title: Etanercept Promotes Bone Formation via Suppression of Dickkopf-1 Expression in Rats with Collagen-Induced Arthritis.
abstract: BACKGROUND
  Various clinical reports suggest etanercept (ETN) has some efficacy in bone formation in rheumatoid arthritis (RA). To examine this effect, we investigated the gene expression of cytokines relevant to osteoblast/osteoclast differentiation, and evaluated histomorphometric findings in mature rats with collagen-induced arthritis (CIA).
  
  
  METHODS
  Total RNA was extracted from knee joints with CIA after ETN or placebo administration. Subsequently, realtime-PCR was carried out to quantify the mRNAs encoding Wnt-1, Dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegelin (OPG) and TNF (tumor necrosis factor)-alpha. In histomorphometric analysis, the infiltrating pannus volume and pannus surface, and the following items in contact with pannus surface were measured: osteoclast number, osteoid surface, osteoid volume and labeling surface. These were evaluated in the distal femur with CIA with or without ETN administration.
  
  
  RESULTS
  TNF-alpha, RANKL and OPG mRNA expressions, linked to osteoclastogenesis, were not significantly different with or without ETN administration. ETN administration significantly increased Wnt-1 mRNA expression, the osteoblast promoter, and decreased DKK-1 mRNA expression, the Wnt signal inhibitor. In histomorphometric analysis, pannus volume, pannus surface and osteoclast number, parameters of bone destruction, were not significantly different among groups. Osteoid volume, osteoid surface and labeling surface, parameters of bone formation, increased significantly with ETN administration.
  
  
  CONCLUSIONS
  Our results suggest that ETN suppresses DDK-1 expression, and, as a result, Wnt expression is promoted and osteoblastogenesis becomes more active, independent of the regulation of osteoclast activity. Marked bone formation is attributed to the fact that ETN directly promotes osteoblastogenesis, not as a result of suppressing osteoclastogenesis.
authors.affiliation: Division of Orthopedic Surgery, Department of Medicine of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanida
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kishimoto
authors.forename: Toru
authors.initials: T
authors.lastname: Okano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hagino
keywords: Dickkopf-1; Wnt; bone formation; etanercept; rheumatoid arthritis
references.citation: J Rheumatol. 2005 Jul;32(7):1232-42
references.pmid: 15996057
references.citation: Ann Rheum Dis. 2003 Nov;62 Suppl 2:ii10-2
references.pmid: 14532139
references.citation: Arthritis Rheum. 1996 May;39(5):797-809
references.pmid: 8639177
references.citation: Arthritis Rheum. 2004 Jan;50(1):265-76
references.pmid: 14730625
references.citation: Arthritis Rheum. 1995 Feb;38(2):151-60
references.pmid: 7848304
references.citation: Arthritis Rheum. 1990 Mar;33(3):305-15
references.pmid: 2180403
references.citation: J Rheumatol. 2003 May;30(5):1102-7
references.pmid: 12734916
references.citation: Curr Rheumatol Rep. 2002 Jun;4(3):226-31
references.pmid: 12010607
references.citation: Lancet. 2004 Feb 28;363(9410):675-81
references.pmid: 15001324
references.citation: J Exp Med. 1977 Sep 1;146(3):857-68
references.pmid: 894190
references.citation: Gene. 2003 Dec 4;321:1-15
references.pmid: 14636987
references.citation: Arthritis Rheum. 2006 Jan;54(1):76-81
references.pmid: 16385498
references.citation: N Engl J Med. 2000 Nov 30;343(22):1586-93
references.pmid: 11096165
references.citation: Biomaterials. 2009 Dec;30(34):6638-47
references.pmid: 19765818
references.citation: Mod Rheumatol. 2004;14(2):123-9
references.pmid: 17143661
references.citation: Rheumatology (Oxford). 2004 Dec;43(12):1496-503
references.pmid: 15353610
references.citation: Nat Clin Pract Rheumatol. 2008 Oct;4(10):550-6
references.pmid: 18820702
references.citation: J Rheumatol. 1995 Jun;22(6):1048-54
references.pmid: 7674229
references.citation: Arthritis Rheum. 2002 Jun;46(6):1443-50
references.pmid: 12115173
references.citation: J Clin Invest. 2006 May;116(5):1202-9
references.pmid: 16670761
references.citation: J Immunol. 1987 Feb 1;138(3):775-9
references.pmid: 3805716
references.citation: Endocrinology. 2000 Nov;141(11):3956-64
references.pmid: 11089525
references.citation: Nat Med. 2007 Feb;13(2):156-63
references.pmid: 17237793
references.citation: Curr Osteoporos Rep. 2007 Jun;5(2):73-80
references.pmid: 17521509
references.citation: J Rheumatol. 2001 Dec;28(12):2608-15
references.pmid: 11764205