WNT PROTEINS IN ADULT, AGED AND OSTEOARTHRITIC CARTILAGE
Principal Investigator: K E Yates
Abstract: Age-associated changes in cartilage matrix alter its ability to provide pain-free joint movement. Changes in matrix proteoglycans affect cartilage biomechanics, making aged tissue more susceptible to damage. Indeed, age is the major risk factor for osteoarthritis (OA), a chronic degenerative condition that affects ~20 million people in the US. This project tests the hypothesis that Wnt family proteins regulate cartilage matrix synthesis, and that this function is altered in old age and in OA. This hypothesis is synthesized from two well-established lines of evidence: 1) Cartilage matrix glycosaminoglycan (GAG) content, structure, and sulfation change with age and OA, and 2) The amount and sulfation of matrix GAGs influence Wnt signaling and expression. Additional evidence to support our hypotheses is that nuclear b-catenin, an indicator of Wnt signaling, is found in adult cartilage, and our Preliminary Studies show expression of many Wnt ligands, receptors, signaling and target genes in adult chondrocytes. Wnt proteins have also been shown to regulate matrix synthesis by chondrogenic cells in vitro. The proposed studies will use human articular chondrocytes isolated from discarded tissues of patients undergoing total knee replacement. Specific Aim l is to define the Wnt component expression profile of adult chondrocytes (30-50 years), and compare it to aged (>70 years) and OA chondrocytes. Specific Aim II is to investigate the link between Wnt signaling and chondrogenesis, and determine whether this is decreased in aged and OA chondrocytes. Our results will have a significant impact on understanding mechanisms of normal and pathologic aging of cartilage, and may lead to novel therapeutic and preventative strategies to rejuvenate cartilage. This work will also provide a solid foundation for future research on Wnts in cartilage biology.
Funding Period: 2004-08-15 - 2006-07-31
more information: NIH RePORT
- Wnt influence on chondrocyte differentiation and cartilage functionKaren E Yates
Department of Orthopedic Surgery, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
DNA Cell Biol 24:446-57. 2005....
- Alteration of matrix glycosaminoglycans diminishes articular chondrocytes' response to a canonical Wnt signalS Shortkroff
Department of Orthopedic Surgery, Brigham and Women s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
Osteoarthritis Cartilage 15:147-54. 2007..The objective of this study was to determine whether alteration in GAG sulfation or matrix content, such as that occurs in OA cartilage, would affect articular chondrocytes' response to a canonical Wnt stimulus...
- Optimized extraction of glycosaminoglycans from normal and osteoarthritic cartilage for glycomics profilingAlicia M Hitchcock
Department of Biochemistry, Boston University School of Medicine, MS Resource, 670 Albany Street, Boston, MA 02118, USA
Glycobiology 17:25-35. 2007..These results show that the new method has sufficient accuracy to allow determination of topographical distribution of glycoforms in connective tissue...