Bone marrow mesenchymal stem cells improve bone erosion in collagen-induced arthritis by inhibiting osteoclasia-related factors and differentiating into chondrocytes

Abstract

Background 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; however, the underlying mechanism remains unknown. This study aimed to investigate the mechanism underlying MSC-induced improvement of bone destruction in CIA. Methods Wistar 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. Results BMSC 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. Conclusions BMSCs improve bone destruction in CIA by inhibiting the CXCL10/CXCR3 chemotactic axis, regulating the RANKL/OPG ratio, and directly differentiating into chondrocytes.

MSCs Become Collagen-Type I Producing Cells with Different Phenotype in Allogeneic and Syngeneic Bone Marrow Transplantation

“…Hence, it might be feasible that the MSCs differentiate after initially arriving at the tissue site to specify their properties. This behavior was seen by many studies before [ 46 , 47 , 48 ]. Furthermore, Waterman et al demonstrated that toll-like receptor (TLR) 3 and 4 have a contrary effect on collagen expression in MSCs.…”

Mesenchymal Stem Cells Enhance Therapeutic Effect and Prevent Adverse Gastrointestinal Reaction of Methotrexate Treatment in Collagen-Induced Arthritis

“…Sections of the liver, lung, and kidney were performed as the same processes. Immunohistochemical staining was performed with previously described procedures [ 15 ]. Briefly, paraffin sections were incubated with primary antibodies IL-1 β (1 : 200; Abcam, Cambridge, UK) and TNF- α (1 : 200; Abcam, Cambridge, UK) overnight at 4°C.…”

Mesenchymal Stem/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications

“…Numerous studies have also demonstrated the key role played by several chemokines, such as macrophage inflammatory protein 1 (CCL4/MIP-1), monocyte chemoattractant protein 1 (CCL2/MCP-1), regulated upon activation, normal T cell expressed and secreted (CCL5/RANTES), and receptor activator of nuclear factor kappa-Β ligand (RANKL) [ 62 , 76 , 78 ]. In parallel, an increase in IL-10, IFN-γ-induced protein 10 (IP-10) and/or chemokine receptor 3-alternative (CXCR3) anti-inflammatory cytokine levels in serum and synovium have been reported [ 55 , 79 ]. Additionally, an increased frequency of Tregs and IL-10 and TGF-β-secreting T cells with a decrease frequency of IL-17 and IFN-γ-secreting T cells (Th17 and Th1 cells) in spleen and/or draining lymph nodes have also been observed in vivo [ 21 , 78 , 80 ].…”