Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

Abstract

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 TNFmediated 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. Osteoclastcovered 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-1␤ (IL-1␤), 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.

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

“…Treatment with OPG was highly effective in protecting joint integrity in this model, especially when initiated early in disease (66). Similarly, RANKL inhibition did not prevent inflammation in a model of antibody-mediated arthritis (K/BxN mouse serum transfer model) (67), and in a TNF␣-transgenic mouse model, in which mice develop a spontaneous, destructive polyarthritis at an early age, mice treated with OPG still developed severe inflammatory arthritis although the development of osteoclasts was blocked (68). This was accompanied by increased bone mineral density and bone volume in the OPG-treated mice.…”

Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor–mediated arthritis

“…Left tibial bones were fixed in 70% ethanol and embedded undecalcified in methylmetacrylate (K-Plast; Medim, Buseck, Germany). After polymerization, 3-m sections were prepared with a Jung microtome (Jung, Heidelberg, Germany), deplastinated, and stained using Goldner trichrome and von Kossa's stain, as described previously (18,19). Histomorphologic parameters were assessed at 200ϫ magnification using a Zeiss Axioskop 2 microscope (Zeiss, Marburg, Germany) and quantitated using OsteoMeasure software, version 2.2 (Osteometrics, Atlanta, GA).…”

How antirheumatic drugs protect joints from damage in rheumatoid arthritis

“…TNF is an important inducer of osteoclast formation and is thus a key molecular link between inflammation and bone damage ( Figure 1A). Addition of TNF to monocyte cultures challenged with M-CSF and RANKL enhances the formation of osteoclasts, and overexpression of TNF in mice entails increased formation of osteoclasts, resulting in systemic bone loss as well as local bone erosions (52)(53)(54).…”