Abstract
Assuming that mesenchymal stem cells (MSCs) respond to the osteoarthritic joint environment to exert a chondroprotective effect, we aimed at investigating the molecular response setup by MSCs after priming by osteoarthritic chondrocytes in cocultures. We used primary human osteoarthritic chondrocytes and adipose stem cells (ASCs) in mono- and cocultures and performed a high-throughput secretome analysis. Among secreted proteins differentially induced in cocultures, we identified thrombospondin-1 (THBS1) as a potential candidate that could be involved in the chondroprotective effect of ASCs. Secretome analysis revealed significant induction of THBS1 in ASCs/chondrocytes cocultures at mRNA and protein levels. We showed that THBS1 was upregulated at late stages of MSC differentiation toward chondrocytes and that recombinant THBS1 (rTHBS1) exerted a prochondrogenic effect on MSC indicating a role of THBS1 during chondrogenesis. However, compared to control ASCs, siTHBS1-transfected ASCs did not decrease the expression of hypertrophic and inflammatory markers in osteoarthritic chondrocytes, suggesting that THBS1 was not involved in the reversion of osteoarthritic phenotype. Nevertheless, downregulation of THBS1 in ASCs reduced their immunosuppressive activity, which was consistent with the anti-inflammatory role of rTHBS1 on T lymphocytes. THBS1 function was then evaluated in the collagenase-induced OA model by comparing siTHBS1-transfected and control ASCs. The protective effect of ASCs evaluated by histological and histomorphological analysis of cartilage and bone was not seen with siTHBS1-transfected ASCs. Our data suggest that THBS1 did not exert a direct protective effect on chondrocytes but might reduce inflammation, subsequently explaining the therapeutic effect of ASCs in OA.
Highlights
Osteoarthritis (OA) is the most prevalent rheumatic disease characterized by low chronic inflammation and major structural changes of the joint, causing pain, and functional disability
Among differentially secreted proteins induced in coculture, we identified thrombospondin-1 (THBS1) as a potential candidate involved in the chondroprotective effect of adipose stem cells (ASCs) and explored its function both in vitro and in vivo in the collagenase-induced osteoarthritis (CIOA) model [18]
We confirmed a significant increase of THBS1 in cocultures as compared to chondrocyte or ASC monocultures (Figure 1B)
Summary
Osteoarthritis (OA) is the most prevalent rheumatic disease characterized by low chronic inflammation and major structural changes of the joint, causing pain, and functional disability. Hip and knee OA contributes the most to OA burden. Radiographic evidence of knee OA is observed in approximately 30% of men and women over the age of 65. Worldwide estimates are that 9.6% of men and 18.0% of women over the age of 60 years have symptomatic OA along with limitations in movement, and reductions in major activities of daily life (World Health Organization, see http:// www.who.int/chp/topics/rheumatic/en/). OA of the knees and hips has become a major public health problem in the last years and is the third most prevalent musculoskeletal disorder [3]. Development of innovative strategies to reduce the burden of OA and improve the management of the disease is critical [4]
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