Abstract
Current cell based treatment for articular cartilage and osteochondral defects are hampered by issues such as cellular dedifferentiation and hypertrophy of the resident or transplanted cells. The reduced expression of chondrogenic signalling molecules and transcription factors is a major contributing factor to changes in cell phenotype. Gene modification of chondrocytes may be one approach to redirect cells to their primary phenotype and recent advances in nonviral and viral gene delivery technologies have enabled the expression of these lost factors at high efficiency and specificity to regain chondrocyte function. This review focuses on the various candidate genes that encode signalling molecules and transcription factors that are specific for the enhancement of the chondrogenic phenotype and also how epigenetic regulators of chondrogenesis in the form of microRNA may also play an important role.
Highlights
The self-healing capacity of articular cartilage is minimal when damaged, due to the avascular nature of the articular joint surface
embryonic stem cells (ES) cells have been shown to differentiate into chondrocytes in a two-step process, where initially the stem cells change their phenotype to chondrogenic progenitors, followed by differentiation of these progenitor cells into chondrocytes
Specific to cartilage tissue, microRNA-140 has been studied extensively for its ability to inhibit the expression of chemokine (C-X-C Motif) ligand 12 (CXCL12) and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) that lead to articular cartilage degradation in osteoarthritis [77]
Summary
The self-healing capacity of articular cartilage is minimal when damaged, due to the avascular nature of the articular joint surface. In vitro differentiation of these stem cells is highly efficient when combined with a three-dimensional microenvironment, with the addition of growth factors to enhance differentiation [5] Both MSCs and chondrocytes are permissive to gene transfer and as such are excellent candidates for gene modification to enhance their chondrogenic phenotype and promote proliferation, avoiding detrimental cellular dedifferentiation, and senescence [6]. The introduction of foreign DNA encoding a gene of interest directly into a living cell results in the degradation of the naked DNA and requires an efficient carrier for its delivery to the cell nucleus for gene transcription and subsequent protein expression [9] Physical barriers such as the cellular membrane prevent the entry of the nucleic acids reducing the efficiency of transfection. If long-term transgene expression is required, viral based gene delivery techniques should be considered
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