Rheumatology Advance Access published online on June 21, 2008
Rheumatology, doi:10.1093/rheumatology/ken225
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Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis
1Department of Clinical Immunology, State Key Discipline of Cell Biology, Xijing Hospital, Xi'an, 2Second Department of Geriatrics Cardiology, Chinese General Hospital of PLA, Beijing and 3Department of Cell Biology/Cell Engineering Research Centre, Cancer Biology of State Key Laboratory and State Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, China.
Correspondence to:
P. Zhu, Department of Clinical Immunology, State Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, P.R. China. E-mail: zhuping{at}fmmu.edu.cn
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Abstract |
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Objectives. To investigate whether cyclophilin A (CypA) can up-regulate the expression of MMP-2 and MMP-9 in monocytes/macrophages and whether CD147 facilitates this regulation in RA.
Methods. Peripheral blood monocytes were isolated from RA patients and differentiated into macrophages by M-CSF (15 ng/ml). Under CypA stimulation (200 ng/ml), the protein release and activation of MMPs were detected by gelatin zymography and invasion assay. Human monocyte cell line THP-1 cells were selected for the advanced searching for potential interaction between CypA and CD147 in production of MMPs and cell adhesion to extracellular matrix (ECM).
Results. CypA significantly increased production and activation of MMP-9, not MMP-2, in the monocytes/macrophages derived from RA SF. CSA and HAb18G/CD147 antagonistic peptide AP-9 against CD147, respectively, dramatically decreased MMP-2 and MMP-9 expression, both in the absence or presence of CypA. Similar effects of CypA on MMP-9 production and cell invasion were observed in THP-1 cells. CypA-induced nuclear factor 
B (NF-B) activity for MMP-9 transcription were strongly blocked by extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK) inhibitors (U0126 and SP600125, respectively), but not by p38 mitogen-activated protein kinase (MAPK) inhibitors (SB203580). CypA also induced calcium mobilization and increased the adhesion of THP-1 cells to ECM.
Conclusions. These findings suggest that in RA, the abundant CypA, by its direct binding to CD147, up-regulates MMP-9 expression and adhesion of monocytes/macrophages to ECM, and the cyclophilin-CD147 interactions might contribute to the destruction of cartilage and bone.
KEY WORDS: Rheumatoid arthritis, Monocytes/macrophages, CD147, Cyclophilin A, Matrix metalloproteinase
*Z.-n. Chen and P. Zhu equally contributed to this work.
Submitted 14 December 2007;
revised version accepted 15 May 2008.
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