PMID- 35410356
OWN - NLM
STAT- MEDLINE
DCOM- 20220413
LR  - 20220531
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Apr 11
TI  - Adenosine inhibits TNFalpha-induced MMP-3 production in MH7A rheumatoid arthritis 
      synoviocytes via A(2A) receptor signaling.
PG  - 6033
LID - 10.1038/s41598-022-10012-6 [doi]
LID - 6033
AB  - Adenosine causes the anti-inflammatory effect of MTX; however, the contributions 
      of synoviocyte adenosine receptors (AdoRs) are unknown, and matrix 
      metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in 
      response to inflammatory signaling. To understand the mechanism of the clinical 
      observation that the matrix proteinase-3 concentration of patients with 
      rheumatoid arthritis treated successfully with methotrexate does not usually 
      normalize, we investigated the effects of A(2A) AdoR activation and inhibition on 
      tumor necrosis factor-alpha (TNFalpha)-induced MMP-3 release by MH7A human rheumatoid 
      synovial cells. MH7A cells constitutively expressed membrane-associated A(2A) 
      AdoRs, and HENECA enhanced intracellular cAMP. Stimulation with TNFalpha markedly 
      enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and 
      dose-dependently inhibited TNFalpha-evoked MMP-3 release. Similarly, dbcAMP partially 
      inhibited TNFalpha-induced MMP-3 release. Pretreatment with ZM241385 reversed the 
      inhibitory effects of HENECA. Further, TNFalpha induced p38 MAPK and ATF-2 
      phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation. We 
      concluded that adenosine signaling via A(2A) AdoRs, adenylyl cyclase, and cAMP 
      reduces TNFalpha-induced MMP-3 production by interfering with p38 MAPK/ATF-2 
      activity. Activation of A(2A) AdoR signaling alone using HENECA did not reduce 
      TNFalpha-induced MMP-3 production to the basal levels, which may explain why MTX 
      usually decreases but does not eliminate serum MMP-3.
CI  - (c) 2022. The Author(s).
FAU - Konishi, Hiroe
AU  - Konishi H
AD  - Department of Clinical Laboratory Medicine, Hyogo Medical University School of 
      Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
FAU - Kanou, Shun-En
AU  - Kanou SE
AD  - Department of Clinical Laboratory, Hyogo Medical University Hospital, 
      Nishinomiya, Hyogo, 663-8501, Japan.
FAU - Yukimatsu, Rika
AU  - Yukimatsu R
AD  - Department of Clinical Laboratory, Hyogo Medical University Hospital, 
      Nishinomiya, Hyogo, 663-8501, Japan.
FAU - Inui, Mizuki
AU  - Inui M
AD  - Department of Clinical Laboratory, Hyogo Medical University Hospital, 
      Nishinomiya, Hyogo, 663-8501, Japan.
FAU - Sato, Motoya
AU  - Sato M
AD  - Department of Clinical Laboratory, Hyogo Medical University Hospital, 
      Nishinomiya, Hyogo, 663-8501, Japan.
FAU - Yamamoto, Naruto
AU  - Yamamoto N
AD  - Department of Clinical Laboratory, Hyogo Medical University Hospital, 
      Nishinomiya, Hyogo, 663-8501, Japan.
FAU - Nakano, Masayoshi
AU  - Nakano M
AD  - Department of Clinical Laboratory Medicine, Hyogo Medical University School of 
      Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
FAU - Koshiba, Masahiro
AU  - Koshiba M
AD  - Department of Clinical Laboratory Medicine, Hyogo Medical University School of 
      Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. 
      mkoshiba@hyo-med.ac.jp.
AD  - Department of Clinical Laboratory, Hyogo Medical University Hospital, 
      Nishinomiya, Hyogo, 663-8501, Japan. mkoshiba@hyo-med.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20220411
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Receptor, Adenosine A2A)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.17 (MMP3 protein, human)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - K72T3FS567 (Adenosine)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Adenosine/pharmacology
MH  - *Arthritis, Rheumatoid/pathology
MH  - Humans
MH  - Matrix Metalloproteinase 3/*metabolism
MH  - Methotrexate/pharmacology/therapeutic use
MH  - Receptor, Adenosine A2A/*metabolism
MH  - Synovial Membrane/pathology
MH  - *Synoviocytes/pathology
MH  - Tumor Necrosis Factor-alpha/pharmacology/therapeutic use
MH  - p38 Mitogen-Activated Protein Kinases
PMC - PMC9001689
COIS- The authors declare no competing interests.
EDAT- 2022/04/13 06:00
MHDA- 2022/04/14 06:00
PMCR- 2022/04/11
CRDT- 2022/04/12 05:19
PHST- 2021/09/24 00:00 [received]
PHST- 2022/03/31 00:00 [accepted]
PHST- 2022/04/12 05:19 [entrez]
PHST- 2022/04/13 06:00 [pubmed]
PHST- 2022/04/14 06:00 [medline]
PHST- 2022/04/11 00:00 [pmc-release]
AID - 10.1038/s41598-022-10012-6 [pii]
AID - 10012 [pii]
AID - 10.1038/s41598-022-10012-6 [doi]
PST - epublish
SO  - Sci Rep. 2022 Apr 11;12(1):6033. doi: 10.1038/s41598-022-10012-6.