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Étude des potentialités modulatrices du domaine « netrin-like » de la protéine FRZB/sFRP3 et de ses effets Wnts-dépendants dans les tissus ostéo-articulaires

Abstract : Osteoarthritis is a disease characterized by a progressive destruction of articular cartilage. The socio-economic cost increases with the increase in life expectancy. The Hippo / YAP / TAZ and Wnt signaling pathways are deregulated during osteoarthritis. Deregulation of the Wnts pathways results in the activation of the canonical pathway (dependent on β-catenin), contributing to a loss of the chondrocyte phenotype. Frizzled-related Protein (FRZB, also known as secreted frizzled related protein-3 (sFRP3)) is a physiological modulator of Wnt signaling pathways. Polymorphisms in the FRZB gene have been associated with osteoarthritis. In addition, FRZB expression levels have been shown to rapidly decrease during osteoarthritis. The "netrin-like" domain of FRZB (NTN-FRZB) is critical in the ability of FRZB to antagonize the canonical pathway and stimulate the non-canonical Wnts pathway (dependent on the Calmodulin kinase (CamK) II pathway). However, the mechanism by which NTN-FRZB operates is not clearly defined at present. The objectives of this study were (i) to generate peptides from NTN-FRZB, able to mimic its effects in vitro, and (ii) in a long-term perspective, to assess the therapeutic potential of these peptides in vivo. Thus, two peptides derived from NTN-FRZB were generated by in silico analyses of the primary sequence and the predicted secondary structure of NTN-FRZB, in order to better understand its mechanism of action. Only one of these peptides, PEP16, was able to reproduce all or part of the effects of NTN-FRZB. The effects of PEP16 were evaluated on the production of proteoglycans, the gene expression of healthy and hypertrophic markers of the chondrocyte, the canonical and non-canonical Wnt signaling pathways and also on the Hippo / YAP / TAZ pathway. It has been shown to be effective in chondrogenic and osteogenic cell lines, in primary chondrocytes of the femoral head of mice, in cartilage biopsies of arthritis patients and in vivo in a transgenic mouse model Frzb-/-. For a problem of intellectual property, 5 other peptides were generated from the sequence of PEP16. The effects of the PEP16bis sequence have been shown to be similar to those of PEP16. Thus, in view of the results, PEP16 and PEP16bis could be considered for a potential new treatment for osteoarthritis, with the need to validate them in pre-clinical studies.
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Submitted on : Monday, March 22, 2021 - 2:43:04 PM
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  • HAL Id : tel-03176544, version 1


Marion Claudel. Étude des potentialités modulatrices du domaine « netrin-like » de la protéine FRZB/sFRP3 et de ses effets Wnts-dépendants dans les tissus ostéo-articulaires. Biochimie, Biologie Moléculaire. Université de Lorraine, 2020. Français. ⟨NNT : 2020LORR0127⟩. ⟨tel-03176544⟩



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