gms | German Medical Science

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016)

25.10. - 28.10.2016, Berlin

Remodeling human osteoarthritic articular cartilage rAAV-mediated via combined gene transfer and overexpression of TGF-beta and sox9

Meeting Abstract

  • presenting/speaker Ke Tao - Institute of arthritis, Peking University People's Hospital, Peking Universität Health Science Center, Universitätsklinikum des Saarlandes, Homburg/Saar, Beijing, China
  • Janina Frisch - Zentrum für Experimentelle Orthopädie, Lehrstuhl für Exp. Orthopädie und Arthroseforschung, Universitätsklinikum des Saarlandes, Homburg, Germany
  • Ana Rey Rico - Zentrum für Experimentelle Orthopädie, Lehrstuhl für Exp. Orthopädie und Arthroseforschung, Universitätsklinikum des Saarlandes, Homburg, Germany
  • Jagadeesh K. Venkatesan - Zentrum für Experimentelle Orthopädie, Lehrstuhl für Exp. Orthopädie und Arthroseforschung, Universitätsklinikum des Saarlandes, Homburg, Germany
  • Gertrud Schmitt - Zentrum für Experimentelle Orthopädie, Lehrstuhl für Exp. Orthopädie und Arthroseforschung, Universitätsklinikum des Saarlandes, Homburg, Germany
  • Henning Madry - Universitätsklinikum des Saarlandes, Zentrum für Experimentelle Orthopädie, Homburg, Germany
  • Jian Hao Lin - der Peking-Universität Volkskrankenhaus, Beijing, China
  • Magali Cucchiarini Madry - Universitätsklinikum des Saarlandes, Klinik für Orthopädie und Orthopädische Chirurgie, Zentrum für Experimentelle Orthopädie, Homburg, Germany

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016). Berlin, 25.-28.10.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. DocPO20-1183

doi: 10.3205/16dkou659, urn:nbn:de:0183-16dkou6595

Veröffentlicht: 10. Oktober 2016

© 2016 Tao et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objectives: Direct administration of therapeutic candidate gene sequences using the safe and effective recombinant adeno-associated virus (rAAV) vectors is a promising strategy to stimulate the biologic activities of articular chondrocytes as an adapted tool to treat human osteoarthritic (OA) cartilage.

Methods: In the present study, we developed a combined gene transfer approach based on the co-delivery of the pleiotropic transformation growth factor beta (TGF-beta) with the specific transcription factor Sox9 via rAAV to human normal and OA chondrocytes in vitro and cartilage explants in situ in light of the mitogenic and pro-anabolic properties of these factors.

Results and Conclusion: Effective, durable co-overexpression of TGF-beta and sox9 significantly enhanced the levels of cell proliferation both in human normal and OA chondrocytes and cartilage explants over an extended period of time (21 days), while stimulating the biosynthesis of key matrix components (proteoglycans, type-II collagen) compared with control conditions (reporter lacZ gene transfer, absence of vector treatment). Of further note, expression of hypertrophic type-X collagen significantly decreased following co-treatment by the candidate vectors.

Here, we examined the feasibility of combining the transfer of two crucial factors with chondroreparative activities (TGF-beta and sox9) via direct, dual rAAV gene transfer as a means to enhance the remodelling of human OA chondrocytes in vitro and OA cartilage in situ. Our results first show that concomitant expression of TGF-beta and sox9 was successfully achieved via rAAV both in human normal and OA chondrocytes in vitro and in human normal and OA cartilage explants in situ for at least 21 days, probably due to a good penetration and maintenance of the vectors in the targets as noted when using individual gene treatments. The data further indicate that high, durable levels of rAAV-co-delivered TGF-beta/sox9 were capable of activating the biological (proliferation, ECM synthesis) activities of human normal and OA chondrocytes in vitro and normal and OA cartilage explants in situ over an extended period of time (up to 21 days) compared with control treatments, consistent with the properties of these factors and with our previous findings using independent TGF-beta and sox9 gene transfer.

The present findings show the value of combining the transfer and expression of potent candidate factors in human OA cartilage as a means to re-establish essential features of normal cartilage and counteract the pathological shift of homeostasis. These observations support the concept of developing dual therapeutic rAAV gene transfer strategies as future, adapted tools for the direct treatment of human OA.