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Osteoprotegerin protects from generalized bone loss in TNF-transgenic mice

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Arthritis Res Ther20035 (Suppl 1) :40

  • Received: 14 January 2003
  • Published:


  • Rheumatoid Arthritis
  • Bone Mineral Density
  • Bone Mass
  • Bisphosphonates
  • Bone Volume


Chronic inflammatory conditions, such as rheumatoid arthritis, are characterized by generalized loss of bone mass. Proinflammatory cytokines, such as TNF, are believed to play a central role in this process by increasing bone resorption.


We have investigated systemic bone changes in human TNF-transgenic (hTNFtg) mice, which spontaneously develop severe inflammatory arthritis.


Osteodensitometry revealed a significant decrease of trabecular bone mineral density (BMD) (-37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (-85%) in comparison with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinolin crosslinks were significantly elevated, suggesting increased osteoclast-mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF-mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast-covered bone surface and serum levels of deoxypyridinolin crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF-receptor-1, IL-1β and IL-6. However, OPG decreased bone formation parameters, which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice.


These data indicate that TNF-mediated generalized bone loss is primarily dependent on RANKL/RANK signaling and can be blocked by OPG. Thus, OPG may represent a potent tool to prevent generalized loss of bone mass in chronic inflammatory disorders, especially rheumatoid arthritis.

Authors’ Affiliations

Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Vienna, Austria
Department of Pathology, Amgen, Inc., Thousand Oaks, CA, USA
Center for Biomedical Research, University of Vienna, Vienna, Austria
Institute of Immunology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece


© The Author(s) 2003