title: 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.
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: 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.
authors: Xin
authors: X
authors: Wang
authors: 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.
authors: Hua
authors: H
authors: Wang
authors: 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.
authors: Hao
authors: H
authors: Yang
authors: 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.
authors: Jun
authors: J
authors: Li
authors: Department of Bone and Soft Tissue, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
authors: Qiqing
authors: Q
authors: Cai
authors: Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Irving M
authors: IM
authors: Shapiro
authors: Department of Orthopedic Surgery and the Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: makarand.risbud@jefferson.edu.
authors: Makarand V
authors: MV
authors: Risbud
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D007403:Intervertebral Disc / Q000378:metabolism / Q000473:pathology; D055959:Intervertebral Disc Degeneration / Q000276:immunology / Q000378:metabolism*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000276:immunology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D053671:Syndecan-4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D053671:Syndecan-4; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3