Overexpression of human matrix metalloproteinase-12 enhances the development of inflammatory arthritis in transgenic rabbits.
Increased proteolytic activity of matrix metalloproteinases (MMPs) may promote articular destruction such as occurs in rheumatoid arthritis and osteoarthritis. Recently, we reported that synovial tissue and fluid obtained from patients with rheumatoid arthritis contained higher activity of macrophage elastase (MMP-12). To examine the hypothesis that MMP-12 may potentially enhance the progression of arthritis, we investigated the effects of overexpression of MMP-12 on inflammatory arthritis in transgenic rabbits that express the human MMP-12 transgene in the macrophage lineage. Inflammatory arthritis was produced by articular injection of carrageenan solution and the degree of inflammatory arthritis in transgenic rabbits was compared with that in control rabbits. We found that overexpression of MMP-12 in transgenic rabbits significantly enhanced the arthritic lesions, resulting in severe synovial thickening, pannus formation, and prominent macrophage infiltration at an early stage and a marked destruction of articular cartilage associated with loss of proteoglycan at a later stage. These results demonstrate that excessive MMP-12 expression exacerbates articular connective tissue and cartilage degradation and thus plays a critical role in the development of inflammatory joint disease.
Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, 305-8575, Japan.
Xiaofei
X
Wang
Jingyan
J
Liang
Tomonari
T
Koike
Huijun
H
Sun
Tomonaga
T
Ichikawa
Shuji
S
Kitajima
Masatoshi
M
Morimoto
Hisataka
H
Shikama
Teruo
T
Watanabe
Yasuyuki
Y
Sasaguri
Jianglin
J
Fan
D000818:Animals; D030801:Animals, Genetically Modified; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D015152:Blotting, Northern; D015153:Blotting, Western; D002351:Carrageenan / Q000008:administration & dosage; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D007270:Injections, Intra-Articular; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D010003:Osteoarthritis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D002351:Carrageenan; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12