PMID- 25063530 OWN - NLM STAT- MEDLINE DCOM- 20150423 LR - 20211021 IS - 1525-2191 (Electronic) IS - 0002-9440 (Print) IS - 0002-9440 (Linking) VI - 184 IP - 9 DP - 2014 Sep TI - Tumor necrosis factor-alpha- and interleukin-1beta-dependent matrix metalloproteinase-3 expression in nucleus pulposus cells requires cooperative signaling via syndecan 4 and mitogen-activated protein kinase-NF-kappaB axis: implications in inflammatory disc disease. PG - 2560-72 LID - S0002-9440(14)00359-9 [pii] LID - 10.1016/j.ajpath.2014.06.006 [doi] AB - Matrix metalloproteinase-3 (MMP-3) plays an important role in intervertebral disc degeneration, a ubiquitous condition closely linked to low back pain and disability. Elevated expression of syndecan 4, a cell surface heparan sulfate proteoglycan, actively controls disc matrix catabolism. However, the relationship between MMP-3 expression and syndecan 4 in the context of inflammatory disc disease has not been clearly defined. We investigated the mechanisms by which cytokines control MMP-3 expression in rat and human nucleus pulposus cells. Cytokine treatment increased MMP-3 expression and promoter activity. Stable silencing of syndecan 4 blocked cytokine-mediated MMP-3 expression; more important, syndecan 4 did not mediate its effects through NF-kappaB or mitogen-activated protein kinase (MAPK) pathways. However, treatment with MAPK and NF-kappaB inhibitors resulted in partial blocking of the inductive effect of cytokines on MMP-3 expression. Loss-of-function studies confirmed that NF-kappaB, p38alpha/beta2/gamma/delta, and extracellular signal-regulated kinase (ERK) 2, but not ERK1, contributed to cytokine-dependent induction of MMP3 promoter activity. Similarly, inhibitor treatments, lentiviral short hairpin-p65, and short hairpin-IkappaB kinase beta significantly decreased cytokine-dependent up-regulation in MMP-3 expression. Finally, we show that transforming growth factor-beta can block the up-regulation of MMP-3 induced by tumor necrosis factor (TNF)-alpha by counteracting the NF-kappaB pathway and syndecan 4 expression. Taken together, our results suggest that cooperative signaling through syndecan 4 and the TNF receptor 1-MAPK-NF-kappaB axis is required for TNF-alpha-dependent expression of MMP-3 in nucleus pulposus cells. Controlling these pathways may slow the progression of intervertebral disc degeneration and matrix catabolism. CI - Copyright (c) 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Wang, Xin AU - Wang X AD - Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Bone and Soft Tissue, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. FAU - Wang, Hua AU - Wang H AD - Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. FAU - Yang, Hao AU - Yang H AD - Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. FAU - Li, Jun AU - Li J AD - Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. FAU - Cai, Qiqing AU - Cai Q AD - Department of Bone and Soft Tissue, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. FAU - Shapiro, Irving M AU - Shapiro IM AD - Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. FAU - Risbud, Makarand V AU - Risbud MV AD - Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: makarand.risbud@jefferson.edu. LA - eng GR - R01 AR064733/AR/NIAMS NIH HHS/United States GR - AR050087/AR/NIAMS NIH HHS/United States GR - R01 AR050087/AR/NIAMS NIH HHS/United States GR - AR064733/AR/NIAMS NIH HHS/United States GR - AR055655/AR/NIAMS NIH HHS/United States GR - R01 AR055655/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140722 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Interleukin-1beta) RN - 0 (NF-kappa B) RN - 0 (Syndecan-4) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM CIN - Am J Pathol. 2014 Sep;184(9):2371-3. PMID: 25072503 MH - Adult MH - Animals MH - Blotting, Western MH - Female MH - Humans MH - Interleukin-1beta/immunology/*metabolism MH - Intervertebral Disc/metabolism/pathology MH - Intervertebral Disc Degeneration/immunology/*metabolism MH - Male MH - Matrix Metalloproteinase 3/immunology/*metabolism MH - Mitogen-Activated Protein Kinases/metabolism MH - NF-kappa B/metabolism MH - Rats MH - Real-Time Polymerase Chain Reaction MH - Signal Transduction/*physiology MH - Syndecan-4/metabolism MH - Tumor Necrosis Factor-alpha/immunology/*metabolism PMC - PMC4188173 EDAT- 2014/07/27 06:00 MHDA- 2015/04/24 06:00 PMCR- 2015/09/01 CRDT- 2014/07/27 06:00 PHST- 2014/04/18 00:00 [received] PHST- 2014/05/28 00:00 [revised] PHST- 2014/06/04 00:00 [accepted] PHST- 2014/07/27 06:00 [entrez] PHST- 2014/07/27 06:00 [pubmed] PHST- 2015/04/24 06:00 [medline] PHST- 2015/09/01 00:00 [pmc-release] AID - S0002-9440(14)00359-9 [pii] AID - 10.1016/j.ajpath.2014.06.006 [doi] PST - ppublish SO - Am J Pathol. 2014 Sep;184(9):2560-72. doi: 10.1016/j.ajpath.2014.06.006. Epub 2014 Jul 22.