Role of melatonin in regulating matrix metalloproteinase‐9 via tissue inhibitors of metalloproteinase‐1 during protection against endometriosis

Abstract

Endometriosis is a gynecological disease of women and plausibly regulated by matrix metalloproteinases (MMPs). However, mechanisms of alterations in MMPs during endometriosis remain unclear. Human endometriotic tissues possessing varying degrees of severity were examined for expression of MMPs and tissue inhibitors of metalloproteinase (TIMP)-1. In addition, endometriosis was generated in mice and endometriotic tissues were tested for MMP-9 activity. Results show significant upregulation of secreted and synthesized proMMP-9 activity with duration and severity of endometriosis. Along with upregulation of activity, the expression of proMMP-9 was found increased while TIMP-1 expression followed an inverse trend. The effect of melatonin, a major secretory product of the pineal gland, on endometriosis was examined in preventive and therapeutic models in mice. The results show that melatonin arrested lipid peroxidation and protein oxidation and downregulated proMMP-9 activity and expression in a time and dose-dependent manner while protecting and regressing peritoneal endometriosis. Moreover, the attenuated activity and expression of proMMP-9 were associated with subsequent elevation in the expression of TIMP-1. Our study reveals for the first time the role of melatonin in arresting peritoneal endometriosis in mice and a novel marker, expression ratio of proMMP-9 versus TIMP-1, was identified for assessing severity and progression of endometriosis.

Melatonin inhibits IL1β-induced MMP9 expression and activity in human umbilical vein endothelial cells by suppressing NF-κB activation

“…MMPs are involved in the development processes of experimental colitis (Esposito et al 2008b), endometriosis (Paul et al 2008), liver injury (Mishra et al 2011), traumatic experimental spinal cord injury (Esposito et al 2008a), acute ischemic stroke (Ramos-Fernandez et al 2010), and neurodegenerative diseases (Reyes et al 2009, Rosenberg 2009, Bauer et al 2010. Meanwhile, many studies also show that MMPs have contributed to tumor invasion, metastasis, and angiogenesis (Toth & Fridman 2001, Zhang et al 2003, Kessenbrock et al 2010, Pratheeshkumar & Kuttan 2011.…”

Melatonin treatment results in regression of endometriotic lesions in an ooferectomized rat endometriosis model

“…In the mouse model it was shown that melatonin down-regulated proMMP-9 and MMP-3 expression and activity, and enhanced the expression of a natural inhibitor of MMPs known as TIMP-1 (tissue inhibitors of metalloproteinases) in a dose-dependent manner. The preventive and therapeutic action in endometriosis-like lesions was confirmed, with an increased apoptotic index (34,48). Our study showed that treatment with melatonin effectively regressed endometriotic explants in a rat model.…”

“…Therefore, it may interfere with the oxidative stress seen in endometriosis. It may also have an impact on the extracellular matrix remodelling seen in this disease, through the regulation of the zinc-requiring proteolytic enzymes MMPs, as there is indirect evidence that melatonin inhibits the production of adhesion molecules that promote the binding of leukocytes to endothelial cells (32)(33)(34). Therefore, melatonin may be an effective treatment modality in endometriosis.…”

Novel Medical Treatment Modalities of Endometriosis

“…It caused regression and atrophy of endometriotic lesions in rats. It also, had a more pronounced regression of surgically induced endometriotic foci when compared with letrozole in a rat model 42,43 . Th e possible eff ect of melatonin on the regulation of endometriosis was tested by interfering with matrix metalloproteinase activity in the mice model.…”