Improving Chondrogenesis: Potential and Limitations ofSOX9Gene Transfer and Mechanical Stimulation for Cartilage Tissue Engineering

Abstract

Articular cartilage injuries and degeneration affect a large proportion of the population in developed countries world wide. Stem cells can be differentiated into chondrocytes by adding transforming growth factor-beta1 and dexamethasone to a pellet culture, which are unfeasible for tissue engineering purposes. We attempted to achieve stable chondrogenesis without any requirement for exogenous growth factors. Human mesenchymal stem cells were transduced with an adenoviral vector containing the SRY-related HMG-box gene 9 (SOX9), and were cultured in a three-dimensional (3D) hydrogel scaffold composite. As an additional treatment, mechanical stimulation was applied in a custom-made bioreactor. SOX9 increased the expression level of its known target genes, as well as its cofactors: the long form of SOX5 and SOX6. However, it was unable to increase the synthesis of sulfated glycosaminoglycans (GAGs). Mechanical stimulation slightly enhanced collagen type X and increased lubricin expression. The combination of SOX9 and mechanical load boosted GAG synthesis as shown by (35)S incorporation. GAG production rate corresponded well with the amount of (endogenous) transforming growth factor-beta1. Finally, cartilage oligomeric matrix protein expression was increased by both treatments. These findings provide insight into the mechanotransduction of mesenchymal stem cells and demonstrate the potential of a transcription factor in stem cell therapy.

Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures

“…Indeed, a modest elevation in mRNA expression of key enzymes involved in GAG-synthesis (HAS, CHST11) was detected. Similar findings have been reported when mechanical stimulus was applied on hydrogel cultures of MSCs [41].…”

Hydrogels for the Repair of Articular Cartilage Defects

“…107,195,211,212 The combination of mechanical loading and adenoviral transduction of the cartilage transcription factor Sox9 resulted in increased chondrogenesis of bone marrow-derived MSCs in a fibrin-polyurethane hydrogel-scaffold composite, although the expression of the cartilage markers collagen type II and aggrecan was much lower than with the addition of exogenous growth factors. 213 These studies suggest that MSCs derived from a variety of sources are suitable for cartilage tissue engineering when cultured under specific conditions.…”

The effects of different molecular weight chondroitin-4-sulfates in chondrocyte pellet culture

“…A common observation is that these substances seem to facilitate cartilage repair by reducing inflammation and blocking the loss of PGs (Kupcsik et al 2010;Derfoul et al 2007;Kagita et al 2010). However, no comprehensive mechanism by which GAGs and CS can be administered to moderate the side effects of OA has been elucidated.…”