The role of suppressor of cytokine signalling-3 (SOCS-3) in chondrocytes during development and disease

细胞因子是一个细胞产生和分泌的信使蛋白，然后与其他细胞表面的特定受体结合。结合后，会发生一系列称为信号传递的细胞内事件，导致靶细胞改变其行为。如果允许细胞因子信号不加控制地继续进行，可能会导致各种疾病状态。细胞因子信号转导抑制蛋白(SOCS)是细胞内细胞因子信号转导的关键负性调节因子。它们是由广泛的刺激诱导的，特别是来自一种名为IL-6家族的刺激。我们有初步数据表明，软骨细胞(软骨细胞)通常会产生一种特殊的SOCS蛋白，称为SOCS-3。我们还表明，当SOCS-3的产生受到失调时，软骨细胞会经历过度的增殖。正常的软骨细胞功能在骨骼发育过程中很重要，骨关节炎等疾病被认为是软骨细胞行为异常的结果。SOCS-3可能在软骨细胞功能调节中起关键作用。因此，这项建议的目的是研究SOCS-3在软骨细胞、发育过程和疾病中的作用。我们对SOCS蛋白作用的大部分了解来自于构建缺乏特定SOCS蛋白的突变小鼠。当在整个动物中制造出缺乏SOCS-3的突变小鼠时，小鼠在出生前就会死亡，因此几乎不知道SOCS-3在软骨细胞中的作用以及在疾病状态下对软骨的影响，如关节炎。为了回答这个问题，我们将创造出软骨细胞中特别缺乏SOCS-3的小鼠。在退行性和炎症性疾病状态下，评估SOCS-3在软骨发育和软骨细胞功能中的作用，对于提高我们对关节炎和软骨修复的认识具有重要的临床意义。

Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on the surface of other cells. After binding, a series of intracellular events occurs, termed signalling, that results in the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in various disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of cytokine signalling within the cell. They are induced by a wide range of stimuli, especially from a group called the IL-6 family. We have preliminary data showing that cartilage cells (chondrocytes) normally produce a particular SOCS protein, called SOCS-3. We have also shown that when SOCS-3 production is dysregulated, the chondrocytes undergo excessive proliferation. Normal chondrocyte function is important during skeletal development and diseases such as osteoarthritis are thought to result from abnormal chondrocyte behaviour. It is likely that SOCS-3 has a key role in regulating chondrocyte function. The aim of this proposal is therefore to examine the role of SOCS-3 in chondrocytes, during development and in disease. Much of our understanding of the role of the SOCS proteins comes from the construction of mutant mice that lack a particular SOCS protein. When mutant mice are made that lack SOCS-3 in the whole animal the mice die before birth and so virtually nothing is known about the role of SOCS-3 in chondrocytes and the implications for cartilage in disease states, such as arthritis. To answer this we will create mice that lack SOCS-3 specifically in their chondrocytes. Evaluating the role of SOCS-3 in cartilage development and chondrocyte function during degenerative and inflammatory disease states is potentially of major clinical importance in improving our understanding of arthritis and of cartilage repair.