Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen‐induced arthritis

Sims, Natalie A.; Green, Jonathan R.; Glatt, Markus; Schlict, S.; Martın, Thomas; Gillespie, Matthew T.; Romas, E.

doi:10.1002/art.20382

Cited by 126 publications

(84 citation statements)

References 38 publications

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“…Therefore, more potent bisphosphonates, such as zoledronate, may be efficacious. Recently, 2 groups have reported that zoledronate effectively prevents the bone erosion that occurs in the inflamed joints of TNF-Tg mice or animals with collagen-induced arthritis (48,49). Unfortunately, in those studies, the authors focused on investigating zoledronate-induced inhibition of osteoclast function, rather than survival.…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2

et al. 2005

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Objective. To investigate why bisphosphonates are less effective at preventing focal bone loss in rheumatoid arthritis (RA) patients than in those with generalized osteoporosis, and the mechanisms involved.Methods. The response of osteoclasts to alendronate (ALN) in tumor necrosis factor-transgenic (TNFTg) mice that develop erosive arthritis and in wild-type littermates was studied. TNF-Tg and wild-type mice were given ALN, and the osteoclast numbers in the inflamed joints and in the long bones were compared. The expression levels of Bcl-xL in the osteoclasts of TNF-Tg and wild-type mice were examined by immunostaining. The effect of overexpression of Bcl-xL and Ets-2 proteins on ALN-induced osteoclast apoptosis was determined using an in vitro osteoclast survival assay and retrovirus transfer approach.Results. ALN reduced osteoclast numbers in the metaphyses by 97%, but by only 46% in the adjacent inflamed joints. Bcl-xL expression was markedly higher in osteoclasts in the joints than in those in the metaphyses of TNF-Tg mice. Bcl-xL or Ets-2 overexpression protected osteoclasts from ALN-induced apoptosis, and TNF stimulated Bcl-xL and Ets-2 expression in osteoclasts. Overexpression of Ets-2 increased Bcl-xL messenger RNA in osteoclasts, while a dominant-negative form of the Ets-2 blocked the protective effect of Bcl-xL or TNF on ALN-induced apoptosis.Conclusion. The reduced efficacy of bisphosphonates to stop bone erosion in the inflamed joints of RA patients may result from local high levels of TNF up-regulating Ets-2 expression in osteoclasts, which in turn stimulates Bcl-xL expression in them and reduces their susceptibility to bisphosphonate-induced apoptosis.

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Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2

et al. 2005

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“…Given the fact that osteoclasts are primarily responsible for bone damage, this observation suggests that the elements needed to drive bone destruction are formed very early in the course of arthritis progression. Interestingly, bone erosion does not occur, even if arthritis is highly aggressive and longstanding, in animals in which osteoclasts have been targeted by genetic deletion of essential genes needed for osteoclast development or by administration of effective drugs that interfere with osteoclastogenesis (5)(6)(7)(14)(15)(16)(17)(18)(19)(20)(21)(22). Since osteoclasts are also a common feature in the joints of patients with RA, their contribution to the genesis of irreversible bone damage in human disease is quite likely (8,9,26,27).…”

Section: Discussionmentioning

confidence: 99%

“…Agents that inhibit the action of osteoclasts, such as bisphosphonates or the RANKL-binding soluble receptor osteoprotegerin, can inhibit or even arrest bone erosion (5)(6)(7)(14)(15)(16)(17)(18)(19). Gene therapy with molecules that inhibit drivers of osteoclastogenesis effectively inhibit bone erosion (20).…”

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confidence: 99%

Analysis of the kinetics of osteoclastogenesis in arthritic rats

Schett¹,

Stolina²,

Bolon³

et al. 2005

Arthritis & Rheumatism

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Objective. To analyze the kinetics of osteoclastogenesis in 2 models of chronic immune-mediated arthritis and 1 model of acute arthritis.Methods. Adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in Lewis rats were used as models of chronic arthritis. Acute arthritis was induced in Lewis rats by injecting carrageenan into the hind paw. Osteoclasts were identified by cathepsin K immunohistochemistry at various time points after the onset of arthritis. The location, size, and nucleation of osteoclasts were also analyzed.Results. In both AIA and CIA, multinucleated and cathepsin K-positive osteoclasts first were observed on the day of disease onset. Initially, osteoclasts were localized at the periosteum next to the synovial membrane and in subchondral bone channels. The number, size, and nucleation of osteoclasts rapidly increased, leading to severe bone loss within days after disease onset. In addition, numerous mononucleated cathepsin K-positive osteoclast precursor cells emerged in the synovial membrane. All osteoclasts (cathepsin K-positive, multinucleated, attached to bone) and osteoclast precursors (cathepsin K-positive, mononucleated or multinucleated, within synovial tissue) were also positive for a macrophage-specific marker. Upon induction of acute arthritis with carrageenan, osteoclasts formed transiently in subchondral bone, but regressed 7 days after disease onset. Conclusion.Functional osteoclasts are generated at the earliest stage of arthritis, and new precursors are continuously formed in the synovial membrane to replenish the osteoclast pool. These data indicate that antiresorptive therapies may provide the most effective bone protection, when treatment is started soon after the onset of arthritis.

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“…The BXD2 mouse model is a valuable model of spontaneous and early erosive disease that can be used to optimize single or combination anticytokine therapy for both treatment of inflammation and prevention of bone erosion in patients with rheumatoid arthritis (44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Synovial fibroblasts promote osteoclast formation by RANKL in a novel model of spontaneous erosive arthritis

Liu

et al. 2005

Arthritis & Rheumatism

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Objective. Erosion of cartilage and bone is a hallmark of rheumatoid arthritis (RA). This study was undertaken to explore the roles of hyperproliferating synovial fibroblasts and macrophages in abnormal osteoclast formation, using the recently described BXD2 mouse model of RA.Methods. Cell distribution in the joints was analyzed by immunohistochemistry, using tartrateresistant acid phosphatase (TRAP) staining to identify osteoclasts. To identify the defective cells in BXD2 mice, mouse synovial fibroblasts (MSFs) were cultured with bone marrow-derived macrophages. Osteoclast formation was assayed by TRAP staining and bone resorption pit assay, and the cytokine profiles of the MSFs and macrophages were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay.Results. In BXD2 mice, TRAP-positive osteoclasts were found at sites of active bone erosion, in close proximity to hyperproliferating synovial fibroblasts. On coculture, MSFs from BXD2 mice, but not C57BL/6 mice, produced high levels of RANKL messenger RNA, induced macrophages to form osteoclasts, and actively eroded bone slices, through a mechanism(s) that could be blocked by pretreatment with osteoprotegerin. Although macrophages from BXD2 mice expressed higher basal levels of tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤), and IL-6 than those from C57BL/6 mice, abnormal osteoclast formation was not due to enhanced sensitivity of the BXD2 mouse macrophages to RANKL. TNF␣, produced by both BXD2 MSFs and BXD2 mouse macrophages, had a strong stimulatory effect on RANKL expression. Conclusion. BXD2 MSFs produce RANKL and induce the development of osteoclasts from macrophages. The enhanced production of RANKL is possibly due to autocrine stimulation, together with paracrine stimulation by factors produced by macrophages.Rheumatoid arthritis (RA) is characterized by synovial hyperplasia, immune cell infiltration, cartilage destruction, and bone erosion (1,2). The presence of osteoclasts at the site of active bone erosions in patients with RA implicates these cells in the erosive disease (3). It has been shown that receptor activator of NF-B ligand (RANKL; also known as osteoclast differentiation factor, osteoprotegerin [OPG] ligand, TRANCE, and tumor necrosis factor [TNF] superfamily 11), is essential for the development of monocyte/macrophages into mature osteoclasts (4). During normal bone metabolism, RANKL is expressed by the stromal cells and osteoblast precursor cells of the bone marrow and is one of the factors that couple osteoclast formation and osteoblast formation such that bone turnover is balanced appropriately (5). In patients with RA, both the T cells and the synovial fibroblasts have been found to produce RANKL, and it has been proposed that this promotes osteoclast development (6,7). In the TNF␣-transgenic mouse model of arthritis, OPG, a decoy receptor of RANKL, protects against joint erosions, suggesting that the production of RANKL plays a pathogenic role in the development of the erosions (8).

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Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen‐induced arthritis

Cited by 126 publications

References 38 publications

Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2

Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2

Analysis of the kinetics of osteoclastogenesis in arthritic rats

Synovial fibroblasts promote osteoclast formation by RANKL in a novel model of spontaneous erosive arthritis

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