Stimulation of matrix metalloprotease 3 release from human chondrocytes by the interaction of stromal cell-derived factor 1 and CXC chemokine receptor 4.
OBJECTIVE
The chemokine family of secreted proteins regulates cellular activities through interaction with G protein-coupled chemokine receptors. The aim of this study was to analyze the role of a chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 in rheumatoid arthritis (RA) and osteoarthritis (OA) by examining their gene expression in joint cartilage and synovium and by determining the effect of their interaction on the release of matrix metalloproteases (MMPs) from chondrocytes.


METHODS
SDF-1 protein levels in synovial fluid from the knee joints of 58 RA patients, 55 OA patients, and 60 control patients without arthritis were quantified by enzyme-linked immunosorbent assay. SDF-1 and CXCR4 messenger RNA (mRNA) levels in chondrocytes and synovial fibroblasts were determined by reverse transcriptase-polymerase chain reaction. Isolated human chondrocytes were stimulated with 100 ng/ml of SDF-1, and the response was analyzed by quantifying the release of MMPs 1 and 3.


RESULTS
We found that the concentration of SDF-1 in synovial fluid increased 3.57-fold in OA patients and 10.71-fold in RA patients compared with normal controls. The source of SDF-1 in synovial fluid was synovium, since SDF-1 mRNA was synthesized by synovial fibroblasts but not by chondrocytes. Conversely, CXCR4 was expressed by chondrocytes but not by synovial fibroblasts. The interaction of SDF-1, which was abundant in synovial fluid from RA and OA patients, with CXCR4-positive chondrocytes resulted in a specific elevation of the release of the cartilage matrix-degrading enzyme MMP-3 (stromelysin 1).


CONCLUSIONS
Our findings suggest a novel mechanism by which synovial cells induce degradation of cartilage matrix through SDF-1 signaling in RA and OA.
Kanbe
Katsuaki
K
The Pennsylvania State University College of Medicine, Hershey 17033-0850, USA.
Takagishi
Kenji
K
Chen
Qian
Q
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019902:Chondrocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism; D013582:Synovial Fluid / Q000737:chemistry; D013583:Synovial Membrane / Q000166:cytology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D019278:Matrix Metalloproteinase 3