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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=655042
• 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。骨关节炎是一种关节疾病，其特征是软骨丧失，表现为疼痛、僵硬和活动范围丧失，约有1/6的15岁以上加拿大人致残。软骨在受损时几乎没有修复能力。目前的治疗只能缓解症状，不能阻止疾病的进展，因此最终受损的关节将需要用假体进行关节置换。这些都是由金属和塑料制成的，最终会失败。显然，非常需要新的生物细胞疗法来修复/替换受损的软骨，以完全恢复关节功能和健康。这些治疗所需的细胞可以从许多来源获得，例如关节软骨本身或干细胞。干细胞是不合适的，因为这些细胞分化为关节软骨细胞，使适当的软骨至今还不可能。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，它们失去了制造软骨的能力，因为有利于增殖的条件导致软骨细胞去分化（关节软骨细胞特征的丧失）。这可能是由于培养皿比天然软骨更硬的事实。 因此，我们研究计划的长期目标是了解培养中生长的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。拟议的研究将检查是否聚合的肌动蛋白细胞骨架负责翻译的影响，通过激活特定的信号转导途径，调节软骨细胞去分化的外在基板刚度。了解调节软骨细胞去分化的机制将有助于材料的设计和/或新药的开发，这将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损的细胞。实现这一目标将促进我们对软骨细胞表型的理解，以及再生医学方法在软骨修复和关节健康恢复方面的临床转化。此外，这些研究可能导致开发新的治疗方法来治疗骨关节炎。