Author(s): Carrie Gaut [*] aff1 aff2 , Kiminobu Sugaya aff3
articular cartilage osteoarthritis; chondrogenesis; differentiation; mesenchymal stem cells; tissue engineering
Osteoarthritis represents the most common form of over 100 types of arthritis and affects more than 124 million people worldwide. Damage from trauma, infection, autoimmune disorders or age produces inflammation in articular cartilage (AC), which worsens over time causing pain, swelling of joints and diminished range of motion. Because it impairs function, it creates a significant burden on society. The impact stems from the cost of radiographic diagnosis, palliative treatment, surgical procedures, loss of productivity and co-morbid diseases. Current treatment of osteoarthritis focuses on alleviating the symptoms. After the onset of osteoarthritis, existing therapies are unable to reverse or prevent the progression of the disease. In advanced cases with severe pain that do not respond to symptomatic treatments, surgical procedures such as autologous chondrocyte implantation (ACI) or joint replacement may be recommended [1,2 ].
Because the spontaneous repair process of cartilage is temporary and inefficient, defects are often healed by the formation of fibrocartilage that is functionally inferior to the native hyaline cartilage [3 ]. Chondrogenesis, the processes by which cartilage is formed, is the result of a several steps orchestrated by signaling molecules [4-6 ], receptors, transcription factors [7 ], interaction of cells with the matrix [8 ] and other environmental factors. Mesenchymal stem cells (MSCs) are recruited and condense, beginning to proliferate and differentiate into a chondrogenic phenotype. This is followed by continued differentiation into mature chondrocytes during which they secrete cartilage-specific extracellular matrix (ECM) proteins such as type II collagen and aggrecan. Finally, unwanted terminal differentiation occurs when the chondrocytes become hypertrophic and bone tissue replaces the original cartilage. Control of the process of chondrogenesis is in damaged joints, these activities are not happening efficiently.
Encouraging advances in the field of stem cell research give hope for better options in treating cartilage damage. Researchers attempt to bioengineer cartilage for treatment of traumatic lesions where the healthy environment can support regeneration [9,10 ]. Stem cell or bioactive injectables are being tested for treating the more complicated pathogenesis of osteoarthritis [11-13 ]. For stem cell therapy to be effective and lasting, the aforementioned variables must be manipulated to achieve ideal conditions. Optimization of chondrogenesis relies on the appropriate combination of the different signals, the timing of those signals, concentration of required factors, mechanical stimulation, the upregulation and downregulation of specific genes through transcription factors and micro-RNAs [14 ], and the epigenetic modification of DNA via methylation and acetylation. The obstacle to effective stem cell transplantation therapies lies in getting the cells to differentiate and behave in the desired way, integrating and working with the host's other cells in a way that mimics native tissue. In order for stem cell-based tissue engineering of AC to be successful, a matrix surrounding the cells with the same mechanical and protective properties as native cartilage must be produced. The environment surrounding stem cells has a direct influence on how they differentiate, what signaling factors are...