The Mechanism of TGFBR2 Action in Joint Degeneration.

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DESCRIPTION (provided by applicant): Osteoarthritis is the leading cause of disability in the industrialized world but almost nothing is known about mechanisms of cartilage destruction associated with osteoarthritis. Most of the bones in the body develop by a process called endochondral bone formation in which a cartilage model is made first and then replaced with bone. Although most of the cartilage model is transient, there are several sites where mature cartilage persists including the articular cartilage, which is required for proper joint function. Recent advances in the genetic manipulation of mice have lead to new animal models and new concepts that are relevant to understanding osteoarthritis in humans. The long-term objective of my laboratory is to understand the factors that mediate the development, persistence, and repair of articular cartilage and to identify specific targets for prevention and treatment strategies for osteoarthritis. TGF-b is a multifunctional peptide that has been shown to regulate cellular differentiation and tissue-specific gene expression. Previously, we generated transgenic mice that express a dominant-negative mutation of the TGF-b type II receptor (Tgfbr2) in articular cartilage, periosteum/ perichondrium, and synovium. Altered responsiveness to TGF-b in these cell types resulted in a progressive skeletal disease that resembled osteoarthritis in humans. Osteoarthritis symptoms were preceded by both a decrease in the pericellular matrix surrounding chondrocytes and inappropriate hypertrophic differentiation of chondrocytes. The data suggest that TGF-b normally prevents joint degeneration, however, the downstream effectors of TGF-b in the articular cartilage are not known. The objective of this study is to characterize a new mouse model of joint degeneration that can be used to determine the mechanism of TGF-b action in maintenance and repair of articular cartilage. The following aims are proposed: 1. To characterize mice with an inducible and conditional deletion of Tgfbr2 in post-natal cartilage and 2. To develop specific hypotheses about the mechanism of TGF-b action in articular cartilage by correlating gene expression profiles with the onset and progression of joint degeneration in wild type and Col2aCreER;Tgfbr2lox/lox mice and by identifying downstream effectors of TGF-b signaling in articular cartilage. Future studies will determine the role of selected TGF-b-regulated genes in maintaining the cartilage phenotype. PUBLIC HEALTH RELEVANCE. Osteoarthritis is the most common form of arthritis and the leading cause of musculoskeletal disability in the industrialized world. Our preliminary data and results from other laboratories suggest that TGF-b signaling has a critical role in cartilage homeostasis and repair, nevertheless, very little is know about the molecular mechanism of TGF-b action in articular cartilage. We propose to identify downstream targets of TGF-b signaling in articular cartilage that can be used as specific therapeutic targets for prevention and treatment of osteoarthritis.