BRAF Drives Synovial Fibroblast Transformation in Rheumatoid Arthritis
| Autor: | Robert N. Nishimura, Keith K. Colburn, Richard H. Weisbart, Emil R. Heinze, Rachel Mory, Grace Chan |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
musculoskeletal diseases
Adult Cartilage Articular Male Proto-Oncogene Proteins B-raf endocrine system diseases Cellular differentiation Arthritis Biology Biochemistry Bone and Bones Arthritis Rheumatoid medicine Humans RNA Small Interfering Fibroblast skin and connective tissue diseases Molecular Biology neoplasms Aged Cell Proliferation Aged 80 and over Oncogene Cartilage Synovial Membrane Cell Biology Fibroblasts Middle Aged medicine.disease digestive system diseases Protein Structure Tertiary medicine.anatomical_structure Protein kinase domain Rheumatoid arthritis Immunology Mutation Cancer research Female RNA Splice Sites Synovial membrane Reports |
| Popis: | Synovial fibroblasts destroy articular cartilage and bone in rheumatoid arthritis, but the mechanism of fibroblast transformation remains elusive. Because gain-of-function mutations of BRAF can transform fibroblasts, we examined BRAF in rheumatoid synovial fibroblasts. The strong gain-of-function mutation, V600R, of BRAF found in melanomas and other cancers was identified in first passage synovial fibroblasts from two of nine rheumatoid arthritis patients and confirmed by restriction site mapping. BRAF-specific siRNA inhibited proliferation of synovial fibroblasts with V600R mutations. A BRAF aberrant splice variant with an intact kinase domain and partial loss of the N-terminal autoinhibitory domain was identified in fibroblasts from an additional patient, and fibroblast proliferation was inhibited by BRAF-specific siRNA. Our finding is the first to establish mechanisms for fibroblast transformation responsible for destruction of articular cartilage and bone in rheumatoid arthritis and establishes a new target for therapeutic intervention. |
| Databáze: | OpenAIRE |
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