Substrate stiffness and the role of actin in regulating chondrocyte dedifferentiation

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Articular cartilage covers the ends of bone facilitating joint movement and transfer of forces. Osteoarthritis is a disease of joints characterized by loss of the cartilage, and manifests as pain, stiffness and loss of range of motion disabling approximately 1 in 6 Canadians over the age of 15. Cartilage has little ability to repair when damaged. Current treatments alleviate symptoms only and do not stop disease progression so ultimately the damaged joint will require joint replacement with a prosthesis. These are made from metals and plastic and will ultimately fail. Clearly there is a great need for novel biological cell therapies to repair/replace the damaged cartilage that will fully restore joint function and health to normal. The cells required for these treatments can be obtained from a number of sources, such as articular cartilage itself or from stem cells. Stem cells are not suitable as differentiation of these cells to articular chondrocytes that make proper cartilage has not been possible to date. Articular cartilage is the optimal source of cells but chondrocytes, the cells of cartilage, are too few in number to use. When they are grown in culture to increase cell number they lose their ability to make cartilage as conditions that favour proliferation results in chondrocyte dedifferentiation (loss of articular chondrocyte characteristics). This may be due to the fact that the culture dish is more stiff than native cartilage. Thus the long term goal of our research program is to understand how growing cells in culture modulates the articular chondrocyte phenotype. We have evidence that actin, the skeleton of the cell, regulates cell phenotype. The proposed studies will examine whether polymerization of the actin cytoskeleton is responsible for translating the effects of the extrinsic substrate stiffness by activating specific signal transduction pathways that modulate chondrocyte dedifferentiation. Understanding the mechanisms regulating chondrocyte dedifferentiation will facilitate design of materials and/or the development of novel drugs that will ensure that it will be possible to increase articular chondrocyte numbers and still have cells that can repair cartilage defects with proper articular cartilage tissue. Accomplishing this will advance our understanding of chondrocyte phenotype as well as the clinical translation of regenerative medicine approaches to cartilage repair and restoration of joint health. Also these studies could lead to the development of novel therapeutics to treat osteoarthritis.