Osteoprotegerin protects from generalized bone loss in TNF-transgenic mice

Background

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.

Objective

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

Results

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.

Conclusion

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.