title: The growth factor midkine may play a pathophysiological role in rheumatoid arthritis.
abstract: OBJECTIVE
  Midkine (MK) is involved in cell proliferation, differentiation, migration, and survival. In this study, we measured serum MK levels in rheumatoid arthritis (RA) and investigated the correlation of serum MK with RA disease activity. Expression and effect of MK in RA synovial tissue were also examined.
  
  
  METHODS
  Serum MK and production of inflammatory mediators by rheumatoid synovial fibroblasts (RSFs) were measured by enzyme-linked immunosorbent assay. MK expression in synovial tissue was examined by immunohistochemistry. MK receptor expression was analyzed by RT-PCR and Western blotting.
  
  
  RESULTS
  RA patients had a significantly higher serum MK level than healthy controls. In RA patients, the MK level was correlated with DAS28-ESR, disability index of the Health Assessment Questionnaire, and rheumatoid factor level. The serum MK level tended to be decreased by anti-TNF therapy. MK was expressed by synovial lining cells in RA synovial tissues and it enhanced the production of IL-6, IL-8, and CCL2 by RSFs. RSFs expressed LDL receptor-related protein 1, candidate receptor for MK.
  
  
  CONCLUSIONS
  The serum MK level could be a marker of disease activity in RA and an indicator of a poor prognosis. MK may have a role in the pathogenesis of RA via induction of inflammatory mediators.
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Shindo
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kusunoki
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shikano
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Kawazoe
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Kaichi
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Muraoka
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kaburaki
authors.affiliation: b Division of Chronic Inflammatory Diseases , the Center for Advanced Research, Graduate School of Medical Science, Toho University , Tokyo , Japan , and.
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Akasaka
authors.affiliation: c Division of General and Gastroenterological Surgery, Department of Surgery , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hasunuma
authors.affiliation: a Division of Rheumatology, Department of Internal Medicine , Toho University School of Medicine , Tokyo , Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawai
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000078792:Midkine; D062072:Patient Acuity; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D018932:Chemokine CCL2; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D000078792:Midkine
keywords: Chemokine; Cytokine; Disease activity; Midkine; Rheumatoid arthritis