PMID- 28668088
OWN - NLM
STAT- MEDLINE
DCOM- 20180403
LR  - 20181113
IS  - 1471-2474 (Electronic)
IS  - 1471-2474 (Linking)
VI  - 18
IP  - 1
DP  - 2017 Jul 1
TI  - Transforming growth factor activating kinase 1 regulates extracellular matrix 
      degrading enzymes and pain-related molecule expression following tumor necrosis 
      factor-alpha stimulation of synovial cells: an in vitro study.
PG  - 283
LID - 10.1186/s12891-017-1648-4 [doi]
LID - 283
AB  - BACKGROUND: Recent studies have suggested that the tumor necrosis factor-alpha 
      (TNF-alpha) pathway is a potential target for the management of osteoarthritis (OA). 
      Transforming growth factor (TGF)-beta-activated kinase 1 (TAK1) is essential in 
      several cytokine-mediated cascades, including the TNF-alpha, interleukin-1 (IL-1), 
      and TGF-beta pathways. The role of TAK1 in synovial tissue in OA is not fully 
      understood. Using synovial cells harvested from OA patients during surgery, we 
      investigated whether TAK1 inhibition suppresses production of TNF-alpha-induced 
      extracellular matrix degrading enzymes and expression of pain-related molecules. 
      METHODS: Synovial tissues were harvested from ten subjects with radiographic 
      evidence of osteoarthritis (OA) during total knee arthroplasty. Synovial cells 
      were cultured and stimulated with control (culture media), 10 ng/mL human 
      recombinant TNF-alpha, or 10 ng/mL TNF-alpha and 10 muM of the TAK1 inhibitor 
      (5Z)-7-oxozeaenol for 24 h. Real-time polymerase chain reaction (PCR) analysis 
      was used to monitor expression of mRNA of the extracellular matrix degrading 
      enzymes matrix metalloproteinase-3 (MMP-3) and a disintegrin-like and 
      metalloprotease (reprolysin type) with thrombospondin type 1 motif, 4 (ADAMTS-4); 
      and of the pain-related molecules cyclooxygenase-2 (COX-2), microsomal 
      prostaglandin E synthase-1 (mPGES-1), and nerve growth factor (NGF). MMP-3 and 
      NGF protein concentrations in cell supernatant were measured by enzyme-linked 
      immunosorbent assay (ELISA). COX-2, mPGES-1 and ADAMTS-4 protein expression was 
      also evaluated by western blotting. RESULTS: TNF-alpha stimulated increases in 
      ADAMTS-4 and MMP3 mRNA (2.0-fold and 1.6-fold, respectively, p < 0.05) and 
      protein expression (21.5-fold and 2.0-fold, respectively). Treatment with the 
      TAK1 inihibitor (5Z)-7-oxozeaenol reduced ADAMTS-4 and MMP3 mRNA (0.5-fold and 
      0.6-fold, respectively) and protein expression (1.4-fold and 0.5-fold, 
      respectively) in OA synovial cells. COX-2, mPGES-1 and NGF mRNA (11.2-fold, 
      3.1-fold and 2.7-fold, respectively) and protein expression (3.0-fold, 2.7-fold 
      and 2.2-fold, respectively) were increased by TNF-alpha. (5Z)-7-oxozeaenol treatment 
      reduced mPGES1 and NGF mRNA (1.5-fold and 0.8-fold, respectively) and protein 
      (1.5-fold and 0.5-fold, respectively). CONCLUSION: TAK1 plays an important role 
      in the regulation of TNF-alpha induced extracellular matrix degrading enzymes and 
      pain-related molecule expression. TAK1 may be a potential target for therapeutic 
      strategies aimed at preventing osteoarthritis progression and pain.
FAU - Uchida, Kentaro
AU  - Uchida K
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan. 
      kuchida@med.kitasato-u.ac.jp.
FAU - Takano, Shotaro
AU  - Takano S
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Matsumoto, Toshihide
AU  - Matsumoto T
AD  - Department of Pathology, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Nagura, Naoshige
AU  - Nagura N
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Inoue, Gen
AU  - Inoue G
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Itakura, Makoto
AU  - Itakura M
AD  - Department of Biochemistry, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Miyagi, Masayuki
AU  - Miyagi M
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Aikawa, Jun
AU  - Aikawa J
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Iwase, Dai
AU  - Iwase D
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Minatani, Atsushi
AU  - Minatani A
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Fujimaki, Hisako
AU  - Fujimaki H
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
FAU - Takaso, Masashi
AU  - Takaso M
AD  - Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 
      Minami-ku, Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan.
LA  - eng
PT  - Journal Article
DEP - 20170701
PL  - England
TA  - BMC Musculoskelet Disord
JT  - BMC musculoskeletal disorders
JID - 100968565
RN  - 0 (7-oxozeanol)
RN  - 0 (Lactones)
RN  - 0 (Resorcinols)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP kinase kinase kinase 7)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Arthralgia/*metabolism/surgery
MH  - Arthroplasty, Replacement, Knee/trends
MH  - Cells, Cultured
MH  - Extracellular Matrix/drug effects/*enzymology
MH  - Female
MH  - Gene Expression
MH  - Humans
MH  - Lactones/pharmacology
MH  - MAP Kinase Kinase Kinases/*antagonists & inhibitors/*physiology
MH  - Male
MH  - Middle Aged
MH  - Osteoarthritis, Knee/metabolism/surgery
MH  - Resorcinols/pharmacology
MH  - Synovial Fluid/drug effects/*metabolism
MH  - Tumor Necrosis Factor-alpha/*pharmacology
PMC - PMC5493881
OTO - NOTNLM
OT  - A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 
      1 motif, 4
OT  - Cyclooxygenase-2
OT  - Matrix metalloproteinase 3
OT  - Nerve growth factor
OT  - Synovium
OT  - TGF-beta-activated kinase 1
OT  - Tumor necrosis factor-alpha
OT  - mPGES-1
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: This study was approved by the Ethics 
      Review Board of Kitasato University (reference number: KMEO B13-113). Consent to 
      participate was obtained from the participants for the harvesting of their 
      synovial tissue for use in this study. CONSENT FOR PUBLICATION: Not applicable. 
      COMPETING INTERESTS: The authors declare that they have no competing interests. 
      PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional 
      claims in published maps and institutional affiliations.
EDAT- 2017/07/03 06:00
MHDA- 2018/04/04 06:00
PMCR- 2017/07/01
CRDT- 2017/07/03 06:00
PHST- 2017/01/15 00:00 [received]
PHST- 2017/06/27 00:00 [accepted]
PHST- 2017/07/03 06:00 [entrez]
PHST- 2017/07/03 06:00 [pubmed]
PHST- 2018/04/04 06:00 [medline]
PHST- 2017/07/01 00:00 [pmc-release]
AID - 10.1186/s12891-017-1648-4 [pii]
AID - 1648 [pii]
AID - 10.1186/s12891-017-1648-4 [doi]
PST - epublish
SO  - BMC Musculoskelet Disord. 2017 Jul 1;18(1):283. doi: 10.1186/s12891-017-1648-4.