Substrate stiffness and the role of actin in regulating chondrocyte dedifferentiation

关节软骨覆盖骨的末端，促进关节运动和力的转移。骨关节炎是一种以软骨丧失为特征的关节疾病，表现为疼痛、僵硬和活动范围丧失，大约六分之一的加拿大人在15岁以上致残。软骨受损后几乎没有修复能力。目前的治疗只能缓解症状，并不能阻止疾病的发展，因此最终受损的关节将需要用假体进行关节置换。它们是由金属和塑料制成的，最终会失效。显然，我们非常需要新的生物细胞疗法来修复/替换受损的软骨，从而使关节功能和健康完全恢复正常。

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.