Electromechanobiology of Cartilage and Osteoarthritis

Nagelli, Christopher V, Evans, Christopher H, De la Vega, Rodolfo E, Nagelli, Christopher V., Evans, Christopher H., De la Vega, Rodolfo E.

Delivering genes to chondrocytes offers new possibilities both clinically, for treating conditions that affect cartilage, and in the laboratory, for studying the biology of chondrocytes. Advances in gene therapy have created a number of different viral and non-viral vectors for this purpose. These vectors may be deployed in an ex vivo fashion, where chondrocytes are genetically modified outside the body, or by in vivo delivery where the vector is introduced directly into the body; in the case of articular and meniscal cartilage in vivo delivery is typically by intra-articular injection. Ex vivo delivery is favored in strategies for enhancing cartilage repair as these can be piggy-backed on existing cell-based technologies, such as autologous chondrocyte implantation, or used in conjunction with marrow-stimulating techniques such as microfracture. In vivo delivery to articular chondrocytes has proved more difficult, because the dense, anionic, extra-cellular matrix of cartilage limits access to the chondrocytes embedded within it. As Grodzinsky and colleagues have shown, the matrix imposes strict limits on the size and charge of particles able to diffuse through the entire depth of articular cartilage. Empirical observations suggest that the larger viral vectors, such as adenovirus (~100 nm), are unable to transduce chondrocytes in situ following intra-articular injection. However, adeno-associated virus (AAV; ~25 nm) is able to do so in horse joints. AAV is presently in clinical trials for arthritis gene therapy, and it will be interesting to see whether human chondrocytes are also transduced throughout the depth of cartilage by AAV following a single intra-articular injection. Viral vectors have been used to deliver genes to the intervertebral disk but there has been little research on gene transfer to chondrocytes in other cartilaginous tissues such as nasal, auricular or tracheal cartilage.