Dissecting the role of ß1 integrins in articular cartilage function and pathology

关节软骨作为关节的承重组织，其愈合能力较差，因此与年龄相关的代谢变化或创伤性损伤经常导致其退行性变和骨关节炎，是世界范围内普遍存在的残疾原因。β1整合素是异二聚体(α/β)整合素受体中最大的亚家族，它通过黏附复合体将细胞外基质中的化学和机械信号传递到软骨细胞内，并启动对软骨功能至关重要的信号级联反应。尽管整合素具有预期的重要性，但我们对整合素在关节软骨生理学和病理生理学中的体内作用的了解是有限的。这项建议的主要目的是从机制上深入了解β1整合素在关节软骨中的功能；骨关节炎的病理机制以及使用转基因小鼠品系的软骨再生过程。为了实现这一目标，在肢体芽间充质前体细胞或成人关节软骨软骨细胞中Beta1整合素基因条件失活的小鼠将在1)体外髋关节损伤，2)自发性骨关节炎，3)手术诱导的骨关节炎和4)再生模型中进行检测。这些互补的实验方法将提供对软骨退行性疾病的更好的了解，并可能识别促进和改善关节软骨修复的新的分子靶点。

Articular cartilage, the load-bearing tissue of the joints, has poor healing potential thus age-related metabolic changes or traumatic lesions frequently lead to its degeneration and osteoarthritis, a prevalent cause of disability worldwide. Beta1 integrins comprise the largest subfamily of the heterodimeric (alpha/beta) integrin receptors that transmit both chemical and mechanical signals from the extracellular matrix into chondrocytes through adhesion complexes and initiate divers signalling cascades that are believed to be important for cartilage function. Despite their anticipated importance, our knowledge about the in vivo role of integrins in articular cartilage physiology and pathophysiology is limited. The primary purpose of this proposal is to gain mechanistic insights into the function of beta1 integrins in the articular cartilage; the pathomechanisms of osteoarthritis and the process of cartilage regeneration using genetically-modified mouse strains. To achieve this aim, mice with conditional inactivation of the beta1 integrin gene either in limb bud mesenchyme precursors or in adult articular cartilage chondrocytes will be examined in 1) ex vivo hip injury, 2) spontaneous osteoarthritis; 3) surgically induced osteoarthritis and 4) regeneration models. These complementary experimental approaches will provide a better understanding of cartilage degenerative diseases and may identify novel molecular targets that facilitate and improve articular cartilage repair.