High levels of chromium and cobalt in a pregnant patient with metal-on-metal hip arthroplasty
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Osteolysis
Abstract Particle‐induced osteolysis is a major issue, and it is most likely the result of enhanced osteoclast activation in the pathogenesis of various skeletal diseases. This study investigated whether the inhibitory effect that Polycan has on osteoclast differentiation can be used to treat osteolysis induced by titanium (Ti) particles. To this end, the effects of Polycan were examined in terms of the cytotoxicity, osteoclast differentiation, cytokine expression, and Ti‐induced calvarial osteolysis. Polycan had no significant cytotoxic effects on bone marrow macrophages (BMMs) but instead increased BMM proliferation. High levels of interleukin (IL)‐6, IL‐12, and macrophage colony‐stimulating factor (M‐CSF) were expressed in BMM cells in the presence of Polycan, suggesting that Polycan drives the differentiation of BMMs into M1 macrophages. Polycan significantly inhibited osteoclast differentiation induced by M‐CSF and the receptor activator of nuclear factor kappa‐B ligand (RANKL). The expression levels of the osteoclast marker genes significantly decreased, and Polycan induced and maintained the expression of IL‐12, which suppressed osteoclast differentiation. In contrast, the RANKL signaling pathway was not inhibited by Polycan. An in vivo calvarial osteolysis model revealed that Polycan significantly decreased the osteoclast numbers and suppressed osteolysis. Our results suggest that the natural compound Polycan is a good candidate for therapeutic intervention against enhanced osteoclast differentiation and Ti particle‐induced osteolysis. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1170–1175, 2016.
Osteolysis
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1958 Objectives The goal of this study was to validate 64Cu-CB-TE2A-c(RGDyK) (64Cu-RGD) as a biomarker for osteoclast number. A change in osteoclast number was monitored by biodistribution and microPET imaging with CT in mice treated with osteoprotegerin (OPG) and Receptor Activator for Nuclear Factor κ B Ligand (RANKL). OPG is a negative regulator of osteoclasts and should decrease osteoclast number. RANKL is a positive regulator of osteoclast differentiation and leads to an increase in osteoclast number. Methods C57BL/6 mice were treated with OPG at 0.2, 1.0 and 5.0 mg/kg twice a week for two weeks or with RANKL at 0.1 and 0.3 mg/kg twice a day for 10 days. On day 15 (OPG) or day 11 (RANKL) treated and control mice were injected with 64Cu-RGD followed by PET imaging and biodistribution. Standard uptake values (SUVs) were determined. Bones were collected for histology. Results Mice treated with 5 mg/kg of OPG or 0.3 mg/kg of RANKL showed a significant difference compared to control. The normal tissue biodistribution of the tracer did not vary greatly between the control and treated mice. PET images of animals treated with 0.3 mg/kg RANKL demonstrated significantly increased SUVs as compared to the control group. Histology and TRAP5b levels supported the biodistribution, PET, and TRAP5b data. Conclusions Analysis of the PET images showed that 64Cu-RGD bone uptake correlated with the osteoclast number and could be quantified as SUVs in leg bones. Taken together, these data support the use of 64Cu-RGD as the osteoclast turnover imaging biomarker.
Biodistribution
RANK Ligand
Imaging biomarker
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Periprosthetic osteolysis is the most common cause of aseptic loosening in total joint arthroplasty. The role of inflammatory mediators such as prostaglandin E2 (PGE2) and osteoclast promoting factors including RANKL in the pathogenesis of osteolysis has been well characterized. However, the PGE2 receptor (EP1, EP2, or EP4), and cell type in which it is expressed, which is responsible for PGE2 induction of RANKL during wear debris-induced osteolysis, has yet to be elucidated. To address this, we used mice genetically deficient in these EP receptors to assess PGE2 and wear debris responses in vitro and in vivo. Wear debris-induced osteolysis and RANKL expression were observed at similar levels in WT, EP1(-/-), and EP2(-/-) mice, indicating that these receptors do not mediate PGE2 signals in this process. A conditional knockout approach was used to eliminate EP4 expression in FSP1(+) fibroblasts that are the predominant source of RANKL. In the absence of EP4, fibroblasts do not express RANKL after stimulation with particles or PGE2, nor do they exhibit high levels of osteoclasts and osteolysis. These results show that periprosthetic fibroblasts are important mediators of osteolysis through the expression of RANKL, which is induced after PGE2 signaling through the EP4 receptor.
Osteolysis
Prostaglandin E2 receptor
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It was recently shown that physiological bone remodeling depends on the dynamic balance of two cytokines that are predominantly secreted by osteoblasts. RANKL promotes the differentiation of osteoclastic precursors and the activation of osteoclasts, whereas osteoprotegerin (OPG)inhibits RANKL action. During the development of many tumors, enhanced osteolysis results in pathological bone destruction. Tumor-associated osteolysis is characterized by the degradation and inhibition of osteoprotegerin (OPG) and increased RANKL expression and secretion by tumor tissue. The resulting RANKL/OPG imbalance causes increased generation and activation of osteoclasts and, finally, a significant decrease in bone mass and pathological bone fractures. Tumor cells may also produce many other factors which affect the RANK/RANKL/OPG system and accelerate osteolysis, including IL-1, IL-6, TNF, and MIP-1alpha. The elucidation of the key mechanisms of tumor osteolysis has led to clinical trials of biological therapies based on the inhibition of RANKL and stimulation of OPG activity.
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RANK Ligand
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Osteoclast differentiation/activation is involved in orthodontic tooth movement at the compression sites of the alveolar bone. RANKL, a member of the TNF family expressed in osteoblasts, binds to RANK, a member of the TNF receptor family expressed on preosteoclasts, resulting in differentiation of preosteoclasts into mature osteoclasts. Several members of the TNF family, such as TNF and Fas ligand, can induce apoptosis by activation of caspase-3. We have investigated whether caspase-3 be involved in the late stage of RANKL-induced osteoclast differentiation. Increased active caspase-3 was found in mouse monocytic RAW264 cells differentiated into mature osteoclasts by treatment with RANKL for 3 days. Co-treatment with Z-Asp-CH₂-DCB, a caspase-3-specific inhibitor, augmented RANKL-induced osteoclast differentiation in RAW264 cells, also seen in mouse bone marrow macrophages. This suggests that activation of caspase-3 may play an inhibitory role at the late stage of RANKL-induced osteoclast differentiation.
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Abstract The cellular mechanism through which osseous breast cancer metastases induce the focal destruction of bone (tumor osteolysis) is unknown. An athymic mouse model designed for the study of tumor osteolysis was developed and the influence of two human breast cancer tumors on bone was studied. Tumor‐induced osteolysis occurred between 7 and 10 weeks after inoculation of mouse femora with MDA‐MB‐231 or MDA‐MB‐435s breast cancer cells. An increase in osteoclast number and an increase in osteoclast size (area) were detected when tumor‐bearing and sham‐injected limbs were compared. In vitro analysis of the influence of the tumor‐conditioned medium on osteoclast‐mediated bone resorption revealed that this conditioned medium stimulated the resorption by increasing both the number of osteoclasts bound to bone and the number of bone resorption pits formed per osteoclast. In addition, in vitro analysis of the influence of breast cancer tumor cells on osteoclast formation or survival, or both, demonstrated that breast cancer cells induced a dramatic increase in the number of osteoclasts detected in culture. Taken in total, these findings suggest that human breast cancer tumors induce osteolysis by enhancing osteoclast adherence to bone, stimulating osteoclast‐mediated bone resorption, and either prolonging the survival of osteoclasts or increasing osteoclast formation.
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Abstract Several reports indicate that macrophage colony stimulating factor (MCSF) is one of the major factors required for osteoclast proliferation and differentiation. Paradoxically, it has also been reported that MCSF inhibits osteoclastic activity. We therefore decided to investigate in detail the effects of MCSF on resorption and osteoclast formation to try and clarify this issue. Osteoclast-containing cultures were obtained from rabbit long bones and cultured on plastic culture dishes or devitalized bovine bone slices. MCSF (4–400 ng/ml) stimulated osteoclastic bone resorption in a time-dependent manner and at all doses examined. After 48 h of culture in the presence of MCSF, we observed a 2-fold increase in the total area of bone resorbed, as well as a significant increase in the area of bone resorbed per osteoclast and the number of resorption pits per osteoclast. This effect was paralleled by an increase in the number of larger osteoclasts (as determined by the number of nuclei per cell) and an increase in the size and depth of the resorption pits. Since the total number of osteoclasts remained the same, the MCSF-induced increase in resorptive activity appeared to be related to an increase in the average size of the osteoclasts. When resorption was expressed as the amount of bone resorbed per osteoclast nucleus, larger osteoclasts resorbed more per nucleus, suggesting that large osteoclasts, as a population, are more effective resorbers than small osteoclasts. Interestingly, when osteoclasts were plated at one-fifth the standard density, the amount of bone resorbed per osteoclast decreased considerably, indicating that resorptive activity is also affected by cell density of osteoclasts and/or of other cells present. However, at this lower density MCSF still increased osteoclast size and resorption by the same fold increase over control, suggesting that the effect of MCSF was independent of factors related to cell density.
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The effect of lipopolysaccharides (LPS) on periodontal tissue was studied in 11-week-old Wistar rats. Four injections of 500 micrograms LPS induced marked osteoclastic alveolar bone resorption, whereas no alveolar bone resorption occurred after four injections of physiological saline. The osteoclast count increased progressively during the four injections of 500 micrograms LPS. After eight injections, however, the osteoclast count fell from the maximum level after four injections, although osteoclasts continued to increase in size and demonstrate an increased number of nuclei. Comparison of the osteoclast number between a series of four injections of 5, 50 or 500 micrograms LPS each revealed a dose-dependent increase. This strongly suggests LPS induction of osteoclastic bone resorption in vivo. Combined use of indomethacin, a prostaglandin synthesis inhibitor, with LPS injections inhibited both the LPS-induced alveolar bone resorption and osteoclast increase, suggesting a possible participation of prostaglandins in osteoclast-mediated bone resorption.
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Bone remodeling
Tartrate-resistant acid phosphatase
RANK Ligand
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Objectives: Receptor-activator of nuclear factor-κB ligand (RANKL) is an essential stimulating factor for inducing osteoclast differentiation, feasibly resulting in osteoporosis. The bioactive extract of Agrocybe chaxingu mushroom, CHX, has been shown to have osteoclastic inhibitory activity. Accordingly, we investigated if CHX would inhibit or disrupt RANKL-induced osteoclast differentiation, implying possible prevention of osteoporosis. Materials and Methods: Monocyte/macrophage RAW264.7 cells (RAW cells) were employed as our experimental model and treated with varying concentrations of RANKL alone or with CHX for 5 days. Formation of osteoclasts was then assessed using tartrateresistant acid phosphatase (TRAP) assay, counting stained cells as osteoclasts under a light microscope. The inhibitory mechanism of CHX was also explored by examining the RANKLmediated signaling pathways, oxidative stress (OXS), antioxidant enzymes, and apoptosis. Results: RANKL (100 ng/mL)-induced osteoclast differentiation in RAW cells was significantly (~20%) inhibited with 10 μg/mL of CHX. This was accompanied by the downregulation of two key signaling pathways and activation of antioxidant enzymes that likely led to the reduction in OXS. Moreover, CHX ultimately induced undifferentiated or RANKLunresponsive cells to apoptosis, indicated by the modulation of apoptotic regulators. These findings may then account for a disruption of osteoclast differentiation with CHX. Conclusion: CHX appears to have the inhibitory effect on RANKL-induced osteoclast differentiation in RAW cells. It is thus plausible that CHX may have potential clinical implications in osteoclast-mediated bone diseases/disorders, including osteoporosis.
Multinucleate
RANK Ligand
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