Original Article Celecoxib reduces inflammation and angiogenesis in mice with adenomyosis
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Am J Transl Res 2021;13(4):2858-2866
www.ajtr.org /ISSN:1943-8141/AJTR0128630
Original Article
Celecoxib reduces inflammation and
angiogenesis in mice with adenomyosis
Shuang Liang1, Lu-Ying Shi1, Jing-Ya Duan1, Huan-Huan Liu2, Ting-Ting Wang3, Can-Yu Li1
1
Department of Gynecology, The Third Affiliated Hospital of Zhengzhou University, China; 2Department of
Obstetrics and Gynecology, Xinxiang Central Hospital, China; 3Department of Gynecology, Kaifeng Obstetrics and
Gynecology Hospital, China
Received December 20, 2020; Accepted January 28, 2021; Epub April 15, 2021; Published April 30, 2021
Abstract: Objective: This study aimed to explore the effect of COX-2 selective inhibitor (celecoxib) on adenomyosis
and its mechanism. Methods: By establishing a mouse model of adenomyosis and using celecoxib to treat adeno-
myosis, newly born female mice were randomly divided into a control group, adenomyosis model group, and cele-
coxib group. Hematoxylin-eosin (H&E) staining was used to observe the depth of endometrial infiltration of mouse
adenomyosis. RT-PCR (reverse transcription PCR) and western blot were used to detect the expression of Cyclooxy-
genase-2 (COX-2), Vascular growth factor (VEGF), Nerve growth factor (NGF), and Corticotropin-releasing hormone
(CRH) mRNA and protein in mice before and after celecoxib treatment. Results: After treatment with celecoxib, the
depth of endometrial infiltration of mouse adenomyosis was reduced. COX-2 and VEGF decreased significantly after
celecoxib inhibited expression of COX-2 (P0.05). Conclusion: This study indicated that COX-2 may be an important factor related to the pathogen-
esis of adenomyosis, and it may become an important molecular target for the treatment of adenomyosis.
Keywords: Adenomyosis, celecoxib, COX-2, VEGF, NGF, CRH, EMT
Introduction For the treatment strategy, surgical resection
may be the recommendation for refractory
Adenomyosis refers to a benign gynecological adenomyosis, whereas many patients with fer-
disease. The pathologic feature is diffuse or tility requirements and uterine preservation are
localized infiltration of the myometrium by reluctant to choose surgery [12, 13]. Acco-
endometrial glands and interstitial cells. The rdingly, exploring new target drugs to treat ade-
clinical symptoms include progressive dysmen- nomyosis is the aim of the present study. Non-
orrhea, chronic pelvic pain, or subsequent steroidal anti-inflammatory drugs (NSAIDs) are
symptoms (e.g., primary infertility), seriously the most widely used therapeutic drugs to treat
affecting the patient’s body and mind [1, 2]. inflammation and pain, and have extensive
Adenomyosis is closely related to endometrio- applications to treat rheumatoid joint disease
sis [3, 4], and they exhibit many common fea- and osteoarthritis. However, by its inhibiting
tures for symptoms, histology and molecular effect on the expressions of COX-1 and COX-2
changes [5-7]. Though they are benign diseas- to varying degrees, it imposes damage on the
es, they both exhibit several characteristics of gastrointestinal system [14]. COX-1 and COX-2
malignant tumors (e.g., angiogenesis, local or are isoenzymes performing prostaglandin syn-
distant invasion and metastasis) [8, 9]. thesis. COX-1 is constitutively expressed in nor-
However, some differences are revealed in their mal tissues, while COX-2 can be induced and
pathogenesis [10]. Over the past few years, up-regulated in pain and inflammatory path-
studies have shown that angiogenesis, inflam- ways [15]. Celecoxib refers to a potent COX-2
matory mediators, and nerve growth factors selective inhibitor, inhibiting the prostaglandin
(NGF) may be related to the occurrence, devel- cascade by preventing the binding of arachidic
opment, and pain symptoms of adenomyosis acid and the active site of cyclooxygenase-2. It
[11]. is an anti-inflammatory, analgesic, and anti-
Role of celecoxib in adenomyosis
pyretic drug [16]. In recent years, celecoxib number method. The control group only took
has also been investigated for tumor therapy the solvent (the mixture of peanut oil/lecithin/
by inhibiting angiogenesis, epithelial-mesen- condensed milk, the volume ratio was 2:0.5:3)
chymal transition (EMT), cell proliferation, and all the time. The mice in the adenomyosis
invasion [17-19]. model group and celecoxib group received oral
tamoxifen to induce adenomyosis. Mice in the
COX-2 and VEGF facilitate the formation of new adenomyosis model group and celecoxib group
blood vessels, a necessary condition for the received 2.7 µmol/L tamoxifen suspended in a
endometrium to invade the myometrium [20, peanut oil/lecithin/condensed milk mixture
21]. Besides angiogenesis factors, inflamma- (volume ratio 2:0.5:3) on the 2nd to 5th day
tory factors, and intimal and interstitial inva- after birth (birthday is the first day) at a dose
sion are also pathogenic factors in adenomyo- volume of 5 μl/g, furthermore, from the 6th day,
sis [22]. Among inflammatory mediators, adre- the mice in the celecoxib group were fed with
nal cortex hormone releasing hormone (CRH) celecoxib 30 mg/(Kg·d), and the adenomyosis
is of critical significance. It is highly express- model group received the same amount of sol-
ed in endometriotic lesions and related to vent every day.
stress and pain mechanisms [23]. Moreover,
nerve growth factor (NGF) and its receptor are Specimen collection
involved in the development of nociceptors,
and facilitate the release of histamine from Mice were breast-fed by mothers at the age of
mast cells, accelerating the production of hy- 1 to 21 days. From 22 d onwards, mice and
peralgesia. However, the correlation between mothers are kept in separate cages. Mice could
COX-2, VEGF, CRH, and NGF with adenomyosis eat and drink freely. The three groups (the cele-
have rarely been explored. This study aims to coxib group, the adenomyosis group, and the
explore the relationship between those cyto- control group) of mice were all raised for 3
kines with adenomyosis and attempts to ex- months and then euthanized. Uterine tissues
plore their likely pathogenesis for adenomy- were taken, embedded in paraffin, and paraf-
osis. fin-embedded sections were subjected to H&E
staining to observe the degree of myometrial
Materials and methods gland infiltration.
Chemicals In this study, all experiments were conducted
under the guidance of the “Guidelines for the
Tamoxifen (Shanghai Fudan Fuhua Pharma- Care and Use of Laboratory Animals” of the
ceutical Co., Ltd); Celecoxib (Pfizer Pharmace- National Research Council and approved by the
uticals LLC), The H&E staining kit was pur- Laboratory Animal Review Committee.
chased from Beijing Solarbio Technology Co.,
Ltd. RT-PCR
Mice adenomyosis model and animal treat- The total RNA was extracted according to the
ment instructions of the Trizol kit, and the expression
of COX-2, VEGF, NGF, and CRH mRNA in adeno-
6 ICR pregnant mice aged 17-19 days of ge- myosis were detected by two-step RT-PCR. The
station, weighing 38~40 g, were purchased amplification program was as follows: 94°C for
from Qinglongshan Animal Breeding Farm in 5 min, followed by 28 cycles of 94°C for 30 s,
Jiangning District, Nanjing (Nanjing, China). annealing temperature 56°C for 30 s, and 72°C
The pregnant mice were kept in separate cages for 10 s, and finally 5 min at 72°C for a final
during the whole pregnancy period. Newborn extension. The product was subjected to 2%
female mice were selected for follow-up agarose gel electrophoresis, with the glyceral-
research. All mice could take in food and drink- dehyde phosphate dehydrogenase (GAPDH)
ing water freely with 12 hours of light every day. gene as an internal reference, and the gel elec-
According to the research of Parrott et al. [24], trophoresis image was photographed and
newborn female mice were selected and divid- saved using Image J software to analyze the
ed into control group (n=6), adenomyosis model expression of the target gene. Refer to Table 1
group (n=6), celecoxib group (n=6) by random for primer design.
2859 Am J Transl Res 2021;13(4):2858-2866
Role of celecoxib in adenomyosis
Table 1. RT-PCR primer sequences Statistical analysis
Forward sequences Reverse sequences
The SPSS statistical analy-
COX-2 5’-GGAATGTATGAGCACAGGAT-3’ 5’-ATGATTAAACTTCGCAGGAA-3’ sis software package 22.0
VEGF 5’-ATGAACTTTCTGCTCTCTTG-3’ 5’-GTCGGGGTACTCCTGGAAGA-3’ was used for statistical an-
NGF 5’-ATGTCCATGTTGTTCTACAC-3’ 5’-CAGCTATTGGTGCAGTAGGG-3’ alysis. The comparison be-
CRH 5’-ATGCGGCTGCGGCTGCTGGT-3’ 5’-GACTTCTGTTGAGATTCCCC-3’ tween multiple groups was
GAPDH 5’-GGTGAAGGTCGGTGTGAACG-3’ 5’-CTCGCTCCTGGAAGATGGTG-3’ performed by one-way anal-
ysis of variance (one-Way
ANOVA), and the LSD meth-
od was used for multiple test verification. P<
0.05 indicated a significant difference.
Results
Detection of the modelling of adenomyosis in
mice
According to the evaluation criteria of Bird et
al. [25], one of the histologic diagnostic criteria
of mouse adenomyosis is that endometrial
Figure 1. Uterus of 90-day-old in control group, ce- glands infiltrate the myometrium but do not
lecoxib group, and adenomyosis model group. V- penetrate the serosa. The other diagnostic cri-
shaped mouse uterus was stretched into a straight teria are the destruction of concentric and lon-
line. The red arrow points to the cervix.
gitudinal smooth muscle bands. In addition, the
infiltration of the endometrium into the myome-
Western blotting trium is graded as follows: Grade 0, the endo-
metrium is not infiltrating into the myometrium;
We took the mouse uterus tissue from each Grade I, subbasal adenomyosis (adenomyosis
group, extracted the total protein according to in a low-power field below the basal endometri-
the kit instructions, determined the protein um, without further penetration); Grade II, uter-
concentration by BCA method, separated the ine adenomyosis penetrates into the middle of
protein with 8% and 12% SDS-PAGE, then the myometrium; Grade III, adenomyosis pene-
transfered to polyvinylidene fluoride (PVDF) trates beyond the middle of the myometrium.
membrane. Blocking was with 5% skim milk. The uterus of mice of 90-day-old in control
Membrane was washed with TBST buffer 3 group, celecoxib group and adenomyosis mo-
times Primary antibody was added (COX-2 rab- del group are shown in Figure 1. H&E staining
bit.no.ab62331, 1:1,000; VEGF rabbit.AF5153, images of uterus of mice aged 90 days in the
control group, celecoxib group and adenomyo-
1:1,000; NGF rabbit.no.ab52918, 1:1,000;
sis model group are shown in Figure 2. Figure
CRH rabbit.no.DF6258, 1:1,000), and incu-
2A shows that the smooth muscle layer fibers
bated at 4°C overnight. The membrane was
of the mouse myometrium circulate centrally
washed with TBST solution 3 times. Horsera-
and regularly outside the endometrium, and
dish Peroxidase (HRP)-labeled corresponding there is no pathological change of adenomyo-
secondary antibody (diluted 1:4,000) was sis. Figure 2B and 2C, demonstrate that the
added and incubated at 37°C for 60 min. endometrial glands are located in the muscular
The membrane was washed again with TBST layer. At the same time, the smooth muscle
solution 3 times. Enhanced chemilumines- structure of the muscular layer is obviously dis-
cence (ECL) kit was used for substrate develop- ordered, and the boundary with the endometri-
ment. GAPDH was the internal reference. An um is not clear. The depth of the endometrium
image was taken after storage. Image J soft- infiltration into the myometrium of the celecox-
ware was used for analysis, and the ratio of the ib group was less than that of the adenomyosis
target protein band to the gray value of GAPDH model group. As demonstrated in Figure 2D,
indicated the expression level of the target compared with the control group, the endome-
protein. trial infiltration depth of mice in the adenomyo-
Am J Transl Res 2021;13(4):2858-2866Role of celecoxib in adenomyosis Figure 2. In a mouse model of tamoxifen-induced adenomyosis, Celecoxib reduces the depth of endometrial infil- tration into the myometrium. (A-C) represent H&E stained images of mouse uterus in the control group, celecoxib group, and adenomyosis model group respectively. Ectopic endometrium gland (arrow) invades to the superficial and deep myometrium in (B and C) (scale bar: 100 μm and 20 μm). (D) represents quantified grades of myometrial infiltration by the endometrium in the control group, celecoxib group, and adenomyosis model group at 3 months after birth. sis model group was significantly increased 2, VEGF, NGF, and CRH by western blot (Figure (P
Role of celecoxib in adenomyosis
in the endometrium in adeno-
myosis [15]. COX-2 was dem-
onstrated extensively to be
closely related to the occur-
rence, development, and me-
tastasis of tumors, which pro-
motes the production of PGs
and induces EMT by up-regu-
lating the expression of COX-2
[30, 31]. Epithelial-mesenchy-
mal transition (EMT) indicates
the process by which epitheli-
al cells lose their epithelial
phenotype and acquire a me-
Figure 3. RT-PCR analysis of COX-2, VEGF, NGF, and CRH mRNA expression in
each group of mice. Expression of COX-2, and VEGF mRNA was significantly senchymal phenotype. Estro-
inhibited by celecoxib, but the expression of NGF and CRH mRNA had no gen-related epithelial-mesen-
significant difference. ***PRole of celecoxib in adenomyosis
lated based on the above data that inhibiting pating in cell differentiation or acting as a
COX-2 cannot completely prevent the occur- pro-inflammatory factor [41]. In endometriosis,
rence of adenomyosis, but it can reduce the high expression of CRH induces an increase in
degree of adenomyosis. Besides inflammation the number of activated mast cells, probably
and angiogenesis, other factors or mechanisms causing inflammation and fibrosis of the en-
may be also involved. dometrium [42]. In joint synovial tissue, CRH
stimulates the production of PGE2 by COX-2
Nerve growth factor (NGF) is a multifunctional activity, and it acts in an autocrine manner in
mediator. It can act as a pain mediator. Nerve the synovium by facilitating the production of
growth factor is related to the pain of various PGE2. Prostaglandin E2 was suggested to im-
diseases (e.g., osteoarthritis, synovitis and low prove CRH synthesis in synovial cells of rheu-
back pain) [36]. NGF locally produced in pa- matoid arthritis [43]. As revealed from the
tients with endometriosis helps produce and results of this study, the expression of CRH in
maintain endometriosis-related pain (e.g., dys- the adenomyosis model group and celecoxib
menorrhea and dyspareunia) [37]. Interestingly, group was higher than that in the controls. After
as suggested from the research results of treatment with celecoxib, no significant differ-
Barcena de Arellano [38] the overexpression of ence was identified in CRH expression between
nerve growth factor in the peritoneal fluid of the adenomyosis model group and celecoxib
patients with endometriosis is not tightly asso- group, demonstrating that the production of
ciated with the production of endometriosis CRH in adenomyosis is not completely depen-
pain. It is therefore considered that the overex- dent on PGS. It may be an inflammatory reac-
pression of NGF promotes the overexpression tion attributable to adenomyosis, and it acts on
of proinflammatory factors and pain mediators, the uterine tissue by an autocrine/paracrine
induces sensitization of nociceptors around the method. The specific mechanism requires more
ectopic endometrium, and then produces pain specific studies.
sensation. The overexpression of factors and
pain mediators leads to the sensitization of In summary, the pathogenesis of adenomyosis
nociceptors around the ectopic endometrium, displays a close relationship to COX-2. After
which in turn produces pain. As revealed from the use of celecoxib to inhibit COX-2, the degree
existing studies, in cultured endometriotic stro- of infiltration of the muscularis in the endome-
mal cells, NGF is capable of stimulating COX-2/ trium of mice with adenomyosis was down-reg-
PGS signaling, which is considered a vital part ulated. The mechanism by which celecoxib
of the pain attributed to inflammation in endo- works may be multfactorial (e.g., inhibition of
metriosis [39]. Moreover, as revealed from endometrial inflammation, EMT, and angiogen-
existing studies, NGF in rat mast cells can esis). Accordingly, this study deduces that inhi-
induce COX-2 expression and its accompanying bition of COX-2 may have promise for treating
PGD2 production [40]. According to this study, adenomyosis. This study performed only in vivo
the expression of NGF in the adenomyosis experiments and there was no in vitro detec-
model group and the celecoxib group exceeded tion of the expression of each factor after
that in the controls, demonstrating that NGF COX-2 inhibition. In addition, this experiment
may be involved in the occurrence of adenomy- was an animal experiment, and the number of
osis and pain-related symptoms. No significant samples was small. The therapeutic mecha-
difference was identified in the expression of nism of COX-2 selective inhibitors in adenomyo-
NGF after celecoxib was employed, revealing sis requires in-depth studies.
that NGF impacts the formation of adenomyo-
sis by other signal pathways, instead of the Acknowledgements
COX-2/PGS pathway, in the pathogenesis of
adenomyosis. Accordingly, the expression of We are grateful to all those who have contrib-
NGF did not significantly decrease after COX-2 uted to this research. This work was supported
was inhibited. by the Henan Science and Technology Research
Project (No. 182102310142 to Canyu, Li), and
Corticotropin-releasing hormone (CRH) regu- the Henan Health Commission Medical Scien-
lates the neurohormones of the hypothalamic- ce and Technology Project (No. 2018020167 to
pituitary-adrenal axis, and is capable of partici- Canyu, Li).
Am J Transl Res 2021;13(4):2858-2866Role of celecoxib in adenomyosis
Disclosure of conflict of interest osis. Biochem Biophys Res Commun 2018;
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None. [10] Lacheta J. Uterine adenomyosis: pathogene-
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of Zhengzhou University, 7 Kangfu Front Street, Chapron C, Guo SW and Petraglia F. Pathogen-
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