Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts.

Abstract	The role of TGF-beta/bone morphogenetic protein signaling in the chondrogenic differentiation of human synovial fibroblasts (SFs) was examined with the adenovirus vector-mediated gene transduction system. Expression of constitutively active activin receptor-like kinase 3 (ALK3CA) induced chondrocyte-specific gene expression in SFs cultured in pellets or in SF pellets transplanted into nude mice, in which both the Smad and p38 pathways are essential. To analyze downstream cascades of ALK3 signaling, we utilized adenovirus vectors carrying either Smad1 to stimulate Smad pathways or constitutively active MKK6 (MKK6CA) to activate p38 pathways. Smad1 expression had a synergistic effect on ALK3CA, while activation of p38 MAP kinase pathways alone by transduction of MKK6CA accelerated terminal chondrocytic differentiation, leading to type X collagen expression and enhanced mineralization. Overexpression of Smad1 prevented MKK6CA-induced type X collagen expression and maintained type II collagen expression. In a mouse model of osteoarthritis, activated p38 expression as well as type X collagen staining was detected in osteochondrophytes and marginal synovial cells. These results suggest that SFs can be differentiated into chondrocytes via ALK3 activation and that stimulating Smad pathways and controlling p38 activation at the proper level can be a good therapeutic strategy for maintaining the healthy joint homeostasis and treating degenerative joint disorders.
Authors	Hiroaki Seto, Satoshi Kamekura, Toshiki Miura, Aiichiro Yamamoto, Hirotaka Chikuda, Toru Ogata, Hisatada Hiraoka, Hiromi Oda, Kozo Nakamura, Hisashi Kurosawa, Ung-Il Chug, Hiroshi Kawaguchi, Sakae Tanaka
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 113 Issue 5 Pg. 718-26 (Mar 2004) ISSN: 0021-9738 [Print] United States
PMID	14991070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Collagen Type X DNA-Binding Proteins SMAD1 protein, human Smad Proteins Smad1 Protein Smad1 protein, mouse Trans-Activators RNA Collagen Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases Activin Receptors MAP Kinase Kinase 6 MAP2K6 protein, human Map2k6 protein, mouse
Topics	Activin Receptors (metabolism) Adenoviridae (genetics) Adult Aged Animals Blotting, Northern Calcium-Calmodulin-Dependent Protein Kinases (metabolism) Cartilage (metabolism) Cell Differentiation Cells, Cultured Chondrocytes (metabolism) Collagen (metabolism) Collagen Type X (chemistry) DNA-Binding Proteins (physiology) Enzyme Activation Fibroblasts (metabolism) Gene Expression Regulation Genetic Vectors Humans Immunoblotting MAP Kinase Kinase 6 Mice Mice, Nude Middle Aged Mitogen-Activated Protein Kinases (physiology) Osteoarthritis (metabolism) RNA (metabolism) Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Smad Proteins Smad1 Protein Synovial Membrane (cytology) Trans-Activators (physiology) p38 Mitogen-Activated Protein Kinases

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