Serum amyloid A binding to formyl peptide receptor-like 1 induces synovial hyperplasia and angiogenesis.
Serum amyloid A (SAA) is a major acute-phase reactant, and has been demonstrated to mediate proinflammatory cellular responses. Although SAA has been used as an indicator for a variety of inflammatory diseases, the role of SAA in synovial hyperplasia and proliferation of endothelial cells, a pathological hallmark of rheumatoid arthritis (RA), has yet to be elucidated. In this study, we have demonstrated that SAA promotes the proliferation of human fibroblast-like synoviocytes (FLS). In addition, SAA protects RA FLS against the apoptotic death induced by serum starvation, anti-Fas IgM, and sodium nitroprusside. The activity of SAA appears to be mediated by the formyl peptide receptor-like 1 (FPRL1) receptor, as it was mimicked by the WKYMVm peptide, a specific ligand for FPRL1, but completely abrogated by down-regulating the FPRL1 transcripts with short interfering RNA. The effect of SAA on FLS hyperplasia was shown to be caused by an increase in the levels of intracellular calcium, as well as the activation of ERK and Akt, which resulted in an elevation in the expression of cyclin D1 and Bcl-2. Moreover, SAA stimulated the proliferation, migration, and tube formation of endothelial cells in vitro, and enhanced the sprouting activity of endothelial cells ex vivo and neovascularization in vivo. These observations indicate that the binding of SAA to FPRL1 may contribute to the destruction of bone and cartilage via the promotion of synoviocyte hyperplasia and angiogenesis, thus providing a potential target for the control of RA.
Lee
Mi-Sook
MS
Division of Molecular Life Sciences, Pohang University of Science and Technology, Pohang, Korea.
Yoo
Seung-Ah
SA
Cho
Chul-Soo
CS
Suh
Pann-Ghill
PG
Kim
Wan-Uk
WU
Ryu
Sung Ho
SH
D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000209:etiology*; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011485:Protein Binding / Q000502:physiology; D044042:Receptors, Formyl Peptide / Q000378:metabolism / Q000502:physiology*; D044067:Receptors, Lipoxin / Q000378:metabolism / Q000502:physiology*; D000685:Serum Amyloid A Protein / Q000378:metabolism / Q000502:physiology*; D013583:Synovial Membrane / Q000473:pathology*
C105101:FPR2 protein, human; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D000685:Serum Amyloid A Protein