title: rAAV-mediated combined gene transfer and overexpression of TGF-β and SOX9 remodels human osteoarthritic articular cartilage.
abstract: 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. In the present study, we developed a combined gene transfer approach based on the co-delivery of the pleiotropic transformation growth factor beta (TGF-β) 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. Effective, durable co-overexpression of TGF-β 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. 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. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2181-2190, 2016.
authors.affiliation: Institute of Arthritis, Peking University People's Hospital, Beijing, 100044, People's Republic of China.|Peking University Health Science Center, Beijing, 100191, People's Republic of China.|Center of Experimental Orthopedics, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Ke
authors.initials: K
authors.lastname: Tao
authors.affiliation: Center of Experimental Orthopedics, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Rey-Rico
authors.affiliation: Center of Experimental Orthopedics, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Frisch
authors.affiliation: Center of Experimental Orthopedics, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Jagadeesh K
authors.initials: JK
authors.lastname: Venkatesan
authors.affiliation: Center of Experimental Orthopedics, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Schmitt
authors.affiliation: Center of Experimental Orthopedics, Saarland University Medical Center, Homburg/Saar, Germany.|Department of Orthopaedic Surgery, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Madry
authors.affiliation: Institute of Arthritis, Peking University People's Hospital, Beijing, 100044, People's Republic of China.|Peking University Health Science Center, Beijing, 100191, People's Republic of China.
authors.forename: Jianhao
authors.initials: J
authors.lastname: Lin
authors.affiliation: Center of Experimental Orthopedics, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Magali
authors.initials: M
authors.lastname: Cucchiarini
mesh_terms: D000368:Aged; D002358:Cartilage, Articular / Q000378:metabolism*; D049109:Cell Proliferation; D000229:Dependovirus; D015316:Genetic Therapy; D006801:Humans; D010003:Osteoarthritis / Q000628:therapy*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
chemical_list: D055758:SOX9 Transcription Factor; D016212:Transforming Growth Factor beta
keywords: SOX9; TGF-β; combined gene transfer; human osteoarthritic cartilage; rAAV