Chondroleukin and Articular Cartilage

描述(申请人提供)：我们研究的长期目标是实现关节软骨的可重复修复和再生。一般说来，组织的再生和修复概括了胚胎发育和形态发生。因此，参与形态发生和发育的因素在成人组织再生中可能是有用的。骨和关节软骨是相邻的组织。然而，骨骼具有相当大的修复潜力，而关节软骨的修复是顽固的。我们对关节软骨修复中的内源性形态因子和细胞因子进行了系统的研究。以前，我们将骨形态发生蛋白(BMPs)和软骨来源的形态发生蛋白(CDMPs)确定为软骨形成的形态发生蛋白。最近，我们在关节软骨中发现了一种新的细胞因子--软骨细胞因子。这项拟议的研究将研究一种新型细胞因子软骨白质的细胞生物学，它是一种由180个氨基酸残基组成的蛋白质，与人白介素17有40%的同源性。因此，软骨白质也被称为IL-17B。此外，我们还鉴定并克隆了一个在关节软骨中表达的新的IL-17受体样分子(IL-17RL)。该受体通过RNA转录物的选择性剪接表达为膜结合和可溶性诱骗受体。我们推测，IL-17B及其功能性受体形成了一个细胞因子信号系统，调控BMP和CDMP诱导的软骨形成、分化和维持基质内环境的稳定。本研究的具体目的是：1.确定IL-17B在关节软骨动态平衡中的合成代谢和分解代谢靶点。目标2 A。鉴定关节软骨细胞中IL-17B的同源受体。目标2B。为了验证新的IL-17受体样分子(IL-17RL)是关节软骨中的功能性受体的假设。

DESCRIPTION (provided by applicant): The long-term objective of our research is to achieve reproducible repair and regeneration of articular cartilage. Regeneration and repair of tissues in general recapitulates embryonic development and morphogenesis. Hence, factors involved in morphogenesis and development may be of utility in regeneration of adult tissues. Bone and articular cartilage are adjacent tissues. Yet bone has considerable potential for repair and articular cartilage is recalcitrant to repair. We have undertaken a systematic investigation of endogenous morphogens and cytokines for articular cartilage repair. Previously, we identified bone morphogenetic proteins (BMPs) and cartilage-derived morphogenetic proteins (CDMPs) as chondrogenic morphogens. Recently we identified a novel cytokine chondroleukin in articular cartilage. The proposed research will investigate the cell biology of the novel cytokine chondroleukin, a protein of 180 amino acid residues with 40% homology to human Interleukin 17. Therefore, chondroleukin is also known as IL-17B. In addition, we have identified and cloned a novel lL-17 receptor-like molecule (IL-17RL) that is expressed in articular cartilage. This receptor is expressed both as membrane-bound and soluble decoy receptor by alternative splicing of RNA transcripts. We hypothesize that chondroleukin (IL-17B) and its functional receptors form a cytokine signaling system that modulates BMP- and CDMP-induced chondrogenesis, differentiation, and maintenance of matrix homeostasis. The Specific Aims of our investigation are: Aim 1. To determine the anabolic and catabolic targets of lL-17B (chondroleukin) in articular cartilage homeostasis. Aim 2A. To identify the cognate receptors of lL-17B in articular chondrocytes. Aim 2B. To examine the hypothesis that the novel lL-17 receptor-like molecule (IL-1 7RL) is a functional receptor in articular cartilage.