title: Intra-articular fms-like tyrosine kinase 3 ligand expression is a driving force in induction and progression of arthritis.
abstract: BACKGROUND
  One of the hallmarks of rheumatoid arthritis (RA) is hyperplasia and inflammation of the synovial tissue being characterized by in situ occurrence of highly differentiated leukocytes. Fms-like tyrosine kinase 3 (Flt3) has a crucial role in hematopoiesis, regulation of cell proliferation, differentiation and apoptosis. Typically, Flt3 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand (Flt3-L). The highly differentiated cellular pattern in the synovium of the RA patients made us hypothesize that Flt3-L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis.
  
  
  RESULTS
  To investigate occurrence of Flt3-L in RA we have measured its levels in matched serum and synovial fluid samples from 130 patients and 107 controls. To analyse the pro-inflammatory role of Flt3-L, we continuously overexpressed this protein locally in healthy mouse joints using homologous B-cell line transfected with Flt3-L gene. Additionally, recombinant Flt3-L was instillated intra-articularly in combination with peptidoglycans, a Toll Like Receptor 2-ligand with stong arthritogenic properties. Our results show significantly higher levels of Flt3-L in the synovial fluid as compared to serum levels in RA subjects (p = 0.0001). In addition, RA synovial fluid levels of Flt-3-L were significantly higher than these obtained from synovial fluids originating from non-inflammatory joint diseases (p = 0.022). Intra-articular administration of B-cell line transfected with Flt3-L gene resulted in highly erosive arthritis while inoculation of the same B-cell line without hyperexpression of Flt3-L did not induce erosivity and only in a minority of cases caused synovial proliferation! Flt3-ligand potentiated peptidoglycan induced arthritis as compared to mice injected with peptidoglycan alone (p<0.05).
  
  
  CONCLUSIONS
  Our findings indicate that Flt3-L is strongly expressed at the site of inflammation in human RA. It exerts both pro-inflammatory and tissue destructive properties once in the joint cavity. Owing to these properties, treatment attempts to neutralize this molecule should be considered in RA.
authors.affiliation: Department of Rheumatology and Inflammation Research, Göteborg University, Göteborg, Sweden. mats.dehlin@vgregion.se
authors.forename: Mats
authors.initials: M
authors.lastname: Dehlin
authors.forename: Maria
authors.initials: M
authors.lastname: Bokarewa
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foster
authors.forename: Mattias
authors.initials: M
authors.lastname: Magnusson
authors.forename: Leif E
authors.initials: LE
authors.lastname: Dahlberg
authors.forename: Andrej
authors.initials: A
authors.lastname: Tarkowski
mesh_terms: D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000637:transplantation; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000276:immunology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010457:Peptidoglycan / Q000008:administration & dosage / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D001426:Bacterial Proteins; D008565:Membrane Proteins; D010457:Peptidoglycan; C084881:flt3 ligand protein