Chondroleukin and Articular Cartilage

描述（由申请人提供）：我们研究的长期目标是实现关节软骨的可再生修复和再生。组织的再生和修复一般重演胚胎发育和形态发生。因此，参与形态发生和发育的因子可能在成体组织的再生中具有实用性。骨和关节软骨是相邻组织。然而，骨具有相当大的修复潜力，而关节软骨难以修复。我们对关节软骨修复的内源性形态发生素和细胞因子进行了系统的研究。以前，我们确定骨形态发生蛋白（BMPs）和软骨衍生的形态发生蛋白（CDMPs）作为软骨形成的形态。最近我们在关节软骨中发现了一种新的细胞因子软骨白细胞素。拟议的研究将调查新型细胞因子软骨白细胞介素的细胞生物学，软骨白细胞介素是一种与人白细胞介素17具有40%同源性的180个氨基酸残基的蛋白质。因此，软骨白介素也被称为IL-17 B。此外，我们已经鉴定并克隆了一种在关节软骨中表达的新型IL-17受体样分子（IL-17 RL）。这种受体通过RNA转录物的选择性剪接表达为膜结合和可溶性诱饵受体。我们假设软骨白细胞介素（IL-17 B）及其功能性受体形成一个细胞因子信号传导系统，调节BMP和CDMP诱导的软骨形成，分化和维持基质稳态。我们研究的具体目标是：目标1。确定IL-17 B（软骨白细胞介素）在关节软骨稳态中的合成代谢和分解代谢靶标。目标2A。鉴定关节软骨细胞中IL-17 B的同源受体。目标2B为了检验新的IL-17受体样分子（IL-17 RL）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.