Abstract | BACKGROUND CONTEXT: 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.
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Authors | Zili Wang, William C Hutton, S Tim Yoon |
Journal | The spine journal : official journal of the North American Spine Society
(Spine J)
Vol. 14
Issue 3
Pg. 505-12
(Mar 01 2014)
ISSN: 1878-1632 [Electronic] United States |
PMID | 24176808
(Publication Type: Journal Article)
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Copyright | Copyright © 2014 Elsevier Inc. All rights reserved. |
Chemical References |
- Aggrecans
- Alginates
- Bone Morphogenetic Protein 7
- Collagen Type II
- Hexuronic Acids
- NF-kappa B
- RNA, Messenger
- Tumor Necrosis Factor-alpha
- Glucuronic Acid
- ADAM Proteins
- ADAMTS5 Protein
- ADAMTS5 protein, human
- Procollagen N-Endopeptidase
- ADAMTS4 Protein
- ADAMTS4 protein, human
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Topics |
- ADAM Proteins
(metabolism)
- ADAMTS4 Protein
- ADAMTS5 Protein
- Adult
- Aged
- Aggrecans
(metabolism)
- Alginates
- Bone Morphogenetic Protein 7
(pharmacology)
- Cells, Cultured
- Collagen Type II
(metabolism)
- Extracellular Matrix
(drug effects, metabolism)
- Glucuronic Acid
- Hexuronic Acids
- Humans
- In Vitro Techniques
- Intervertebral Disc
(cytology, drug effects, metabolism)
- Intervertebral Disc Degeneration
(metabolism)
- Microspheres
- Middle Aged
- NF-kappa B
(drug effects, metabolism)
- Procollagen N-Endopeptidase
(metabolism)
- RNA, Messenger
(metabolism)
- Signal Transduction
(drug effects)
- Tumor Necrosis Factor-alpha
(pharmacology)
- Up-Regulation
(drug effects)
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