Abstract
BackgroundRheumatoid arthritis (RA) is characterized by joint inflammation and damage to the cartilage and bone in collagen-induced arthritis (CIA). Mesenchymal stem cells (MSCs) can improve articular symptoms and reduce bone erosion in CIA rats; however, the underlying mechanism remains unknown. This study aimed to investigate the mechanism underlying MSC-induced improvement of bone destruction in CIA.MethodsWistar rats were divided into a normal group, CIA control group, MTX intervention group, and BMSC intervention group, each comprising 8 rats. Serum RANKL, OPG, and CXCL10 levels of all groups were determined via flow cytometry after 42 days of interventions. RANKL, OPG, TRAF6, CXCL10, and CXCR3 were detected on the synovial membrane via immunohistochemistry, and their relative mRNA levels were determined via RT-PCR analysis. BMSCs were labeled with GFP and administered to CIA rats via the tail vein. At different time points, the distribution of implanted GFP-MSCs in synovial tissues was observed using a fluorescence microscope, and the potential of GFP-MSCs to differentiate into chondrocytes was assessed via immunofluorescence analysis.ResultsBMSC transplantation improved joint inflammation and inhibited bone destruction in CIA rats. BMSCs inhibited the expression of serum CXCL10 and CXCL10 and CXCR3 expression at the synovial membrane. Moreover, protein and mRNA expression analyses revealed that BMSCs potentially regulated RANKL/OPG expression levels in the serum and synovial tissue. Upon implantation into CIA rats, GFP-MSCs were traced in the joints. GFP-positive cells were observed in the cartilage tissue from day 11 and until 42 days after transplantation. Anti-type II collagen/GFP double-positive cells were observed in the articular cartilage (especially damaged cartilage) upon immunofluorescence staining of anti-type II collagen.ConclusionsBMSCs improve bone destruction in CIA by inhibiting the CXCL10/CXCR3 chemotactic axis, regulating the RANKL/OPG ratio, and directly differentiating into chondrocytes.
Highlights
Rheumatoid arthritis (RA) is characterized by symmetric polyarthritis
The yellow arrow denotes bone tissue; orange, synovial tissue; red, cartilage tissue; and green, bone marrow cavity (× 40). b GFP+ cells in the bone marrow (× 600). c GFP+ cells in the synovium (× 600). d No GFP+ cells were observed at 3 days in the cartilage and bone tissue (× 600). e After 11 days of transplantation, GFP-positive cells were observed in the articular cartilage, primarily spindle cells (× 600). f After 42 days of transplantation, GFPpositive cells were observed in the articular cartilage and bone tissues, primarily comprising oval and spherical cells (× 600)
This study shows that Receptor activator for nuclear factor-κ B ligand (RANKL) protein and mRNA levels and RANKL/OPG ratio in serum and synovial tissue (ST), and TRAF-6 levels in ST increased in collagen-induced arthritis (CIA) rats and decreased after bone marrow Mesenchymal stem cells (MSCs) (BMSCs) intervention
Summary
Rheumatoid arthritis (RA) is characterized by symmetric polyarthritis. Synovial inflammatory infiltration and the interaction between immune cells and synovial fibroblasts result in cartilage and bone erosion. Various biological agents that block cytokines, including TNF-α, IL-1, and IL-6, and target B cells and osteoclasts have been reported, having benefited numerous refractory RA patients. Such drugs exclusively target a certain step in RA pathogenesis and are costly. Rheumatoid arthritis (RA) is characterized by joint inflammation and damage to the cartilage and bone in collagen-induced arthritis (CIA). Mesenchymal stem cells (MSCs) can improve articular symptoms and reduce bone erosion in CIA rats; the underlying mechanism remains unknown. This study aimed to investigate the mechanism underlying MSC-induced improvement of bone destruction in CIA
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