Please use this identifier to cite or link to this item: doi:10.22028/D291-44094
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Title: rAAV-Mediated sox9 Overexpression Improves the Repair of Osteochondral Defects in a Clinically Relevant Large Animal Model Over Time In Vivo and Reduces Perifocal Osteoarthritic Changes
Author(s): Lange, Cliff
Madry, Henning
Venkatesan, Jagadeesh K.
Schmitt, Gertrud
Speicher-Mentges, Susanne
Zurakowski, David
Menger, Michael D.
Laschke, Matthias W.
Cucchiarini, Magali
Language: English
Title: The American Journal of Sports Medicine
Volume: 49
Issue: 13
Publisher/Platform: Sage
Year of Publication: 2021
Free key words: articular cartilage
osteochondral defects
rAAV
gene therapy
SOX9
osteoarthritis
sheep
DDC notations: 610 Medicine and health
Publikation type: Journal Article
Abstract: Background: Gene transfer of the transcription factor SOX9 with clinically adapted recombinant adeno-associated virus (rAAV) vectors offers a powerful tool to durably enhance the repair process at sites of osteochondral injuries and counteract the development of perifocal osteoarthritis (OA) in the adjacent articular cartilage. Purpose: To examine the ability of an rAAV sox9 construct to improve the repair of focal osteochondral defects and oppose perifocal OA development over time in a large translational model relative to control gene transfer. Study Design: Controlled laboratory study. Methods: Standardized osteochondral defects created in the knee joints of adult sheep were treated with rAAV-FLAG-hsox9 relative to control (reporter) rAAV-lacZ gene transfer. Osteochondral repair and degenerative changes in the adjacent cartilage were monitored using macroscopic, histological, immunohistological, and biochemical evaluations after 6 months. The microarchitecture of the subchondral bone was assessed by micro–computed tomography. Results: Effective, prolonged sox9 overexpression via rAAV was significantly achieved in the defects after 6 months versus rAAVlacZ treatment. The application of rAAV-FLAG-hsox9 improved the individual parameters of defect filling, matrix staining, cellular morphology, defect architecture, surface architecture, subchondral bone, and tidemark as well as the overall score of cartilage repair in the defects compared with rAAV-lacZ. The overexpression of sox9 led to higher levels of proteoglycan production, stronger type II collagen deposition, and reduced type I collagen immunoreactivity in the sox9- versus lacZ-treated defects, together with decreased cell densities and DNA content. rAAV-FLAG-hsox9 enhanced semiquantitative histological subchondral bone repair, while the microstructure of the incompletely restored subchondral bone in the sox9 defects was not different from that in the lacZ defects. The articular cartilage adjacent to the sox9-treated defects showed reduced histological signs of perifocal OA changes versus rAAV-lacZ. Conclusion: rAAV-mediated sox9 gene transfer enhanced osteochondral repair in sheep after 6 months and reduced perifocal OA changes. These results underline the potential of rAAV-FLAG-hsox9 as a therapeutic tool to treat cartilage defects and afford protection against OA. Clinical Relevance: The delivery of therapeutic rAAV sox9 to sites of focal injuries may offer a novel, convenient tool to enhance the repair of osteochondral defects involving both the articular cartilage and the underlying subchondral bone and provide a protective role by reducing the extent of perifocal OA.
DOI of the first publication: 10.1177/03635465211049414
URL of the first publication: https://doi.org/10.1177/03635465211049414
Link to this record: urn:nbn:de:bsz:291--ds-440941
hdl:20.500.11880/39443
http://dx.doi.org/10.22028/D291-44094
ISSN: 1552-3365
0363-5465
Date of registration: 22-Jan-2025
Faculty: M - Medizinische Fakultät
Department: M - Chirurgie
M - Orthopädie
Professorship: M - Prof. Dr. Henning Madry
M - Prof. Dr. Michael D. Menger
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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