Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis

Wook Park Yong, Mo Kang Young, Joe Butterfield, Michael Detmar, Jörg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Thrombospondin 2 (TSP2), a matricellular protein with a primary role in modulating cell-matrix interactions, has been implicated in tissue repair and foreign body responses. Here we show that TSP2 has regulatory function in the chronic inflammatory lesions of rheumatoid arthritis. Tissue TSP2, produced by synovial fibroblasts, endothelial cells, and macrophages correlated not only with the intensity of angiogenesis but also with the architecture of lymphoid infiltrates. Synovial tissues with diffuse inflammatory infiltrates had high levels of TSP2, whereas synovial tissues with ectopic germinal center reactions and T cell-B cell aggregates produced low levels. Cell-based gene therapy with TSP2 was used to examine the in vivo effects of the matrix protein on neoangiogenesis and lymphoid organization. Human synovium-severe combined immunodeficiency (SCID) mouse chimeras were treated with TSP2-transfected fibroblasts deposited into the peritoneum. Overexpression of TSP2 led to the accumulation of TSP2 protein in the inflamed synovium and resulted, in a prompt inhibition of lesional vascularization. Beside its anti-angiogenic activity, TSP2 also suppressed the production of the proinflammatory mediators, interferon-γ and tumor necrosis factor-α, and induced the depletion of tissue-residing T cells. We propose that TSP2 is an endogenous regulator of angiogenesis and autoimmune inflammation in the synovium and represents a protective mechanism preventing ectopic lympho-or-ganogenesis and persistent inflammation in this tissue site.

Original languageEnglish (US)
Pages (from-to)2087-2098
Number of pages12
JournalAmerican Journal of Pathology
Volume165
Issue number6
DOIs
StatePublished - Dec 2004

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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