Substrate stiffness and the role of actin in regulating chondrocyte dedifferentiation

基质硬度和肌动蛋白在调节软骨细胞去分化中的作用

• 批准号: RGPIN-2016-06088
• 负责人: Kandel, Rita
• 金额: $ 3.21万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688812
• 关键词: Substrate; stiffness; role; actin; regulating

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.***

关节软骨覆盖骨的末端，促进关节运动和力的传递。骨关节炎是一种以软骨损失为特征的关节疾病，表现为疼痛、僵硬和活动范围丧失，导致大约六分之一的 15 岁以上加拿大人残疾。软骨受损后几乎没有修复能力。目前的治疗只能缓解症状，并不能阻止疾病进展，因此最终受损的关节将需要用假体进行关节置换。它们由金属和塑料制成，最终会失效。显然，非常需要新的生物细胞疗法来修复/替换受损的软骨，从而完全恢复关节功能和健康至正常状态。********这些治疗所需的细胞可以从多种来源获得，例如关节软骨本身或干细胞。干细胞不适合，因为迄今为止还不可能将这些细胞分化为产生适当软骨的关节软骨细胞。关节软骨是细胞的最佳来源，但软骨细胞（软骨细胞）数量太少而无法使用。当它们在培养物中生长以增加细胞数量时，它们会失去制造软骨的能力，因为有利于增殖的条件会导致软骨细胞去分化（关节软骨细胞特征丧失）。这可能是由于培养皿比天然软骨更硬。 因此，我们研究计划的长期目标是了解培养细胞如何调节关节软骨细胞表型。我们有证据表明肌动蛋白（细胞的骨架）调节细胞表型。拟议的研究将检查肌动蛋白细胞骨架的聚合是否通过激活调节软骨细胞去分化的特定信号转导途径来转化外在基质硬度的影响。了解调节软骨细胞去分化的机制将有助于材料的设计和/或新药物的开发，以确保有可能增加关节软骨细胞的数量，并且仍然具有可以用适当的关节软骨组织修复软骨缺陷的细胞。实现这一目标将增进我们对软骨细胞表型的理解以及再生医学方法对软骨修复和关节健康恢复的临床转化。此外，这些研究可能会导致治疗骨关节炎的新疗法的开发。***