2004 Fiscal Year Final Research Report Summary
Research for articular cartilage regeneration using overexpression of intracellular signal transduction molecules.
| Project/Area Number |
15591565
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KARITA Tatsuro The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (80359611)
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| Co-Investigator(Kenkyū-buntansha) |
HIRAOKA Hisatada The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (10262007)
TANAKA Sakae The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (50282661)
KAWANO Hirotaka The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (20345218)
ODA Hiromi Saitama medical University, School of Medicine, Professor, 医学部, 教授 (60101698)
NAKAMURA Kozo The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (60126133)
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| Project Period (FY) |
2003 – 2004
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| Keywords | cartilage regeneration / synovial fibroblast / adenovirus vector |
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| Research Abstract |
Injury to the articular cartilage occurs under various pathological conditions such as trauma, inflammation and aging and is followed by osteoarthritic changes of the affected joints. Recently, several studies have revealed that enough chondrogenic proliferation was obtained using some factors such as TGF-β and bone morphogenetic proteins (BMPs).
The role of TGF-β/BMP 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 (ALK3^<CA>) 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 (MKK6^<CA>) to activate p38 pathways. Smad1 expression had a synergistic effect on ALK3^<CA>, while activation of p38 MAP kinase pathways alone by transduction of MKK6^<CA> accelerated terminal chondrocytic differentiation, leading to type X collagen expression and enhanced mineralization. Overexpression of Smad1 prevented MKK6^<CA> -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.
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Research Products
(4 results)
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[Journal Article] Distinct Role of Smad Pathways and P38 in Cartilage-specific Gene Expression in Synovial Fibroblasts.2004
Author(s)
Seto H, Kamekura S, Miura T, Yamamoto A, Chikuda H, Ogata T, Hiraoka H, Oda H, Nakamura K, Kurosawa H, Chung U, Kawaguchi H, Tanaka S.
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Journal Title
J Clin Invest 113
Pages: 718-726
Description
「研究成果報告書概要(欧文)」より
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