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Doxycycline reduces MMP-2 activity and inhibits invasion of 12Z epithelial endometriotic cells as well as MMP-2 and -9 activity in primary endometriotic stromal cells in vitro


Samartzis, Eleftherios P; Fink, Daniel; Stucki, Manuel; Imesch, Patrick (2019). Doxycycline reduces MMP-2 activity and inhibits invasion of 12Z epithelial endometriotic cells as well as MMP-2 and -9 activity in primary endometriotic stromal cells in vitro. Reproductive Biology and Endocrinology, 17:38.

Abstract

BACKGROUND

Matrix metalloproteinases (MMPs), especially the gelatinases MMP-2 and MMP-9, play a crucial role in the pathogenesis of endometriosis by enabling invasion. Doxycycline is a well-tolerated antibiotic and a potent MMP-inhibitor in subantimicrobial doses.

METHODS

Gelatin zymography and activity assays were used to detect latent and active MMP-2 and -9 in cell culture supernatants of immortalized epithelial (12Z) and two isolates of primary endometriotic stromal cells treated with doxycycline. The invasiveness of 12Z endometriotic cells treated with doxycycline was assessed in matrigel-coated invasion chambers. The effect on latent and active MMP-2 expression of the combination of progesterone and doxycycline was tested in 12Z.

RESULTS

Doxycycline significantly reduced the MMP-2 activity and pro-MMP-2 expression in 12Z and the MMP-2 and -9 activity as well as expression of pro-MMP-2 and -9 in primary endometriotic stromal cells. The percentage of 12Z cells invading through a matrigel-coated membrane was reduced to 65 and 22% of the control after treatment with doxycycline at doses of 1 μg/ml and 10 μg/ml, respectively. Furthermore, a combination of progesterone and doxycycline showed an additive effect in low doses on the reduction of MMP-2 activity and pro-MMP2 expression in 12Z endometriotic cells.

CONCLUSIONS

In conclusion, the MMP-inhibiting features of subantimicrobial-dose doxycycline may be further evaluated as a well-tolerable additional therapeutic approach, e.g. in combination with progestins such as dienogest, in patients with infiltrative endometriosis with insufficient response to current medical treatment options.

Abstract

BACKGROUND

Matrix metalloproteinases (MMPs), especially the gelatinases MMP-2 and MMP-9, play a crucial role in the pathogenesis of endometriosis by enabling invasion. Doxycycline is a well-tolerated antibiotic and a potent MMP-inhibitor in subantimicrobial doses.

METHODS

Gelatin zymography and activity assays were used to detect latent and active MMP-2 and -9 in cell culture supernatants of immortalized epithelial (12Z) and two isolates of primary endometriotic stromal cells treated with doxycycline. The invasiveness of 12Z endometriotic cells treated with doxycycline was assessed in matrigel-coated invasion chambers. The effect on latent and active MMP-2 expression of the combination of progesterone and doxycycline was tested in 12Z.

RESULTS

Doxycycline significantly reduced the MMP-2 activity and pro-MMP-2 expression in 12Z and the MMP-2 and -9 activity as well as expression of pro-MMP-2 and -9 in primary endometriotic stromal cells. The percentage of 12Z cells invading through a matrigel-coated membrane was reduced to 65 and 22% of the control after treatment with doxycycline at doses of 1 μg/ml and 10 μg/ml, respectively. Furthermore, a combination of progesterone and doxycycline showed an additive effect in low doses on the reduction of MMP-2 activity and pro-MMP2 expression in 12Z endometriotic cells.

CONCLUSIONS

In conclusion, the MMP-inhibiting features of subantimicrobial-dose doxycycline may be further evaluated as a well-tolerable additional therapeutic approach, e.g. in combination with progestins such as dienogest, in patients with infiltrative endometriosis with insufficient response to current medical treatment options.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Gynecology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Reproductive Medicine
Life Sciences > Endocrinology
Health Sciences > Obstetrics and Gynecology
Life Sciences > Developmental Biology
Language:English
Date:13 April 2019
Deposited On:29 Jan 2020 15:09
Last Modified:22 Apr 2020 22:27
Publisher:BioMed Central
ISSN:1477-7827
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1186/s12958-019-0481-z
PubMed ID:30981279

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