title: Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration.
abstract: A fine balance between anabolic and catabolic mechanisms maintains extracellular matrix homeostasis in articular cartilage, and shifts toward degradation are associated with joint conditions such as osteoarthritis. To test the possible involvement, relevance and significance of the Wnt/beta-catenin-signaling pathway in those catabolic shifts, rabbit articular chondrocyte cultures were subjected to experimental activation of beta-catenin signaling by Wnt3A treatment or forced expression of constitutive-active beta-catenin (CA-beta-catenin). Both interventions provoked strong gelatinase activity and stimulated gene expression of matrix metalloprotease-3 and -13 and a disintegrin-like and metalloprotease with thrombospondin motif (ADAMTS)-4 and -5 proteases. Furthermore, Wnt3A treatment additively enhanced the effects of intereukin-1beta, a well-known catabolic culprit of proteoglycan matrix loss. To determine whether Wnt/beta-catenin signaling is associated with age-associated osteoarthritic changes in articular cartilage in vivo, we analyzed the presence and intracellular distribution of beta-catenin in a spontaneous guinea pig osteoarthritis model. Healthy articular chondrocytes in young guinea pig knees contained barely detectable levels of beta-catenin. In contrast, the protein was highly abundant in osteoarthritic-like chondrocytes present in older guinea pig joints, and was localized not only in the cytoplasm but also the nucleus, a clear reflection of activated Wnt signaling. These and other data suggest that Wnt/beta-catenin signaling is a powerful stimulator of chondrocyte matrix catabolic action and may be part of mechanisms leading to excessive remodeling and degradation of cartilage matrix in age-associated joint pathologies.
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Takahito
authors.initials: T
authors.lastname: Yuasa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Otani
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Koike
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.forename: Motomi
authors.initials: M
authors.lastname: Enomoto-Iwamoto
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D017077:Culture Media, Conditioned; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D000939:Epitopes; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D006168:Guinea Pigs; D006388:Hemagglutinins / Q000378:metabolism; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D007596:Joints / Q000473:pathology*; D007739:L Cells; D008156:Luciferases / Q000032:analysis / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010003:Osteoarthritis / Q000473:pathology; D011509:Proteoglycans / Q000032:analysis / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D014357:Trypsin / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin
chemical_list: D017077:Culture Media, Conditioned; D000939:Epitopes; D006388:Hemagglutinins; D053583:Interleukin-1beta; D011509:Proteoglycans; D011994:Recombinant Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D008156:Luciferases; D014357:Trypsin; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3