PMID- 24176808 OWN - NLM STAT- MEDLINE DCOM- 20150514 LR - 20181202 IS - 1878-1632 (Electronic) IS - 1529-9430 (Linking) VI - 14 IP - 3 DP - 2014 Mar 1 TI - Bone morphogenetic protein-7 antagonizes tumor necrosis factor-alpha-induced activation of nuclear factor kappaB and up-regulation of the ADAMTS, leading to decreased degradation of disc matrix macromolecules aggrecan and collagen II. PG - 505-12 LID - S1529-9430(13)01463-0 [pii] LID - 10.1016/j.spinee.2013.08.016 [doi] AB - BACKGROUND CONTEXT: Tumor necrosis factor-alpha (TNF-alpha) 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-alpha and ADAMTS are unknown. PURPOSE: We investigated the effects of BMP-7 on the catabolic regulators such as TNF-alpha 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-alpha, or TNF- alpha plus BMP-7, pharmacological inhibitor of ERK1/2 (U0126), p38 (SB203580), or NFkappaB (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)kappaB activity was analyzed by measured phosphorylation and nuclear translocation of the NFkappaB protein p65. RESULTS: TNF-alpha activated NFkappaB 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-alpha-induced activation of NFkappaB protein p65 and blocked TNF-alpha-induced up-regulation of ADAMTS-4 and ADAMTS-5, leading to reversing TNF-alpha-mediated degradation of aggrecan and collagen II. Moreover, BMP-7 antagonized the TNF-alpha-induced activation of NFkappaB signaling by suppressing phosphorylation and nucleus translocation of NFkappaB protein p65. CONCLUSION: BMP-7 antagonizes TNF-alpha-induced activation of NFkappaB 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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Wang, Zili AU - Wang Z AD - 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. FAU - Hutton, William C AU - Hutton WC AD - 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. FAU - Yoon, S Tim AU - Yoon ST AD - 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. LA - eng PT - Journal Article DEP - 20131029 PL - United States TA - Spine J JT - The spine journal : official journal of the North American Spine Society JID - 101130732 RN - 0 (Aggrecans) RN - 0 (Alginates) RN - 0 (Bone Morphogenetic Protein 7) RN - 0 (Collagen Type II) RN - 0 (Hexuronic Acids) RN - 0 (NF-kappa B) RN - 0 (RNA, Messenger) RN - 0 (Tumor Necrosis Factor-alpha) RN - 8A5D83Q4RW (Glucuronic Acid) RN - EC 3.4.24.- (ADAM Proteins) RN - EC 3.4.24.- (ADAMTS5 Protein) RN - EC 3.4.24.- (ADAMTS5 protein, human) RN - EC 3.4.24.14 (Procollagen N-Endopeptidase) RN - EC 3.4.24.82 (ADAMTS4 Protein) RN - EC 3.4.24.82 (ADAMTS4 protein, human) SB - IM MH - ADAM Proteins/*metabolism MH - ADAMTS4 Protein MH - ADAMTS5 Protein MH - Adult MH - Aged MH - Aggrecans/*metabolism MH - Alginates MH - Bone Morphogenetic Protein 7/*pharmacology MH - Cells, Cultured MH - Collagen Type II/*metabolism MH - Extracellular Matrix/drug effects/metabolism MH - Glucuronic Acid MH - Hexuronic Acids MH - Humans MH - In Vitro Techniques MH - Intervertebral Disc/cytology/drug effects/*metabolism MH - Intervertebral Disc Degeneration/metabolism MH - Microspheres MH - Middle Aged MH - NF-kappa B/drug effects/*metabolism MH - Procollagen N-Endopeptidase/*metabolism MH - RNA, Messenger/metabolism MH - Signal Transduction/drug effects MH - Tumor Necrosis Factor-alpha/*pharmacology MH - Up-Regulation/drug effects OTO - NOTNLM OT - ADAMTS OT - BMP-7 OT - Intervertebral discs OT - NF-kappaB OT - TNF-alpha EDAT- 2013/11/02 06:00 MHDA- 2015/05/15 06:00 CRDT- 2013/11/02 06:00 PHST- 2012/05/22 00:00 [received] PHST- 2013/07/23 00:00 [revised] PHST- 2013/08/20 00:00 [accepted] PHST- 2013/11/02 06:00 [entrez] PHST- 2013/11/02 06:00 [pubmed] PHST- 2015/05/15 06:00 [medline] AID - S1529-9430(13)01463-0 [pii] AID - 10.1016/j.spinee.2013.08.016 [doi] PST - ppublish SO - Spine J. 2014 Mar 1;14(3):505-12. doi: 10.1016/j.spinee.2013.08.016. Epub 2013 Oct 29.