PMID- 27441657 OWN - NLM STAT- MEDLINE DCOM- 20171023 LR - 20181113 IS - 2041-4889 (Electronic) VI - 7 IP - 7 DP - 2016 Jul 21 TI - TWEAK favors phosphate-induced calcification of vascular smooth muscle cells through canonical and non-canonical activation of NFkappaB. PG - e2305 LID - 10.1038/cddis.2016.220 [doi] AB - Vascular calcification (VC) is associated with increased cardiovascular mortality in aging, chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM) and atherosclerosis. TNF-like weak inducer of apoptosis (TWEAK) recently emerged as a new biomarker for the diagnosis and prognosis of cardiovascular diseases. TWEAK binding to its functional receptor Fn14 was reported to promote several steps of atherosclerotic plaque progression. However, no information is currently available on the role of TWEAK/Fn14 on the development of medial calcification, which is highly prevalent in aging, CKD and T2DM. This study explored the involvement of TWEAK in human vascular smooth muscle cells (h-VSMCs) calcification in vitro. We report that TWEAK binding to Fn14 promotes inorganic phosphate-induced h-VSMCs calcification, favors h-VSMCs osteogenic transition, decreasing acta2 and myh11 and increasing bmp2 mRNA and tissue non-specific alkaline phosphatase (TNAP), and increases MMP9 activity. Blockade of the canonical NFkappaB pathway reduced by 80% TWEAK pro-calcific properties and decreased osteogenic transition, TNAP and MMP9 activity. Blockade of non-canonical NFkappaB signaling by a siRNA targeting RelB reduced by 20% TWEAK pro-calcific effects and decreased TWEAK-induced loss of h-VSMCs contractile phenotype and MMP9 activity, without modulating bmp2 mRNA or TNAP activity. Inhibition of ERK1/2 activation by a MAPK kinase inhibitor did not influence TWEAK pro-calcific properties. Our results suggest that TWEAK/Fn14 directly favors inorganic phosphate-induced h-VSMCs calcification by activation of both canonical and non-canonical NFkappaB pathways. Given the availability of neutralizing anti-TWEAK strategies, our study sheds light on the TWEAK/Fn14 axis as a novel therapeutic target in the prevention of VC. FAU - Henaut, L AU - Henaut L AD - Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Madrid 28040, Spain. FAU - Sanz, A B AU - Sanz AB AD - Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Madrid 28040, Spain. AD - REDINREN, Madrid 28040, Spain. FAU - Martin-Sanchez, D AU - Martin-Sanchez D AD - Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Madrid 28040, Spain. FAU - Carrasco, S AU - Carrasco S AD - Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Madrid 28040, Spain. FAU - Villa-Bellosta, R AU - Villa-Bellosta R AD - Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Madrid 28040, Spain. FAU - Aldamiz-Echevarria, G AU - Aldamiz-Echevarria G AD - Cardiac Surgery, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Madrid 28040, Spain. FAU - Massy, Z A AU - Massy ZA AD - Division of Nephrology, Ambroise Pare University Hospital, APHP, University of Paris Ouest -Versailles-Saint-Quentin-en-Yvelines (UVSQ), Boulogne-Billancourt, Paris, France. AD - INSERM U1018, Research Centre in Epidemiology and Population Health (CESP) Team 5, Villejuif, Paris, France. FAU - Sanchez-Nino, M D AU - Sanchez-Nino MD AD - Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Madrid 28040, Spain. AD - REDINREN, Madrid 28040, Spain. FAU - Ortiz, A AU - Ortiz A AD - Nephrology, IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Madrid 28040, Spain. AD - REDINREN, Madrid 28040, Spain. AD - Fundacion Renal Inigo Alvarez de Toledo-IRSIN, Madrid 28040, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160721 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (ACTA2 protein, human) RN - 0 (Actins) RN - 0 (BMP2 protein, human) RN - 0 (Bone Morphogenetic Protein 2) RN - 0 (Cytokine TWEAK) RN - 0 (MYH11 protein, human) RN - 0 (Phosphates) RN - 0 (RELB protein, human) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (TNFRSF12A protein, human) RN - 0 (TNFSF12 protein, human) RN - 0 (TWEAK Receptor) RN - 0 (Tumor Necrosis Factors) RN - 147337-75-5 (Transcription Factor RelB) RN - EC 2.7.11.24 (MAPK1 protein, human) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 3.1.3.1 (ALPL protein, human) RN - EC 3.1.3.1 (Alkaline Phosphatase) RN - EC 3.4.24.35 (MMP9 protein, human) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.6.4.1 (Myosin Heavy Chains) SB - IM MH - Actins/genetics/metabolism MH - Alkaline Phosphatase/genetics/metabolism MH - Bone Morphogenetic Protein 2/genetics/metabolism MH - Cytokine TWEAK MH - Gene Expression Regulation MH - Humans MH - Matrix Metalloproteinase 9/genetics/metabolism MH - Mitogen-Activated Protein Kinase 1/genetics/metabolism MH - Mitogen-Activated Protein Kinase 3/genetics/metabolism MH - Muscle, Smooth, Vascular/drug effects/*metabolism/pathology MH - Myocytes, Smooth Muscle/drug effects/*metabolism/pathology MH - Myosin Heavy Chains/genetics/metabolism MH - Phosphates/metabolism/*pharmacology MH - Primary Cell Culture MH - Protein Binding MH - RNA, Messenger/genetics/metabolism MH - RNA, Small Interfering/genetics/metabolism MH - Receptors, Tumor Necrosis Factor/*genetics/metabolism MH - Signal Transduction MH - TWEAK Receptor MH - Transcription Factor RelB/antagonists & inhibitors/*genetics/metabolism MH - Tumor Necrosis Factors/*genetics/metabolism MH - Vascular Calcification/genetics/metabolism/pathology PMC - PMC4973358 EDAT- 2016/07/22 06:00 MHDA- 2017/10/24 06:00 PMCR- 2016/07/01 CRDT- 2016/07/22 06:00 PHST- 2016/03/16 00:00 [received] PHST- 2016/06/10 00:00 [revised] PHST- 2016/06/14 00:00 [accepted] PHST- 2016/07/22 06:00 [entrez] PHST- 2016/07/22 06:00 [pubmed] PHST- 2017/10/24 06:00 [medline] PHST- 2016/07/01 00:00 [pmc-release] AID - cddis2016220 [pii] AID - 10.1038/cddis.2016.220 [doi] PST - epublish SO - Cell Death Dis. 2016 Jul 21;7(7):e2305. doi: 10.1038/cddis.2016.220.