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In vivo rAAV-mediated human TGF-β overexpression reduces perifocal osteoarthritis and improves osteochondral repair in a large animal model at one year

Published:December 05, 2022DOI:https://doi.org/10.1016/j.joca.2022.11.010

      Summary

      Objective

      Osteoarthritis (OA) is a serious consequence of focal osteochondral defects. Gene transfer of human transforming growth factor beta (hTGF-β) with recombinant adeno-associated virus (rAAV) vectors offers a strategy to improve osteochondral repair. However, the long-term in vivo effects of such rAAV-mediated TGF-β overexpression including its potential benefits on OA development remain unknown.

      Method

      Focal osteochondral defects in minipig knees received rAAV-lacZ (control) or rAAV-hTGF-β in vivo. After one year, osteochondral repair and perifocal OA were visualized using validated macroscopic scoring, ultra-high-field MRI at 9.4 T, and micro-CT. A quantitative estimation of the cellular densities and a validated semi-quantitative scoring of histological and immunohistological parameters completed the analysis of microarchitectural parameters.

      Results

      Direct rAAV-hTGF-β application induced and maintained significantly improved defect filling and safranin O staining intensity and overall cartilage repair at one year in vivo. In addition, rAAV-hTGF-β led to significantly higher chondrocyte densities within the cartilaginous repair tissue without affecting chondrocyte hypertrophy and minimized subarticular trabecular separation. Of note, rAAV-hTGF-β significantly improved the adjacent cartilage structure and chondrocyte density and reduced overall perifocal OA development after one year in vivo.

      Conclusions

      rAAV-hTGF-β treatment improves long-term osteochondral repair and delays the progression of perifocal OA in a translational model. These findings have considerable potential for targeted molecular approaches to treat focal osteochondral defects.

      Keywords

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