title: MMP-15 is upregulated in preeclampsia, but does not cleave endoglin to produce soluble endoglin.
abstract: Preeclampsia is a major pregnancy complication, characterized by severe endothelial dysfunction, hypertension and maternal end-organ damage. Soluble endoglin is an anti-angiogenic protein released from placenta and thought to play a central role in causing the endothelial dysfunction and maternal organ injury seen in severe preeclampsia. We recently reported MMP-14 was the protease producing placentally-derived soluble endoglin by cleaving full-length endoglin present on the syncytiotrophoblast surface. This find identifies a specific drug target for severe preeclampsia; interfering with MMP-14 mediated cleavage of endoglin could decrease soluble endoglin production, ameliorating clinical disease. However, experimental MMP-14 inhibition alone only partially repressed soluble endoglin production, implying other proteases might have a role in producing soluble endoglin. Here we investigated whether MMP-15--phylogenetically the closest MMP relative to MMP-14 with 66% sequence similarity--also cleaves endoglin to produce soluble endoglin. MMP-15 was localized to the syncytiotrophoblast layer of the placenta, the same site where endoglin was localized. Interestingly, it was significantly (p = 0.03) up-regulated in placentas from severe early-onset preeclamptic pregnancies (n = 8) compared to gestationally matched preterm controls (n = 8). However, siRNA knockdown of MMP-15 yielded no significant decrease of soluble endoglin production from either HUVECs or syncytialised BeWo cells in vitro. Importantly, concurrent siRNA knockdown of both MMP-14 and MMP-15 in HUVECS did not yield further decrease in soluble endoglin production compared to MMP-14 siRNA alone. We conclude MMP-15 is up-regulated in preeclampsia, but does not cleave endoglin to produce soluble endoglin.
authors: The Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Victoria, Australia. t.klino@unimelb.edu.au
authors: Tu'uhevaha J
authors: TJ
authors: Kaitu'u-Lino
authors: Kirsten
authors: K
authors: Palmer
authors: Laura
authors: L
authors: Tuohey
authors: Louie
authors: L
authors: Ye
authors: Stephen
authors: S
authors: Tong
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism*; D015331:Cohort Studies; D000071063:Endoglin; D005260:Female; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053517:Matrix Metalloproteinase 15 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011247:Pregnancy; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012995:Solubility; D014327:Trophoblasts / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C507098:MMP15 protein, human; D011956:Receptors, Cell Surface; D053517:Matrix Metalloproteinase 15