Interaction between cartilage / subchondral interfaces and MSC in vitro and in vivo
Final Report Abstract
The major aim of the present study was to identify factors which are responsible for the regulation of collagen expression during chondrogenic differentiation of bone marrowderived mesenchymal stem cells (MSC) in an OA microenvironment. A second aim was to determine the influence of cocultured cells on protein synthesis of cartilage explants. Coculture with OA cartilage and subchondral bone induced the expression of three miRs in MSC and chondrocytes: miR-29b-3p, miR-124a and miR-675. For miR-29b-3p we were able to assign a role in collagen I and III regulation. In MSC, miR-29b-3p inhibited collagen I and III expression. Elevated miR-29b-3p expression resulted in higher caspase 3/7 activity and promoted apoptosis of MSC by inhibiting the anti-apoptotic proteins Bcl-2 and Mcl-1. Stimulation with IFN-γ induced miR-29b-3p expression in MSC. Our results suggest that high miR-29b expression during chondrogenic differentiation of MSC in an OA microenvironment appears to be beneficial for adopting the chondrocytic phenotype as inhibition of collagen I, a marker for dedifferentiated chondrocytes, and collagen III, mainly expressed by undifferentiated MSC, might promote formation of a collagen II rich cartilage matrix instead of inferior fibrocartilage. In addition, miR-29b-3p promotes apoptosis which might be considered as a control step preventing unfavorable excessive cell growth. With respect to the second aim we did not detect and identified differentially expressed proteins in cartilage explants which were kept in coculture with either MSC or chondrocytes kept in fibrin gels versus cartilage explants cultured with cell-free fibrin gels.
Publications
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(2017) miR-29b regulates expression of collagens I and III in chondrogenically differentiating BMSC in an osteoarthritic environment. Scientific reports 7 (1) 13297
Mayer, Ute; Benditz, Achim; Grässel, Susanne
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Cartilage- and subchondral bone derived factors regulate collagen production in MSC. Osteoarthritis Cartilage, 20, Suppl. 1: S275, 2012
Leyh M., Bruckmann A., Richter W., Beckmann J., Grifka J., Grässel S.
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Norepinephrine inhibits mesenchymal stem cell and chondrogenic progenitor cell chondrogenesis and accelerates chondrogenic hypertrophy. Arthritis Rheumatol. Sep; 66(9):2472-81, 2014
Jenei-Lanzl Z., Grässel S., Pongratz G. Kees F., Miosge N., Angele P., Straub R.H.
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Osteoarthritic cartilage explants affect extracellular matrix production and composition in cocultured bone-marrow derived mesenchymal stem cells and articular chondrocytes. Stem Cell Res Ther. Jun 10; 5(3):77, 2014
Leyh M., Seitz A., Dürselen L., Springorum H.R., Angele P., Ignatius A., Grifka J., Grässel S.
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The impact of hypoxia on mesenchymal progenitor cells of human skeletal tissue in the pathogenesis of heterotopic ossification. Int Orthop., 2015 Dec; 39(12):2495- 501
Winkler S., Niedermair T., Füchtmeier B., Grifka J., Grässel S., Anders S., Heers G., Wagner F.
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Influence of osteoarthritic cartilage explants on the expression of miRs and predicted targets in cocultured chondrocytes and mesenchymal stem cells. Osteoarthritis Cartilage,24, Suppl.1: S434, 2016
Mayer U., Angele P., Benz K., Springorum H.R., Grässel S.
