Chondroleukin and Articular Cartilage

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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.