Abstract
Rheumatoid arthritis (RA) is a debilitating and painful inflammatory autoimmune disease characterised by the accumulation of leukocytes in the synovium, cartilage destruction and bone erosion. The immunomodulatory effects of bone marrow derived mesenchymal stem cells (MSCs) has been widely studied and the recent observations that syndecan-3 (SDC3) is selectively pro-inflammatory in the joint led us to hypothesise that SDC3 might play an important role in MSC biology. MSCs isolated from bone marrow of wild type and Sdc3−/− mice were used to assess immunophenotype, differentiation, adhesion and migration properties and cell signalling pathways. While both cell types show similar differentiation potential and forward scatter values, the cell complexity in wild type MSCs was significantly higher than in Sdc3−/− cells and was accompanied by lower spread surface area. Moreover, Sdc3−/− MSCs adhered more rapidly to collagen type I and showed a dramatic increase in AKT phosphorylation, accompanied by a decrease in ERK1/2 phosphorylation compared with control cells. In a mouse model of antigen-induced inflammatory arthritis, intraarticular injection of Sdc3−/− MSCs yielded enhanced efficacy compared to injection of wild type MSCs. In conclusion, our data suggest that syndecan-3 regulates MSC adhesion and efficacy in inflammatory arthritis, likely via induction of the AKT pathway.
Highlights
Syndecans are transmembrane heparan sulphate proteoglycans (HSPG) that consist of a core protein with heparan sulphate glycosaminoglycan chains covalently attached to the ectodomain
We previously demonstrated that mesenchymal stem cells (MSCs) reduce inflammation, joint swelling and cartilage destruction in a murine model of antigen-induced arthritis (AIA)[17] and hypothesise that SDC3 might play an important role in MSCs biology
Expression of the general progenitor cell marker CD34 and of the vascular progenitor marker CD105 was highly variable in MSCs isolated from both genotypes, with a general trend of both markers being more commonly expressed in MSCs from Syndecan-3 null (Sdc3−/−)mice compared with MSCs from wild type mice (Fig. 1d,e)
Summary
Syndecans are transmembrane heparan sulphate proteoglycans (HSPG) that consist of a core protein with heparan sulphate glycosaminoglycan chains covalently attached to the ectodomain. The variable ectodomain, which is exposed to the extracellular environment, contains two or more heparan sulphate chains and in some cases chondroitin sulphate chains Through their ectodomain syndecans interact with a variety of extracellular and membrane proteins modulation many signalling pathways and biological processes including adhesion, proliferation, differentiation and inflammation[3,4]. We demonstrated that SDC3 plays a dual role in inflammation depending on the tissue and vascular bed In the joint it is pro-inflammatory, since its deletion leads to reduced leukocyte recruitment and the severity of arthritis. We previously demonstrated that MSCs reduce inflammation, joint swelling and cartilage destruction in a murine model of antigen-induced arthritis (AIA)[17] and hypothesise that SDC3 might play an important role in MSCs biology. Our data further support the idea that pharmacologic targeting of SDC3 might constitute a potentially valuable therapeutic strategy for inflammatory arthritis
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