Immunohistochemical localisation of protein tyrosine kinase receptors Tie-1 and Tie-2 in synovial tissue of rheumatoid arthritis: correlation with angiogenesis and synovial proliferation

doi:10.1136/ard.59.8.607

Annals of the Rheumatic Diseases 2000;59:607-614; doi:10.1136/ard.59.8.607

Ann Rheum Dis 2000;59:607-614 ( August )

Extended report

Immunohistochemical localisation of protein tyrosine kinase receptors Tie-1 and Tie-2 in synovial tissue of rheumatoid arthritis: correlation with angiogenesis and synovial proliferation Takeshi Uchida^a, Masahiro Nakashima^b, Yashuhiro Hirota^a, Yoichi Miyazaki^a, Tomoo Tsukazaki^c, Hiroyuki Shindo^a

^a Department of Orthopaedic Surgery, Nagasaki University School of Medicine, Nagasaki, Japan, ^b Department of Molecular Pathology, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Nagasaki, Japan, ^c First Department of Anatomy, Nagasaki University School of Medicine, Nagasaki, Japan

Correspondence to: Dr Tomoo Tsukazaki, First Department of Anatomy, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan Email: ttsukanet.nagasaki-ac.jp

Accepted for publication 9 February 2000

OBJECTIVE $---$ To investigate the involvement of Tie-1 and Tie-2, receptor tyrosine kinases required for angiogenesis, in synovial proliferationand angiogenesis of rheumatoid arthritis(RA).
METHODS $---$ Synovial tissues from 10 patients with RA and three control subjects were analysed by double immunohistochemistry and reversetranscriptase polymerase chain reaction (RT-PCR).
RESULTS $---$ Expression of Tie-1 and Tie-2 was seen in all synovia, but predominantly in papillary projected portions. In synovial liningcells, Tie-2 was expressed mainly in the basal layer and frequentlycolocalised with vimentin and proliferating cell nuclear antigen(PCNA), whereas Tie-1 was also expressed in the superficial layer.In stromal cells, Tie-2 immunoreactivity was restricted to vimentinpositive fibroblast $---$ but not macrophage derived cells, whereasTie-1 expression was not dependent on the phenotype. Tie receptorswere also highly expressed in the endothelium and surroundingpericytes of capillaries scattered over the papillary proliferatedsynovium without notable difference in the expression of the tworeceptors. Furthermore, Tie positive vessels often overexpressedPCNA. In normal synovia, expression of Tie receptors was restrictedto the capillary endothelium. RT-PCR confirmed the expressionof Tie-1 and Tie-2 in RA synovial tissues and also in the culturedsynoviocytes.
CONCLUSION $---$ The results suggest the possible involvement of overexpressed Tie-1 and Tie-2 in synovial lining and stromal cells in thepathophysiology of RA synovitis, probably through distinct mechanisms.Furthermore, expression of Tie receptors in actively growing vasculaturemay reflect the direct involvement of these receptors in angiogenesisand subsequentvascularisation.

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