Cyclophilin A Up-regulates MMP-9 Expression and Adhesion of Monocytes/macrophages Via CD147 Signalling Pathway in Rheumatoid Arthritis

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 kappaB (NF-kappaB) 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.