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. 2020 May 7;11(1):171.
doi: 10.1186/s13287-020-01684-w.

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

Jinfang Gao  1   2 , Gailian Zhang  1 , Ke Xu  1 , Dan Ma  1   2 , Limin Ren  1 , Jingjing Fan  1 , Jianwen Hou  1 , Jian Han  1 , Liyun Zhang  3
Affiliations

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

Jinfang Gao et al. Stem Cell Res Ther. .

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.

Keywords: Bone destruction; Bone marrow-derived mesenchymal stem cells; Chemokines; Green fluorescent protein; RANKL/OPG; Rheumatoid arthritis; Tissue repair.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Characteristics of BMSCs and GFP-BMSCs. a Cell culture of passage 3 (original magnification × 100). b GFP-BMSCs under the fluorescence microscope (original magnification × 100). c Flow cytometry results showed that cells were positive for CD44, CD105, and CD29, while negative for CD45, CD34, and CD31. d Osteogenic differentiation of BMSCs indicated by Alizarin Red staining (original magnification × 100). e Oil red O staining of BMSCs after induction of adipogenic differentiation (original magnification × 100). f, g After induction of chondrogenic differentiation, toluidine blue staining and collagen type II immunohistochemical staining were positive (original magnification × 200)
Fig. 2
Fig. 2
BMSCs alleviated inflammatory responses and prevented joint damage in CIA rats. a Swelling of the ankle joints in CIA rats was obvious and relieved after BMSCs or MTX intervention. b Compared with the normal group, the arthritis index (AI) value in the CIA model group increased; however, it showed a downward trend from the second week after BMSC and MTX intervention. *P < 0.05; **P < 0.01; ***P < 0.001. c X-ray image showed that CIA rats had a narrow ankle and toe joint space, bristle edge, and joint destruction, and joint erosion was reduced after BMSC or MTX intervention. d Significant osteoporosis and bone destruction were observed in the ankle joint of CIA rats but improved in the BMSC and MTX intervention groups on micro-computed tomographic imaging. e Compared to the CIA group, BMSCs can increase the level of BV/TV, Tb. N, and Tb. Th and reduce the value of Tb. Sp. f Joint pathology findings suggested that synovial hyperplasia, inflammatory cell infiltration, and cartilage destruction were observed in the CIA rat group but were attenuated in the BMSC and MTX intervention group (HE, × 20)
Fig. 3
Fig. 3
Effects of BMSCs on RANKL/OPG/TRAF6 signaling and the CXCL10/CXCR3 chemokine axis in CIA model rats. a Comparison of RANKL, OPG, and CXCL10 levels and RANKL/OPG ratio in the serum among the four groups. b RANKL, OPG, TRAF6, CXCL10, and CXCR3 levels in the synovial membrane. c RANKL, OPG, TRAF6, CXCL10, and CXCR3 mRNA levels in the synovial membrane. *P < 0.05; **P < 0.01; ***P < 0.001
Fig. 4
Fig. 4
The distribution of GFP-labeled bone marrow mesenchymal stem cells (BMSCs) in the synovial cartilage and bone marrow 3 days after transplantation. a BMSCs were distributed in the bone marrow and synovial membrane but not in the cartilage and bone tissue. 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, GFP-positive cells were observed in the articular cartilage and bone tissues, primarily comprising oval and spherical cells (× 600). The red arrows denote cartilage tissue; yellow, bone tissues; and green, bone marrow cavities
Fig. 5
Fig. 5
Immunofluorescence staining of bone marrow mesenchymal stem cells undergoing chondrogenic differentiation. GFP/type II collagen double-positive cells (× 1000)
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