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Bone morphogenetic protein-7 antagonizes tumor necrosis factor-α-induced activation of nuclear factor κB and up-regulation of the ADAMTS, leading to decreased degradation of disc matrix macromolecules aggrecan and collagen II.
Spine J. 2014 Mar 01; 14(3):505-12.SJ

Abstract

BACKGROUND CONTEXT

Tumor necrosis factor-α (TNF-α) is a regulatory cytokine that can increase the activity of enzymes such as ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), which degrade disc matrix. ADAMTS are enzymes that break down disc matrix and thereby mediate disc degeneration. Bone morphogenetic protein-7 (BMP-7), on the other hand, stimulates synthesis of the disc extracellular matrix and is a potential therapeutic molecule for the treatment of disc degeneration. However, the effects of BMP-7 on TNF-α and ADAMTS are unknown.

PURPOSE

We investigated the effects of BMP-7 on the catabolic regulators such as TNF-α and ADAMTS and evaluated the molecular mechanism by which BMP-7 affects the catabolic regulators.

STUDY DESIGN

This was an in vitro study in which we used human intervertebral disc cells cultured in alginate beads.

METHODS

Human intervertebral disc cells were cultured in alginate beads, and treated with TNF-α, or TNF- α plus BMP-7, pharmacological inhibitor of ERK1/2 (U0126), p38 (SB203580), or NFκB (BAY 11-7082). The mRNA levels of target genes were measured by real-time polymerase chain reaction, and the protein levels were determined by the Western blots. The nuclear factor (NF)κB activity was analyzed by measured phosphorylation and nuclear translocation of the NFκB protein p65.

RESULTS

TNF-α activated NFκB signaling and induced up-regulation of the catabolic regulators ADAMTS-4 and ADAMTS-5, contributing to degradation of the disc matrix macromolecules aggrecan and collagen II. BMP-7 antagonized the TNF-α-induced activation of NFκB protein p65 and blocked TNF-α-induced up-regulation of ADAMTS-4 and ADAMTS-5, leading to reversing TNF-α-mediated degradation of aggrecan and collagen II. Moreover, BMP-7 antagonized the TNF-α-induced activation of NFκB signaling by suppressing phosphorylation and nucleus translocation of NFκB protein p65.

CONCLUSION

BMP-7 antagonizes TNF-α-induced activation of NFκB and up-regulation of ADAMTS, leading to decreased degradation of disc matrix macromolecules. These data indicate that BMP-7 has a dual mechanism of action on disc metabolism: (1) the previously well-described positive effect on disc matrix synthesis and (2) an anticatabolic effect that is described here. This understanding is important as BMP-7 is being considered for treatment of disc degeneration.

Authors+Show Affiliations

Emory Spine Center, Emory University School of Medicine and VA Medical Center, VA Research Building, Room # 4A-189, 1670 Clairmont Rd, Decatur, GA 30033, USA. Electronic address: zwang084@gmail.com.Emory Spine Center, Emory University School of Medicine and VA Medical Center, VA Research Building, Room # 4A-189, 1670 Clairmont Rd, Decatur, GA 30033, USA.Emory Spine Center, Emory University School of Medicine and VA Medical Center, VA Research Building, Room # 4A-189, 1670 Clairmont Rd, Decatur, GA 30033, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24176808

Citation

Wang, Zili, et al. "Bone Morphogenetic Protein-7 Antagonizes Tumor Necrosis Factor-α-induced Activation of Nuclear Factor κB and Up-regulation of the ADAMTS, Leading to Decreased Degradation of Disc Matrix Macromolecules Aggrecan and Collagen II." The Spine Journal : Official Journal of the North American Spine Society, vol. 14, no. 3, 2014, pp. 505-12.
Wang Z, Hutton WC, Yoon ST. Bone morphogenetic protein-7 antagonizes tumor necrosis factor-α-induced activation of nuclear factor κB and up-regulation of the ADAMTS, leading to decreased degradation of disc matrix macromolecules aggrecan and collagen II. Spine J. 2014;14(3):505-12.
Wang, Z., Hutton, W. C., & Yoon, S. T. (2014). Bone morphogenetic protein-7 antagonizes tumor necrosis factor-α-induced activation of nuclear factor κB and up-regulation of the ADAMTS, leading to decreased degradation of disc matrix macromolecules aggrecan and collagen II. The Spine Journal : Official Journal of the North American Spine Society, 14(3), 505-12. https://doi.org/10.1016/j.spinee.2013.08.016
Wang Z, Hutton WC, Yoon ST. Bone Morphogenetic Protein-7 Antagonizes Tumor Necrosis Factor-α-induced Activation of Nuclear Factor κB and Up-regulation of the ADAMTS, Leading to Decreased Degradation of Disc Matrix Macromolecules Aggrecan and Collagen II. Spine J. 2014 Mar 1;14(3):505-12. PubMed PMID: 24176808.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bone morphogenetic protein-7 antagonizes tumor necrosis factor-α-induced activation of nuclear factor κB and up-regulation of the ADAMTS, leading to decreased degradation of disc matrix macromolecules aggrecan and collagen II. AU - Wang,Zili, AU - Hutton,William C, AU - Yoon,S Tim, Y1 - 2013/10/29/ PY - 2012/05/22/received PY - 2013/07/23/revised PY - 2013/08/20/accepted PY - 2013/11/2/entrez PY - 2013/11/2/pubmed PY - 2015/5/15/medline KW - ADAMTS KW - BMP-7 KW - Intervertebral discs KW - NF-κB KW - TNF-α SP - 505 EP - 12 JF - The spine journal : official journal of the North American Spine Society JO - Spine J VL - 14 IS - 3 N2 - BACKGROUND CONTEXT: Tumor necrosis factor-α (TNF-α) is a regulatory cytokine that can increase the activity of enzymes such as ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), which degrade disc matrix. ADAMTS are enzymes that break down disc matrix and thereby mediate disc degeneration. Bone morphogenetic protein-7 (BMP-7), on the other hand, stimulates synthesis of the disc extracellular matrix and is a potential therapeutic molecule for the treatment of disc degeneration. However, the effects of BMP-7 on TNF-α and ADAMTS are unknown. PURPOSE: We investigated the effects of BMP-7 on the catabolic regulators such as TNF-α and ADAMTS and evaluated the molecular mechanism by which BMP-7 affects the catabolic regulators. STUDY DESIGN: This was an in vitro study in which we used human intervertebral disc cells cultured in alginate beads. METHODS: Human intervertebral disc cells were cultured in alginate beads, and treated with TNF-α, or TNF- α plus BMP-7, pharmacological inhibitor of ERK1/2 (U0126), p38 (SB203580), or NFκB (BAY 11-7082). The mRNA levels of target genes were measured by real-time polymerase chain reaction, and the protein levels were determined by the Western blots. The nuclear factor (NF)κB activity was analyzed by measured phosphorylation and nuclear translocation of the NFκB protein p65. RESULTS: TNF-α activated NFκB signaling and induced up-regulation of the catabolic regulators ADAMTS-4 and ADAMTS-5, contributing to degradation of the disc matrix macromolecules aggrecan and collagen II. BMP-7 antagonized the TNF-α-induced activation of NFκB protein p65 and blocked TNF-α-induced up-regulation of ADAMTS-4 and ADAMTS-5, leading to reversing TNF-α-mediated degradation of aggrecan and collagen II. Moreover, BMP-7 antagonized the TNF-α-induced activation of NFκB signaling by suppressing phosphorylation and nucleus translocation of NFκB protein p65. CONCLUSION: BMP-7 antagonizes TNF-α-induced activation of NFκB and up-regulation of ADAMTS, leading to decreased degradation of disc matrix macromolecules. These data indicate that BMP-7 has a dual mechanism of action on disc metabolism: (1) the previously well-described positive effect on disc matrix synthesis and (2) an anticatabolic effect that is described here. This understanding is important as BMP-7 is being considered for treatment of disc degeneration. SN - 1878-1632 UR - https://www.unboundmedicine.com/medline/citation/24176808/Bone_morphogenetic_protein_7_antagonizes_tumor_necrosis_factor_α_induced_activation_of_nuclear_factor_κB_and_up_regulation_of_the_ADAMTS_leading_to_decreased_degradation_of_disc_matrix_macromolecules_aggrecan_and_collagen_II_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1529-9430(13)01463-0 DB - PRIME DP - Unbound Medicine ER -