TY - JOUR
T1 - Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis
AU - Yong, Wook Park
AU - Young, Mo Kang
AU - Butterfield, Joe
AU - Detmar, Michael
AU - Goronzy, Jörg J.
AU - Weyand, Cornelia M.
N1 - Funding Information:
Supported in part by grants from the National Institutes of Health ( RO1 AR 42527, RO1 AI 44142, RO1 AR 41974, and RO1 EY 11916 ).
PY - 2004/12
Y1 - 2004/12
N2 - 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.
AB - 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.
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U2 - 10.1016/s0002-9440(10)63259-2
DO - 10.1016/s0002-9440(10)63259-2
M3 - Article
C2 - 15579451
AN - SCOPUS:9644264253
SN - 0002-9440
VL - 165
SP - 2087
EP - 2098
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -