methods-In situ hybridisation and immunohistochemistry were used to localis
e CCN2 (CTGF) and TGF-beta1 in uteri from sexually mature female mice that
had either been (1) mated with sterile males to induce pseudopregnancy or (
2) ovariectomised (OVX) and administered estradiol-17 beta (E-2) or progest
erone (P-4), either alone or in combination. Uteri collected on days 0.5, 1
.5, 2.5, 3.5, 4.5, or 5.5 of pseudopregnancy or at one, three, six, 12, or
24 hours after steroid administration were fixed, sectioned, and incubated
with specific riboprobes or antibodies to permit detection and localisation
of mRNA or protein for CTGF and TGF-beta1.
Results-On days 0.5-2.5 of pseudopregnancy, CCN2 (CTGF) and TGF-beta1 were
principally colocalised to uterine epithelial cells, with much smaller amou
nts in the stroma. On days 3.5-4.5, there was a reduction of CCN2 (CTGF) an
d TGF-beta1 in the epithelium but an increase in stromal and endothelial ce
lls, corresponding to a period of extracellular matrix remodelling and neov
ascularisation within the endometrium. In OVX mice, epithelial cells were w
eakly positive for both CCN2 (CTGF) and TGF-beta1 in the absence of steroid
hormones. Epithelial CTGF mRNA production were strongly but transiently st
imulated in OVX mice cells by E-2. These effects were antagonised by P-4, w
hich itself transiently stimulated epithelial CCN2 (CTGF) production, altho
ugh less robustly than E-2. CTGF and TGF-beta1 protein amounts were high in
epithelial cells throughout steroid treatment and were increased in the st
roma, where they were relatively long lived. Stromal CCN2 (CTGF) and TGF-be
ta1 were lower after co-administration of E-2 and P-4 than in response to e
ach hormone individually. Although ccn2 (ctgf) is a TGF-beta1 inducible gen
e in other systems, and both growth factors were often co-localised in uter
ine tissues in these studies, several treatment regimens resulted in high a
mounts of TGF-beta1 protein in stromal cells without the concomitant produc
tion of ccn2 (ctgf) mRNA.
Conclusions-Maternal factors are principal cues for CCN2 (CTGF) and TGF-bet
a1 production in the uterus because (1) their expression during pseudopregn
ancy is comparable to that seen in pregnancy and (2) they are regulated by
ovarian steroids. TGF-beta dependent and independent mechanisms of ccn2 (ct
gf) gene transcription exist in the uterus that are variably regulated by s
teroid hormones. Collectively, the data support a role for CCN2 (CTGF) in m
ediating the effects of steroid hormones and TGF-beta on endometrial functi
on.