Stem Cell and Developmental Biology, Genome Institute of Singapore, P. O. Box-138672, Singapore
*Corresponding author:
Tong Ming Liu, PhD
Stem Cell and Developmental Biology
Genome Institute of Singapore, P. O. Box-138672, Singapore Tel: 65 6808-8229 Fax: 65 6808-8308 E-mail: dbsliutm@yahoo.com
Received June 21, 2012; Accepted June 23, 2012; Published June 25, 2012
Citation: Liu TM (2012) Gene Therapy for Articular Cartilage Repair. Pharmaceut
Anal Acta 3:e1112. doi:10.4172/2153-2435.1000e112
Gene therapy offers a promising treatment option for repair
of damaged articular cartilage, an unsolved problem in modern
orthopaedics. Articular cartilage is a highly specialized tissue composing
of chondrocytes and extracellular matrix (ECM). As the gliding surface
of joints, healthy articular cartilage allows for smooth and painless
joint motion. However, cartilage diseases are most commonly seen
due to traumatic injury and degenerative diseases, which cause pain
and dysfunction. Due to avascular status, articular cartilage has a very
limited capacity for self-repair and regeneration. Current surgical
therapeutic procedures for cartilage repair fail to restore a normal
articular surface [1-5]. Gene therapy is being developed to generate
long-lasting hyaline cartilage by augmenting the reparative activities or
preventing the degenerative activities.
Gene therapy is the use of DNA as a pharmaceutical agent to treat
disease. The first gene therapy for articular tissues was described to treat
human rheumatoid arthritis [6]. Although considerable progress has
been made in identifying genes that regulate cartilage differentiation
in past 15 years, gene therapy to repair full-thickness cartilage defects
is unsatisfactory. Genes used for cartilage repair include growth
factor genes, cytokine receptor antagonists and transcription factors.
Growth factors improve cartilage repair by stimulating chondrocyte
proliferation and improve chondrogenesis [7-12]. Cytokine receptor
antagonist IL-1Rα and tumor necrosis factor alpha inhibitor prevent
cartilage matrix degradation and reduce inflammation to prevent
arthritis [13-17]. Transcription factors are useful in cartilage repair
by promoting chondrogenesis or maintaining chondrocyte phenotype
[18-20]. Current gene therapy approaches can be achieved by either
administering the desired genes into the sites of damaged cartilage, or
by transplantation of genetically modified cells into the defects. The
selection of gene delivery approaches depends on the need of longterm
or short-term expression and the therapeutic expression level of
the desired genes.
Multiple gene therapy combined with stem cells and scaffold is
desirable and need to be developed for repair of articular cartilage
defects. The optimal choice of therapeutic genes for cell-based cartilage
repair cannot be simply predicted from observations of individual genes
[21]. More efforts need to be made to understand the molecular basis of
cartilage differentiation. So far, gene network of cartilage differentiation
remains poorly understood, the molecular mechanism and the role
of genes during cartilage differentiation are not well defined; the
therapeutic genes identified for articular cartilage are very limited. It is
still challenging to deliver the therapeutic genes to the damaged cartilage
in a safe, efficient manner and express them in a controllable manner.
Taking sox9 as an example, the chondrogenic master regulator sox9
is required for MSC commitment and condensation, and chondrocyte
differentiation and proliferation. However, Sox9 inhibits transition of
proliferating chondrocytes to hypertrophy [19]. Expression level of
sox9 is also critical to chondrocyte, low levels of Sox9 overexpression
enhanced Col2A1 gene transcription whereas high levels of Sox9
overexpression induced an inhibition of Col2A1 gene expression in
chondrocytes [22]. These data suggest that continuous expression of
sox9 is not good for hyaline articular cartilage, controllable expression
of sox9 will be of particular importance to regeneration of hyaline
cartilage. Therefore, efficient delivery and controllable expression of
the therapeutic genes, and multiple strategies will lead to complete and
durable hyaline cartilage regeneration.
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