Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ER|[alpha]|)

doi:doi:10.1038/labinvest.2009.79

Laboratory Investigation (2009) 89, 1076–1083; doi:10.1038/labinvest.2009.79; published online 10 August 2009

Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ER)

Stefan M Gold^1,2, Manda V Sasidhar¹, Laurie B Morales¹, Sienmi Du¹, Nancy L Sicotte¹, Seema K Tiwari-Woodruff¹ and Rhonda R Voskuhl¹

¹Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
²Cousins Center, Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Correspondence: Professor RR Voskuhl, MD, Department of Neurology, University of California, Los Angeles, 635 Charles Young Drive South, NRB1 Room 475D, Los Angeles, CA 90095, USA. E-mail: rvoskuhl@ucla.edu

Received 11 February 2009; Revised 18 June 2009; Accepted 7 July 2009; Published online 10 August 2009.

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Abstract

Matrix metalloproteinases (MMPs) have a crucial function in migration of inflammatory cells into the central nervous system (CNS). Levels of MMP-9 are elevated in multiple sclerosis (MS) and predict the occurrence of new active lesions on magnetic resonance imaging (MRI). This translational study aims to determine whether in vivo treatment with the pregnancy hormone estriol affects MMP-9 levels from immune cells in patients with MS and mice with experimental autoimmune encephalomyelitis (EAE). Peripheral blood mononuclear cells (PBMCs) collected from three female MS patients treated with estriol and splenocytes from EAE mice treated with estriol, estrogen receptor (ER) ligand, ER ligand or vehicle were stimulated ex vivo and analyzed for levels of MMP-9. Markers of CNS infiltration were assessed using MRI in patients and immunohistochemistry in mice. Supernatants from PBMCs obtained during estriol treatment in female MS patients showed significantly decreased MMP-9 compared with pretreatment. Decreases in MMP-9 coincided with a decrease in enhancing lesion volume on MRI. Estriol treatment of mice with EAE reduced MMP-9 in supernatants from autoantigen-stimulated splenocytes, coinciding with decreased CNS infiltration by T cells and monocytes. Experiments with selective ER ligands showed that this effect was mediated through ER. In conclusion, estriol acting through ER to reduce MMP-9 from immune cells is one mechanism potentially underlying the estriol-mediated reduction in enhancing lesions in MS and inflammatory lesions in EAE.