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Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice
Georg Schett1, Kurt Redlich, Silvia Hayer
1Department of Internal Medicine III, Division of Rheumatology, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. georg.schett@akh-wien.ac.at
Objective:
To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.
Methods:
We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.
Results:
Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (-37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (-85%) compared with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinoline 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 deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin-1beta (IL-1beta), and IL-6. However, OPG decreased bone formation parameters (osteoblast-covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti-TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.
Conclusion:
OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.
Insights
Osteoprotegerin (OPG) effectively blocks tumor necrosis factor (TNF)-induced bone loss in inflammatory conditions like rheumatoid arthritis (RA). This study shows OPG prevents systemic bone loss by inhibiting osteoclast activity, offering a promising therapeutic strategy.
Area of Science:
- Immunology and Rheumatology
- Bone Biology and Metabolism
- Pharmacology
Background:
- Chronic inflammatory conditions, such as rheumatoid arthritis (RA), are associated with systemic bone loss.
- Tumor necrosis factor (TNF) plays a significant role in the pathogenesis of these inflammatory diseases and bone resorption.
Purpose of the Study:
- To investigate the role of TNF in systemic bone loss observed in chronic inflammatory conditions.
- To evaluate the therapeutic potential of osteoclast blockade using osteoprotegerin (OPG) in this context.
Main Methods:
- Systemic bone changes were investigated in human TNF transgenic (hTNFtg) mice that spontaneously developed severe inflammatory arthritis.
- Osteodensitometry and histomorphometry were used to assess bone mineral density and bone volume.
- The effects of OPG, bisphosphonates, and anti-TNF treatment on bone loss and inflammatory markers were evaluated.
Main Results:
- hTNFtg mice exhibited significant decreases in trabecular bone mineral density and bone volume, with elevated osteoclast activity and bone resorption markers.
- Osteoprotegerin (OPG) completely blocked TNF-mediated bone loss, significantly increasing bone mineral density and bone volume, and reducing osteoclast activity.
- In contrast, bisphosphonates and anti-TNF treatments did not prevent generalized bone loss in hTNFtg mice at the tested concentrations.
Conclusions:
- Osteoprotegerin (OPG) is a potent therapeutic agent for preventing generalized bone loss in chronic inflammatory disorders, particularly rheumatoid arthritis.
- OPG effectively blocks TNF-mediated bone resorption by inhibiting osteoclast activity, offering a targeted approach to bone protection in inflammatory diseases.