The cannabinoid receptor CB1 contributes to the development of ectopic lesions in a mouse model of endometriosis.
Does signaling via the cannabinoid (CB1) receptor play a role in the pathogenesis of endometriosis in a mouse model?



Mice treated with a CB1agonist developed larger ectopic lesions, while less severe lesions developed in the absence of functional CB1expression.



The expression of components of the endocannabinoid system has been demonstrated in both mouse and human uteri. CB1receptors are expressed in human epithelial and stromal cell lines derived from eutopic endometrium and deep infiltrating endometriosis nodules.



This was a randomized study in a mouse model of endometriosis. In a first set of experiments, mice with endometriosis were treated with the CB1receptor agonist methanandamide (MET) (5 mg/kg, n = 20) on Days 1-5 and 8-12. In a second set of experiments, endometriosis development was evaluated in CB1-/-mice and in their wild-type (WT) littermates.



Endometriosis-like lesions were induced in Balb/c and C57/Bl6 mice. Two weeks after disease induction, the lesions were counted, measured and either included for immunohistochemistry analysis or frozen for gene expression profiling by semi-quantitative real-time PCR. To limit the role of chance, the experiments were conducted under standardized laboratory conditions with appropriate controls.



The lesion total volume was significantly higher in MET-treated compared with vehicle-treated mice (P < 0.05). Expression levels of mRNA for survivin, N-cadherin, integrin β1 and interleukin-6 were increased in the ectopic endometrium of MET-treated versus vehicle-treated mice (P < 0.05). CB1-/-recipients that received endometrial tissue fragments from CB1-/-donors, WT recipients that received endometrial tissue fragments from CB1-/-donors and CB1-/-recipients that received endometrial tissue fragments from WT donors all showed a significant reduction in total lesion volume and lower expression of survivin and N-cadherin compared with WT recipients receiving uterine fragments from WT donors (P < 0.05).



N/A.



We provide evidence that endocannabinoid signaling via CB1receptor plays a role in the development of endometriosis in a mouse model. However, the relative contribution of the CB1-mediated signaling pathways active in inflammatory, uterine and peritoneal cells remains to be ascertained. Since the study was performed in a mouse model, the significance of the findings in the human system warrants further investigation.



Clarifying the function and regulation of CB1and its molecular interactions with endogenous ligands, and how endocannabinoids levels are regulated in women with endometriosis, represent critical areas of research for the potential development of a novel medical treatment of the disease.



A.M.S. was supported by a fellowship from Fondazione Giorgio Pardi. The authors have no conflicts of interest to declare.
Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
Ana-Maria
AM
Sanchez
Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
Federica
F
Quattrone
Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
Maria
M
Pannese
Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
Adele
A
Ulisse
Obstetrics and Gynecology, IRCCS Ospedale San Raffaele, Milan, Italy.
Massimo
M
Candiani
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University , Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Javier
J
Diaz-Alonso
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University , Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
Guillermo
G
Velasco
Reproductive Sciences Laboratory, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy panina.paola@hsr.it.
Paola
P
Panina-Bordignon
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004715:Endometriosis / Q000378:metabolism / Q000473:pathology*; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D010532:Peritoneal Diseases / Q000378:metabolism / Q000473:pathology*; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077022:Survivin
D001095:Arachidonic Acids; C117749:Birc5 protein, mouse; D015820:Cadherins; D063386:Cannabinoid Receptor Agonists; D051034:Inhibitor of Apoptosis Proteins; D019012:Integrin beta1; D015850:Interleukin-6; D043884:Receptor, Cannabinoid, CB1; D012097:Repressor Proteins; D000077022:Survivin; C088155:methanandamide
adhesion; cannabinoid receptor CB1
; endometriosis; inflammation; methanandamide; mouse model