RESEARCH - Ang-1 directly induces destruction of the rheumatoid joint by cooperative, but independent, signaling

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Arthritis Rheum. 2007 Jul;56(7):2170-9.

Angiopoietin 1 directly induces destruction of the rheumatoid joint by

cooperative, but independent, signaling via ERK/MAPK and

phosphatidylinositol 3-kinase/Akt.

Hashiramoto A, Sakai C, Yoshida K, Tsumiyama K, Miura Y, Shiozawa K, Nose M,

Komai K, Shiozawa S.

Kobe University FHS School of Medicine, Kobe University Hospital, Sumaku,

Kobe, Japan.

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.

PMID: 17599743

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve & db=PubMed & list_uids=175997\

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Not an MD