MMP-17: a negative regulator of soluble endoglin production? (#284)
Soluble endoglin (sEng) is one of two anti-angiongenic factors centrally responsible for pre-eclampsia. It is significantly up-regulated in the serum of preeclamptic women and correlates with disease severity. Given sEng’s detrimental effects on maternal endothelium in preeclampsia, it is essential to fully elucidate the mechanisms governing its release.
We have recently identified MMP-14 as the protease that produces soluble endoglin from placenta, however noted that specific inhibition only partially repressed sEng production1. We have subsequently confirmed this in human umbilical vein endothelial cells (HUVECs). This implies that other undiscovered protease(s) might have a role in sEng production.
The objective of this study was to assess the expression and tissue localisation of other membrane-type (MT-)MMPs (MMP-15, -17, 25) in preeclamptic placentas and to determine their contribution to sEng production in vitro.
Real time RT-PCR and Western Blot on a cohort of severe early onset pre-eclamptic (n=20) and gestationally matched pre-term (n=10) placentas confirmed mRNA expression and revealed a significant (p<0.05) increase in MMP-15 and -17 protein expression in pre-eclamptic placentas. In vitro siRNA administration of MMP-15, -17 and -25 siRNA to HUVECs and syncytialised BeWo cells demonstrated no effect of silencing MMP-15 and MMP-25 on soluble endoglin levels whilst inhibition of MMP-17 resulted in a significant increase in sEng levels (p<0.05). Importantly when MMP-17 siRNA was administered in combination with MMP-14 siRNA, sEng levels returned to those achieved with MMP-14 inhibition alone.
Together these results suggest that MMP-17 may act as a negative regulator of sEng production, by directly regulating MMP-14.
- Kaitu’u-Lino et al. Am J Path (2012) 180:888-894