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Tumor necrosis factor-α- and interleukin-1β-dependent matrix metalloproteinase-3 expression in nucleus pulposus cells requires cooperative signaling via syndecan 4 and mitogen-activated protein kinase-NF-κB axis: implications in inflammatory disc disease.
Am J Pathol. 2014 Sep; 184(9):2560-72.AJ

Abstract

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-κB or mitogen-activated protein kinase (MAPK) pathways. However, treatment with MAPK and NF-κB inhibitors resulted in partial blocking of the inductive effect of cytokines on MMP-3 expression. Loss-of-function studies confirmed that NF-κB, p38α/β2/γ/δ, 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-IκB kinase β significantly decreased cytokine-dependent up-regulation in MMP-3 expression. Finally, we show that transforming growth factor-β can block the up-regulation of MMP-3 induced by tumor necrosis factor (TNF)-α by counteracting the NF-κB pathway and syndecan 4 expression. Taken together, our results suggest that cooperative signaling through syndecan 4 and the TNF receptor 1-MAPK-NF-κB axis is required for TNF-α-dependent expression of MMP-3 in nucleus pulposus cells. Controlling these pathways may slow the progression of intervertebral disc degeneration and matrix catabolism.

Authors+Show Affiliations

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.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.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.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.Department of Bone and Soft Tissue, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: makarand.risbud@jefferson.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25063530

Citation

Wang, Xin, et al. "Tumor Necrosis Factor-α- and Interleukin-1β-dependent Matrix Metalloproteinase-3 Expression in Nucleus Pulposus Cells Requires Cooperative Signaling Via Syndecan 4 and Mitogen-activated Protein kinase-NF-κB Axis: Implications in Inflammatory Disc Disease." The American Journal of Pathology, vol. 184, no. 9, 2014, pp. 2560-72.
Wang X, Wang H, Yang H, et al. Tumor necrosis factor-α- and interleukin-1β-dependent matrix metalloproteinase-3 expression in nucleus pulposus cells requires cooperative signaling via syndecan 4 and mitogen-activated protein kinase-NF-κB axis: implications in inflammatory disc disease. Am J Pathol. 2014;184(9):2560-72.
Wang, X., Wang, H., Yang, H., Li, J., Cai, Q., Shapiro, I. M., & Risbud, M. V. (2014). Tumor necrosis factor-α- and interleukin-1β-dependent matrix metalloproteinase-3 expression in nucleus pulposus cells requires cooperative signaling via syndecan 4 and mitogen-activated protein kinase-NF-κB axis: implications in inflammatory disc disease. The American Journal of Pathology, 184(9), 2560-72. https://doi.org/10.1016/j.ajpath.2014.06.006
Wang X, et al. Tumor Necrosis Factor-α- and Interleukin-1β-dependent Matrix Metalloproteinase-3 Expression in Nucleus Pulposus Cells Requires Cooperative Signaling Via Syndecan 4 and Mitogen-activated Protein kinase-NF-κB Axis: Implications in Inflammatory Disc Disease. Am J Pathol. 2014;184(9):2560-72. PubMed PMID: 25063530.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor-α- and interleukin-1β-dependent matrix metalloproteinase-3 expression in nucleus pulposus cells requires cooperative signaling via syndecan 4 and mitogen-activated protein kinase-NF-κB axis: implications in inflammatory disc disease. AU - Wang,Xin, AU - Wang,Hua, AU - Yang,Hao, AU - Li,Jun, AU - Cai,Qiqing, AU - Shapiro,Irving M, AU - Risbud,Makarand V, Y1 - 2014/07/22/ PY - 2014/04/18/received PY - 2014/05/28/revised PY - 2014/06/04/accepted PY - 2014/7/27/entrez PY - 2014/7/27/pubmed PY - 2015/4/24/medline SP - 2560 EP - 72 JF - The American journal of pathology JO - Am. J. Pathol. VL - 184 IS - 9 N2 - 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-κB or mitogen-activated protein kinase (MAPK) pathways. However, treatment with MAPK and NF-κB inhibitors resulted in partial blocking of the inductive effect of cytokines on MMP-3 expression. Loss-of-function studies confirmed that NF-κB, p38α/β2/γ/δ, 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-IκB kinase β significantly decreased cytokine-dependent up-regulation in MMP-3 expression. Finally, we show that transforming growth factor-β can block the up-regulation of MMP-3 induced by tumor necrosis factor (TNF)-α by counteracting the NF-κB pathway and syndecan 4 expression. Taken together, our results suggest that cooperative signaling through syndecan 4 and the TNF receptor 1-MAPK-NF-κB axis is required for TNF-α-dependent expression of MMP-3 in nucleus pulposus cells. Controlling these pathways may slow the progression of intervertebral disc degeneration and matrix catabolism. SN - 1525-2191 UR - https://www.unboundmedicine.com/medline/citation/25063530/Tumor_necrosis_factor_α__and_interleukin_1β_dependent_matrix_metalloproteinase_3_expression_in_nucleus_pulposus_cells_requires_cooperative_signaling_via_syndecan_4_and_mitogen_activated_protein_kinase_NF_κB_axis:_implications_in_inflammatory_disc_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(14)00359-9 DB - PRIME DP - Unbound Medicine ER -