PMID- 17599743
OWN - NLM
STAT- MEDLINE
DCOM- 20070906
LR  - 20181201
IS  - 0004-3591 (Print)
IS  - 0004-3591 (Linking)
VI  - 56
IP  - 7
DP  - 2007 Jul
TI  - Angiopoietin 1 directly induces destruction of the rheumatoid joint by 
      cooperative, but independent, signaling via ERK/MAPK and phosphatidylinositol 
      3-kinase/Akt.
PG  - 2170-9
AB  - OBJECTIVE: To determine whether angiopoietin 1 (Ang-1) potentiates overgrowth of 
      the synovium and joint degradation in rheumatoid arthritis (RA), and to clarify 
      the cell-signaling mechanisms of Ang-1 in the rheumatoid joint. METHODS: 
      Expression of Ang-1, TIE-2 (a receptor for Ang-1), and matrix metalloproteinase 3 
      (MMP-3) was studied by immunohistochemistry. Activation of the ERK/MAPK and 
      phosphatidylinositol (PI) 3-kinase/Akt pathways and of NF-kappaB was determined 
      by Western blotting and an NF-kappaB p65 DNA binding activity assay, 
      respectively. Induction of apoptosis was evaluated by nuclear staining, cell 
      viability assay, and Western blotting of caspases. Synovial cell migration was 
      evaluated by actin polymerization, Western blotting of Rho family proteins, and 
      affinity purification with Rhotekin-Rho and p21-activated kinase 1. Matrix 
      degradation was examined by induction of proMMP-3 secretion from synovial cells 
      followed by in vitro cartilaginous matrix degradation assay. RESULTS: Ang-1 
      stimulated the ERK/MAPK and PI 3-kinase/Akt pathways in a cooperative but 
      independent manner, which enhanced rheumatoid synovium overgrowth and joint 
      destruction. In addition, Ang-1 activated NF-kappaB via Akt to promote cell 
      growth, but also inhibited cell apoptosis via ERK and Akt. Ang-1 directly 
      potentiated the extension of synovial cells in an ERK- and Akt-dependent manner 
      by up-regulating Rho family proteins, which attenuated Rac signaling and led to 
      membrane ruffling. Ang-1 induced proMMP-3 secretion from synovial cells, which 
      resulted in direct degradation of the cartilaginous matrix. CONCLUSION: Ang-1 
      stimulates the ERK/MAPK and PI 3-kinase/Akt pathways cooperatively, but in a 
      manner independent of each other, to directly potentiate synovium overgrowth and 
      joint destruction in RA. In addition to inflammatory cytokines, Ang-1/TIE-2 
      signaling appears to be an independent factor that contributes to the destruction 
      of the rheumatoid joint.
FAU - Hashiramoto, Akira
AU  - Hashiramoto A
AD  - Kobe University FHS School of Medicine, Kobe University Hospital, Sumaku, Kobe, 
      Japan.
FAU - Sakai, China
AU  - Sakai C
FAU - Yoshida, Kohsuke
AU  - Yoshida K
FAU - Tsumiyama, Ken
AU  - Tsumiyama K
FAU - Miura, Yasushi
AU  - Miura Y
FAU - Shiozawa, Kazuko
AU  - Shiozawa K
FAU - Nose, Masato
AU  - Nose M
FAU - Komai, Koichiro
AU  - Komai K
FAU - Shiozawa, Shunichi
AU  - Shiozawa S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (ANGPT1 protein, human)
RN  - 0 (Androstadienes)
RN  - 0 (Angiopoietin-1)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Recombinant Proteins)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, TIE-2)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Angiopoietin-1/*pharmacology
MH  - Arthritis, Rheumatoid/*pathology/*surgery
MH  - Cartilage, Articular/pathology
MH  - Cell Survival/drug effects
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Joints/drug effects/*pathology/surgery
MH  - Kinetics
MH  - NF-kappa B/metabolism
MH  - Oncogene Protein v-akt/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - RNA/genetics/isolation & purification
MH  - RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Receptor, TIE-2/genetics
MH  - Recombinant Proteins/*pharmacology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Synovial Membrane/drug effects/enzymology/*pathology
MH  - Wortmannin
EDAT- 2007/06/30 09:00
MHDA- 2007/09/07 09:00
CRDT- 2007/06/30 09:00
PHST- 2007/06/30 09:00 [pubmed]
PHST- 2007/09/07 09:00 [medline]
PHST- 2007/06/30 09:00 [entrez]
AID - 10.1002/art.22727 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2007 Jul;56(7):2170-9. doi: 10.1002/art.22727.