The role of PEDF (SERPINF1) for terminal chondrocyte differentiation in osteoarthritis and cartilage repair

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Under physiological conditions, articular chondrocytes permanently retain their stable phenotype for many decades. By contrast, osteoarthritis as well as cartilage repair processes are confronted with inadvertant terminal differentiation of chondrocytes, which is associated with cellular hypertrophy, apoptosis and calcification of the matrix. While terminal chondrocyte differentiation is a physiological sequence during endochondral ossification, this process significantly hampers the integrity of adult articular cartilage.Our previous genome-wide expression analyses demonstrated that Pigment Epithelium-Derived Factor (PEDF/ SERPINF1) was a factor that was strikingly higher expressed in repair cartilage compared with healthy articular cartilage. In this context, PEDF was detected most predominantly in areas of prehypertrophic chondrocytes, which basically reflects the expression pattern within the fetal growth plate. In a variety of other cell types, PEDF is known as a potent anti-angiogenic and anti-tumorigenic factor mediating its effects predominantly via pro-apoptotic mechanisms. Therefore, this project is based on the hypothesis that PEDF is responsible for terminal chondrocyte differentiation and that PEDF determines the transient instead of the permanent chondrocyte phenotype.In order to analyse the association of PEDF with the chondrocyte phenotype, its spatial expression pattern will be investigated in fetal epiphyses and adult joint structures. The mechanism of action of PEDF in chondrocytes will be investigated in stimulation experiments using recombinant PEDF and in loss-of-function experiments using siRNA-transfection or neutralizing antibodies. The readout will predominantly focus on effects on cellular hypertrophy and apoptosis of precursor cells as well as healthy and osteoarthritic chondrocytes. Furthermore, it will be investigated if the inhibition of the PEDF-activity will prevent chondrocytes from undergoing terminal differentiation and apoptosis in different culture systems. The aim of this project is to stabilize the chondrocyte phenotype in osteoarthric cartilage and repair cartilage by modulating the PEDF pathway.