title: MT-MMPs in pre-eclamptic placenta: relationship to soluble endoglin production.
abstract: BACKGROUND
  Pre-eclampsia is a serious complication of pregnancy, characterized by severe endothelial dysfunction resulting in hypertension, proteinuria and maternal end-organ damage. Soluble endoglin is an anti-angiogenic factor released from placenta that has been linked to severe pre-eclampsia. We recently reported MMP-14 is capable of cleaving endoglin to release soluble endoglin from placenta, however inhibition studies only partially repressed production. To this end we have sought to identify other proteases that mediate endoglin shedding from placenta. MMP-14 is one of six-membrane-type (MT-) MMPs, a sub-family of the MMP superfamily, so named because they are membrane bound. MMP-15 is phylogenetically the closest MMP relative to MMP-14, however its inhibition has no effect on soluble endoglin production from placenta.
  
  
  METHODS
  Here we aimed to characterize the remaining four MT-MMPs (MMP-16, -17, -24 and -25) in severe early-onset pre-eclamptic placenta and assess their relative contribution to soluble endoglin production.
  
  
  RESULTS
  Immunolocalisation studies revealed MMP-16, -24 and -25 were localized to the syncytiotrophoblast, the same site as endoglin, whilst MMP-17 was predominantly localized to fetal vessels and underlying stroma. MMP-17 protein was significantly (p < 0.05) up-regulated in pre-eclamptic placentas compared to gestationally matched pre-term controls, whilst MMP-25 mRNA was significantly (p < 0.05) down regulated. siRNA knockdown of MMP-16, -17, -24 and -25 in syncytialised BeWo cells did not alter soluble endoglin production in vitro.
  
  
  CONCLUSIONS
  This is the first study to characterize MT-MMP protein localization in human placenta and indicates that MMP-14 is the only MT-MMP that contributes to soluble endoglin production in pre-eclampsia.
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd., Heidelberg 3084, Victoria, Australia. t.klino@unimelb.edu.au
authors.forename: T J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
authors.forename: L
authors.initials: L
authors.lastname: Tuohey
authors.forename: L
authors.initials: L
authors.lastname: Ye
authors.forename: K
authors.initials: K
authors.lastname: Palmer
authors.forename: M
authors.initials: M
authors.lastname: Skubisz
authors.forename: S
authors.initials: S
authors.lastname: Tong
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis*; D016022:Case-Control Studies; D000071063:Endoglin; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D053513:Matrix Metalloproteinase 16 / Q000235:genetics / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D012995:Solubility; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D058851:GPI-Linked Proteins; C507102:MMP16 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C402225:MMP17 protein, human; C492243:MMP24 protein, human; D053513:Matrix Metalloproteinase 16; D053504:Matrix Metalloproteinases, Membrane-Associated; C403928:matrix metalloproteinase 25; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14