PMID- 12438440
OWN - NLM
STAT- MEDLINE
DCOM- 20030131
LR  - 20181113
IS  - 0021-9738 (Print)
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Linking)
VI  - 110
IP  - 10
DP  - 2002 Nov
TI  - Osteoclasts are essential for TNF-alpha-mediated joint destruction.
PG  - 1419-27
AB  - The detailed cellular and molecular mechanisms leading to joint destruction in 
      rheumatoid arthritis, a disease driven by proinflammatory cytokines, are still 
      unknown. To address the question of whether osteoclasts play a pivotal role in 
      this process, transgenic mice that express human TNF (hTNFtg) and that develop a 
      severe and destructive arthritis were crossed with osteopetrotic, c-fos-deficient 
      mice (c-fos(-/-)) completely lacking osteoclasts. The resulting mutant mice 
      (c-fos(-/-)hTNFtg) developed a TNF-dependent arthritis in the absence of 
      osteoclasts. All clinical features of arthritis, such as paw swelling and 
      reduction of grip strength, progressed equally in both groups. Histological 
      evaluation of joint sections revealed no difference in the extent of synovial 
      inflammation, its cellular composition (except for the lack of osteoclasts), and 
      the expression of matrix metalloprotein-ase-3 (MMP-3) and MMP-13. In addition, 
      cartilage damage, proteoglycan loss, and MMP-3, -9, and -13 expression in 
      chondrocytes were similar in hTNFtg and c-fos(-/-)hTNFtg mice. However, despite 
      the presence of severe inflammatory changes, c-fos(-/-)hTNFtg mice were fully 
      protected against bone destruction. These data reveal that TNF-dependent bone 
      erosion is mediated by osteoclasts and that the absence of osteoclasts alters 
      TNF-mediated arthritis from a destructive to a nondestructive arthritis. 
      Therefore, in addition to the use of anti-inflammatory therapies, osteoclast 
      inhibition could be beneficial for the treatment of rheumatoid arthritis.
FAU - Redlich, Kurt
AU  - Redlich K
AD  - Department of Internal Medicine III, Division of Rheumatology, University of 
      Vienna, Vienna, Austria.
FAU - Hayer, Silvia
AU  - Hayer S
FAU - Ricci, Romeo
AU  - Ricci R
FAU - David, Jean-Pierre
AU  - David JP
FAU - Tohidast-Akrad, Makiyeh
AU  - Tohidast-Akrad M
FAU - Kollias, George
AU  - Kollias G
FAU - Steiner, Gunter
AU  - Steiner G
FAU - Smolen, Josef S
AU  - Smolen JS
FAU - Wagner, Erwin F
AU  - Wagner EF
FAU - Schett, Georg
AU  - Schett G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Carrier Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (RANK Ligand)
RN  - 0 (Receptor Activator of Nuclear Factor-kappa B)
RN  - 0 (TNFRSF11A protein, human)
RN  - 0 (TNFSF11 protein, human)
RN  - 0 (Tnfrsf11a protein, mouse)
RN  - 0 (Tnfsf11 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.24.- (Collagenases)
RN  - EC 3.4.24.- (MMP13 protein, human)
RN  - EC 3.4.24.- (Matrix Metalloproteinase 13)
RN  - EC 3.4.24.- (Mmp13 protein, mouse)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Animals
MH  - Arthritis, Rheumatoid/*etiology/pathology/physiopathology/therapy
MH  - Carrier Proteins/metabolism
MH  - Collagenases/metabolism
MH  - Genes, fos
MH  - Humans
MH  - Matrix Metalloproteinase 13
MH  - Matrix Metalloproteinase 3/metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Membrane Glycoproteins/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Osteoclasts/pathology/*physiology
MH  - Osteopetrosis/genetics/pathology/physiopathology
MH  - RANK Ligand
MH  - Receptor Activator of Nuclear Factor-kappa B
MH  - Tumor Necrosis Factor-alpha/deficiency/genetics/*physiology
PMC - PMC151809
EDAT- 2002/11/20 04:00
MHDA- 2003/02/01 04:00
PMCR- 2002/11/15
CRDT- 2002/11/20 04:00
PHST- 2002/11/20 04:00 [pubmed]
PHST- 2003/02/01 04:00 [medline]
PHST- 2002/11/20 04:00 [entrez]
PHST- 2002/11/15 00:00 [pmc-release]
AID - 15582 [pii]
AID - 10.1172/JCI15582 [doi]
PST - ppublish
SO  - J Clin Invest. 2002 Nov;110(10):1419-27. doi: 10.1172/JCI15582.