BRAF drives synovial fibroblast transformation in rheumatoid arthritis.
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.
Weisbart
Richard H
RH
Department of Research, Veterans Affairs Greater Los Angeles Health Care System, Sepulveda, California 91343, USA. rweisbar@ucla.edu
Chan
Grace
G
Heinze
Emil
E
Mory
Rachel
R
Nishimura
Robert N
RN
Colburn
Keith
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D001842:Bone and Bones / Q000201:enzymology / Q000473:pathology; D002358:Cartilage, Articular / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D022821:RNA Splice Sites; D034741:RNA, Small Interfering / Q000235:genetics; D013583:Synovial Membrane
D022821:RNA Splice Sites; D034741:RNA, Small Interfering; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf