α9β1 integrin acts as a critical intrinsic regulator of human rheumatoid arthritis.
OBJECTIVE
The role of the joint tissue microenvironment in the pathogenesis of human RA has recently attracted much attention. The present study investigated the roles of α9β1 integrin and its ligands in synovial specimens of human RA patients in generating the unique human arthritic tissue microenvironment.


METHODS
Synovial fibroblasts and macrophages were isolated from the synovial tissue of patients with RA or OA. The expression of α9β1 integrin was analysed using FACS with multicolour staining. The production of MMPs and proinflammatory cytokines was analysed in cultures of synovial fibroblasts and macrophages with α9β1 integrin ligands.


RESULTS
Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C. In the synovial fibroblasts of RA, the amount of tenascin-C protein produced was much greater than that of osteopontin in synovial fibroblasts of RA. Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages.


CONCLUSIONS
These findings indicate that autocrine and paracrine interaction of α9β1 integrin and tenascin-C in the joint tissue microenvironment contributes to the pathogenesis of RA. Therefore α9β1 integrin may become a potential therapeutic target for RA.
Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. toshi@igm.hokudai.ac.jp.
Tsuyoshi
T
Asano
Norimasa
N
Iwasaki
Shigeyuki
S
Kon
Masashi
M
Kanayama
Junko
J
Morimoto
Akio
A
Minami
Toshimitsu
T
Uede
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology* / Q000503:physiopathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016023:Integrins / Q000502:physiology*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010003:Osteoarthritis / Q000473:pathology* / Q000503:physiopathology*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019063:Tenascin / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
D016207:Cytokines; D016023:Integrins; D008024:Ligands; D019063:Tenascin; C113256:integrin alpha 9 beta 1
integrin; osteopontin; rheumatoid arthritis; synovial fibroblast; tenascin-C