Mu-calpain is involved in the regulation of TNF-alpha-induced matrix metalloproteinase-3 release in a rheumatoid synovial cell line.
Calpain is secreted by intra-articular synovial cells and degrades the main components of cartilage matrix proteins, proteoglycan, and collagen, causing cartilage destruction. Matrix metalloproteinase-3 (MMP-3) has also been detected in synovial fluid and serum, and is involved in the development and progression of rheumatoid arthritis by degradation of the extracellular matrix and cartilage destruction. To investigate the relationship between calpain and MMP-3 in rheumatic inflammation, we utilized the rheumatic synovial cell line, MH7A. Tumor necrosis factor (TNF-alpha) stimulation-induced increased expression of mu-calpain, m-calpain, and MMP-3 in these cells, as well as the release of calpain and MMP-3 into the culture medium. The calpain inhibitors, ALLN (calpain inhibitor I) and calpeptin, did not affect the intracellular expression of MMP-3, but reduced the secretion of MMP-3 in a concentration-dependent manner. Down-regulation of mu- but not m-calpain by small interfering RNAs abolished TNF-alpha-induced MMP-3 release from the synovial cells. These findings suggest that calpain, particularly mu-calpain, regulates MMP-3 release by rheumatic synovial cells, in addition to exerting its own degradative action on cartilage.
Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Masaji
M
Morita
Yoshiko
Y
Banno
Taikoh
T
Dohjima
Satoshi
S
Nozawa
Kazunari
K
Fushimi
De-Gang
DG
Fan
Takatoshi
T
Ohno
Keiji
K
Miyazawa
Naxin
N
Liu
Katsuji
K
Shimizu
D001172:Arthritis, Rheumatoid / Q000201:enzymology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D034622:RNA Interference; D013583:Synovial Membrane / Q000166:cytology / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D015853:Cysteine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D002154:Calpain; C449000:m-calpain; C449002:mu-calpain; D019278:Matrix Metalloproteinase 3