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1.
Previous studies have found that microRNA‐21 (miR‐21) is an important functional factor during osteoclast differentiation. Abnormal osteoclastogenesis induced by wear particles is the main cause of aseptic loosening in joint replacements. The aim of the present study is to investigate the possible role of miR‐21 in the pathogenesis of particle‐induced osteolysis (PIO). miR‐21 expression was examined in a PIO mouse model using real‐time (RT‐PCR). Osteoclastogenesis was determined by a tartrate resistant acid phosphatase (TRAP) quantification method. A toluidine blue staining assay was used to examine calvarial osteolysis. The results demonstrated that miR‐21 was significantly upregulated in the PIO animal model. Knocking out miR‐21 in the particle‐stimulated tissue could ameliorate osteolysis symptoms. Additionally, through our analysis of PDCD4 and AP‐1 expression, we suggest that the feedback loop of AP‐1, miR‐21, and PDCD4 might have an important influence on the development of PIO and that miR‐21 is a potential target for implant loosening therapies. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1837–1842, 2012 相似文献
2.
《Journal of orthopaedic research》2017,35(4):752-759
3.
Ryosuke Tsutsumi Colleen Hock C. Dustin Bechtold Steven T. Proulx Susan V. Bukata Hiromu Ito Hani A. Awad Takashi Nakamura Regis J. O'Keefe Edward M. Schwarz 《Journal of orthopaedic research》2008,26(10):1340-1346
Aseptic loosening of total joint replacements is caused by wear debris‐induced osteoclastic bone resorption, for which bisphosphonates (BPs) and RANK antagonists have been developed. Although BPs are effective in preventing metabolic bone loss, they are less effective for inflammatory bone loss. Because this difference has been attributed to the antiapoptotic inflammatory signals that protect osteoclasts from BP‐induced apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris‐induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model using in vivo micro‐CT and traditional histology. Although micro‐CT proved to be incompatible with titanium (Ti) particles, we were able to demonstrate a 3.2‐fold increase in osteolytic volume over 10 days induced by polyethylene (PE) particles versus sham controls (0.49 ± 0.23mm3 versus 0.15 ± 0.067mm3; p < 0.01). Although OPG and high‐dose ZA completely inhibited this PE‐induced osteolysis (p < 0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p < 0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE‐treated mice confirmed the remarkable suppression of resorption by OPG (p < 0.001) versus the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG versus BPs in both Ti‐ and PE‐treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area versus osteoclast numbers (p < 0.001). © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1340–1346, 2008 相似文献
4.
Yasuhiro Yamanaka John C.F. Clohisy Hiroshi Ito Takeo Matsuno Yousef Abu‐Amer 《Journal of orthopaedic research》2013,31(1):67-72
Particles released from orthopedic implants attract immune host defense cells to the bone‐implant interface and contribute to development of inflammation. The inflammatory microenvironment supports recruitment and differentiation of osteoclasts, the primary culprit of osteolysis. Therefore, understanding the complex signals that contribute to osteoclastogenesis and osteolysis is a sensible approach to design strategies to inhibit bone loss. The signaling cascades that coordinate osteoclastogenesis have been widely investigated. These include MAP kinases, Akt/PI3K pathway, NF‐κB signal transduction pathway, and NFAT pathway. We have recently reported that polymethylmethacrylate (PMMA) particles activate the NFAT pathway in murine osteoclast precursors and that NFAT inhibitors dose‐dependently block PMMA‐induced osteoclastogenesis. In the current study, we examined the role of JNK and NFATc1 in mice in response to PMMA particles using murine calvaria model. We show that locally administered MAPK/JNK inhibitor SP600125 and calcineurin/NFAT inhibitor cyclosporine‐A effectively blocked PMMA‐induced osteolysis in murine calvaria. To buttress the clinical relevance of JNK/NFATc1‐based regulation of PMMA‐induced osteoclastogenesis, we evaluated the effect of PMMA using human macrophages. We demonstrate that SP600125 and cyclosporine‐A abolished particle‐induced osteoclastogenesis in human osteoclast progenitors retrieved from patients undergoing total hip replacement. Thus JNK and NFATc1 appear to act as significant mediators of orthopedic particle‐induced osteolysis in humans. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:67–72, 2012 相似文献
5.
SH3BP2 Cherubism Mutation Potentiates TNF‐α–Induced Osteoclastogenesis via NFATc1 and TNF‐α–Mediated Inflammatory Bone Loss
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Tomoyuki Mukai Shu Ishida Remi Ishikawa Teruhito Yoshitaka Mizuho Kittaka Richard Gallant Yi‐Ling Lin Robert Rottapel Marco Brotto Ernst J Reichenberger Yasuyoshi Ueki 《Journal of bone and mineral research》2014,29(12):2618-2635
Cherubism (OMIM# 118400) is a genetic disorder with excessive jawbone resorption caused by mutations in SH3 domain binding protein 2 (SH3BP2), a signaling adaptor protein. Studies on the mouse model for cherubism carrying a P416R knock‐in (KI) mutation have revealed that mutant SH3BP2 enhances tumor necrosis factor (TNF)‐α production and receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast differentiation in myeloid cells. TNF‐α is expressed in human cherubism lesions, which contain a large number of tartrate‐resistant acid phosphatase (TRAP)‐positive multinucleated cells, and TNF‐α plays a critical role in inflammatory bone destruction in homozygous cherubism mice (Sh3bp2KI/KI). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF‐α–mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF‐α–mediated osteoclast formation and bone loss. Here, we show that bone marrow–derived M‐CSF–dependent macrophages (BMMs) from the heterozygous cherubism mutant (Sh3bp2KI/+) mice are highly responsive to TNF‐α and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase Cγ2 (PLCγ2) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF‐α injection model as well as in a human TNF‐α transgenic mouse model (hTNFtg). SH3BP2 knockdown in RAW264.7 cells results in decreased TRAP‐positive multinucleated cell formation. These findings suggest that the SH3BP2 cherubism mutation can cause jawbone destruction by promoting osteoclast formation in response to TNF‐α expressed in cherubism lesions and that SH3BP2 is a key regulator for TNF‐α–induced osteoclastogenesis. Inhibition of SH3BP2 expression in osteoclast progenitors could be a potential strategy for the treatment of bone loss in cherubism as well as in other inflammatory bone disorders. © 2014 American Society for Bone and Mineral Research. 相似文献
6.
Vbenosawemwinghaye Orhue Arihiko Kanaji Marco S. Caicedo Amarjit S. Virdi Dale R. Sumner Nadim J. Hallab Holger Jahr Kotaro Sena 《Journal of orthopaedic research》2011,29(12):1867-1873
Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor‐α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt–chromium–molybdenum (CoCrMo) particles upregulate TNFα production by MLO‐Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin‐nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle‐induced TNFα production in MLO‐Y4 osteocytes. MLO‐Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle‐induced upregulation of TNFα is reduced to control levels with calcineurin‐NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO‐Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin‐NFAT signaling is involved in TNFα production by MLO‐Y4 osteocytes after CoCrMo particle treatment. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1867–1873, 2011 相似文献
7.
Tetsuro Ohba Hirotaka Haro Takashi Ando Masanori Wako Fumiko Suenaga Yoshinori Aso Kensuke Koyama Yoshiki Hamada Atsuhito Nakao 《Journal of orthopaedic research》2009,27(2):229-235
We previously demonstrated that VEGF and its receptors were expressed in human herniated discs (HD). TNF‐α induced VEGF, resulting in neovascularization of disc tissues in a model of HD. The goal of the current research was to investigate the precise role of TNF‐α–induced VEGF and the mechanism of angiogenesis in disc tissues. We performed ELISAs, Western blots, and immunohistological examinations to assess the role of TNF‐α–induced VEGF using organ disc cultures with wild type, TNF receptor 1‐null (TNF‐RInull), or TNF receptor 2‐null (TNF‐RIInull) mice. VEGF induction was inhibited when we used TNF‐RInull‐derived disc tissues. NF‐κB pathway inhibitors also strongly suppressed VEGF induction. Thus, TNF‐α induced VEGF expression in disc cells primarily through the NF‐κB pathway. In addition, VEGF immunoreactivity was detected predominantly in annulus fibrosus cells and increased after TNF‐α stimulation. TNF‐α treatment also resulted in CD31 expression on endothelial cells and formation of an anastomosing network. In contrast, angiogenic activity was strongly inhibited in the presence of NF‐κB inhibitors or anti‐VEGF antibody. Our data show angiogenesis activity in disc tissues is regulated by VEGF and the NF‐κB pathway, both of which are induced by TNF‐α. The level of angiogenic activity in disc tissues was closely related to aging. Because neovascularization of HD is indispensable for HD resorption, the prognosis of HD and the rate of the resorption process in patients may vary as a function of the patient's age. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:229–235, 2009 相似文献
8.
9.
Jesse E Otero Simon Dai Muhammad A Alhawagri Isra Darwech Yousef Abu‐Amer 《Journal of bone and mineral research》2010,25(6):1282-1294
Monocytes differentiate into osteoclasts through stimulation of receptor activator of NF‐κB (RANK). Many downstream effectors of RANK play a positive role in osteoclastogenesis, but their relative importance in osteoclast differentiation is unclear. We report the discovery that activation of a single pathway downstream of RANK is sufficient for osteoclast differentiation. In this regard, introduction of constitutively activated IKKβ (IKKβSSEE) but not wild‐type IKKβ into monocytes stimulates differentiation of bona fide osteoclasts in the absence of RANK ligand (RANKL). This phenomenon is independent of upstream signals because IKKβSSEE induced the development of bone‐resorbing osteoclasts from RANK and IKKα knockout monocytes and in conditions in which NEMO‐IKKβ association was inhibited. NF‐κB p100 and p105, but not RelB, were critical mediators of this effect. Inflammatory autocrine signaling by tumor necrosis factor α (TNF‐α) and interleukin 1 (IL‐1) were dispensable for the spontaneous osteoclastogenesis driven by IKKβSSEE. More important, adenoviral gene transfer of IKKβSSEE induced osteoclasts and osteolysis in calvariae and knees of mice. Our data establish the sufficiency of IKKβ activation for osteolysis and suggest that IKKβ hyperactivation may play a role in conditions of pathologic bone destruction refractory to RANK/RANKL proximal therapeutic interventions. © 2010 American Society for Bone and Mineral Research 相似文献
10.
目的观察雷尼酸锶(strontium ranelate,SR)对磨损颗粒诱导炎性骨溶解的影响。方法 30只雄性C57BL/J6小鼠,随机分为空白组、对照组和药物组,每组10只。采用钛(Ti)颗粒诱导的小鼠颅骨溶解模型,药物组建模当日经灌胃予SR[600mg/(kg·d)],空白组和对照组不予处理;持续至建模后10d,处死取材。HE染色观察颅骨溶解程度及骨膜厚度;抗酒石酸酸性磷酸酶(tartrate resistant acid phosphatase,TRAP)染色检测成熟破骨细胞;酶联免疫吸附试验(ELISA)检测肿瘤坏死因子(TNF-α)、白细胞介素(IL)-1β和IL-6表达水平。结果HE染色结果,对照组骨膜明显增厚,颅骨溶解区域广;图像分析软件测量结果,对照组骨膜厚度(0.27±0.04)mm,骨溶解率为0.47±0.11,与药物组[(0.11±0.02)mm,0.18±0.05]比较,差异有统计学意义(P〈0.05);TRAP染色结果,对照组颅骨大片紫红色区域,SR治疗后明显减少;ELISA检测结果,SR加入后,TNF-α、IL-1β和IL-6的表达量分别为[(145.6±14.2)ng/L、(130.2±8.2)ng/L和(137.6±8.2)μg/L],与对照组[(210.2±8.9)ng/L、(159.6±9.7)ng/L、(170.8±9.5)μg/L]比较,差异有统计学意义(P〈0.05)。结论 SR能够减轻Ti颗粒引起的炎症反应、减少炎症因子分泌,抑制骨溶解。 相似文献
11.
Christophe Nich Arnaud Marchadier Laurent Sedel Hervé Petite Catherine Vidal Moussa Hamadouche 《Journal of orthopaedic research》2010,28(2):178-183
Postmenopausal osteoporosis is a common disorder that results from increased osteoclastic activity caused by estrogen deficiency. Whether postmenopausal bone remodeling can alter the response to particulate debris is unknown. The purpose of this study was to evaluate the bone response to polyethylene particles in an ovariectomized murine model. Polyethylene particles were implanted onto the calvaria of seven control mice and seven ovariectomized (OVX) mice, as compared with calvaria from sham‐operated and OVX mice. Calvaria were harvested after 14 days. Skulls were analyzed with a high‐resolution micro‐CT and by histomorphometry after staining with Stevenel blue and picrofuschine, and for tartrate‐specific alkaline phosphatase. As assessed by micro‐CT, particle implantation induced a significant decrease in bone thickness in control mice, while bone thickness remained stable in OVX mice. In particle‐implanted animals, the osteoclast number was 2.84 ± 0.3 in control mice and 1.74 ± 0.22 in OVX mice. Mean bone loss was ?12% ± 1.9% in control mice and ?4.7% ± 1.7% in OVX animals. The reduction of osteolytic response suggests that ovariectomy may have a protective role against particle‐induced bone resorption. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:178–183, 2010 相似文献
12.
Local delivery of mutant CCL2 protein‐reduced orthopaedic implant wear particle‐induced osteolysis and inflammation in vivo
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Xinyi Jiang Taishi Sato Zhenyu Yao Michael Keeney Jukka Pajarinen Tzu‐hua Lin Florence Loi Kensuke Egashira Stuart Goodman Fan Yang 《Journal of orthopaedic research》2016,34(1):58-64
Total joint replacement (TJR) has been widely used as a standard treatment for late‐stage arthritis. One challenge for long‐term efficacy of TJR is the generation of ultra‐high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade which may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here, we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle‐induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle‐induced osteolysis and the effects of 7ND treatment were evaluated using micro‐CT, histology, and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle‐induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle‐induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:58–64, 2016. 相似文献
13.
Andrew S. Islam Michelle A. Beidelschies Anne Huml Edward M. Greenfield 《Journal of orthopaedic research》2011,29(2):211-217
Adherent pathogen‐associated molecular patterns (PAMPs) act through toll‐like receptor 2 (TLR2) and TLR4 to increase the biological activity of orthopedic wear particles in cell culture and animal models of implant loosening. This study tested whether this is dependent on TLR association with lipid rafts as reported for the response to soluble TLR ligands. For this purpose, RAW264.7 murine macrophages were activated by exposure to titanium particles with adherent PAMPs, soluble lipopolysaccharide (LPS), soluble lipotecichoic acid (LTA), or heat‐killed bacteria that had been extensively washed to remove soluble PAMPs. Lipid rafts were isolated by two independent methods and the location of TLR4 and TLR2 was analyzed by Western blotting. The cognate TLRs associated with lipid rafts when the macrophages were activated with soluble LPS and LTA but not after stimulation with either titanium particles with adherent PAMPs or heat‐killed bacteria. The lipid raft disruptor, methyl‐β‐cyclodextrin, dose‐dependently inhibited TNF‐α release in response to LPS but had no affect on TNF‐α release in response to titanium particles with adherent PAMPs. We conclude, therefore, that titanium particles with adherent PAMPs and heat‐killed bacteria activate TLR2 and TLR4 in macrophages without inducing either TLR to associate with lipid rafts. These results have important implications for the mechanisms of orthopedic implant loosening as well the mechanisms for TLR activation in other inflammatory situations. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:211–217, 2011 相似文献
14.
Adalimumab treatment leads to reduction of tissue tumor necrosis factor‐alpha correlated with venous leg ulcer improvement: a pilot study
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Joshua D Fox Katherine L Baquerizo‐Nole Brian R Keegan Flor Macquhae Julia Escandon Aliette Espinosa Carmen Perez Paolo Romanelli Robert S Kirsner 《International wound journal》2016,13(5):963-966
Venous leg ulcers (VLUs) have higher tumor necrosis factor‐α (TNF‐α) levels compared with normal skin. Refractory VLUs of long duration have higher TNF‐α levels compared with VLUs of shorter duration. As up to 75% of VLUs fail to heal with standard care, we sought to evaluate the role of anti‐TNF‐α therapy for patients with refractory VLUs. Evaluable data were obtained in four of five subjects with recalcitrant VLUs treated with 80 mg of subcutaneous adalimumab at week 0 and with 40 mg at week 2 along with compression therapy and were followed‐up for 6 weeks. Wound biopsies taken at weeks 0 and 4 were stained with anti‐TNF‐α antibodies. Average 4‐week percent wound size reduction was 20.5% ± 6.4%. Two patients had wound size reduction more than 25%, and their percent wound size reduction correlated to percent TNF‐α staining score reductions (P = 0.02, R2 = 0.999). VLU TNF‐α level decrease 4 weeks post‐adalimumab treatment correlated with wound healing. 相似文献
15.
Increased interleukin-8 (IL-8) expression is related to aseptic loosening of total hip replacement 总被引:2,自引:1,他引:1
Lassus J Waris V Xu JW Li TF Hao J Nietosvaara Y Santavirta S Konttinen YT 《Archives of orthopaedic and trauma surgery》2000,120(5-6):328-332
Aseptic loosening is an increasing problem in total hip replacement (THR). Chronic inflammatory reaction against implant
wear particle results in collageno- and osteolysis, leading to loosening of the implant. Cytokines are known to play a major
role in this particular inflammatory process [10]. The aim of the present study was to examine interleukin-8 (IL-8) in the
synovial-like interface membrane (SLIM) and pseudocapsular tissue of THRs and to compare it to normal knee synovial membrane.
Eleven patients suffering from aseptically loosened THRs were included. All the SLIM and pseudocapsular tissue samples were
obtained during revision operations. Ten control samples of normal synovium were collected per arthroscopy from the superior
recessus of the knee. For immunohistochemical IL-8 detection, polyclonal mouse anti-human immunoglobulin (Ig)G1 IL-8-primary antibody was used with the alkaline phosphatase anti-alkaline phosphatase (APAAP) method. Results were quantitated
using the Vidas image analysis system. The highest count levels (mean ± SEM) were detected in SLIM tissue (386 ± 82 cells/mm2). The difference was statistically significant compared with pseudocapsular tissue (193 ± 36 cells/mm2) and control samples (18 ± 5 cells/mm2). Count levels in control tissue were on average 5% of the SLIM tissues values. The present study determines for the first
time the cellular origin of IL-8 in aseptically loosened THRs and also quantitates the IL-8-producing cells in the periprosthetic
tissue. The results reveal a high rise in IL-8 concentration in SLIM and in synovial tissues. This finding moves us one step
forward in solving the complex network of multiple factors affecting loosening of hip implants.
Received: 10 November 1998 相似文献
16.
Particle‐induced osteolysis is caused by an imbalance in bone resorption and formation, often leading to loss of implant fixation. Bone remodeling biomarkers may be useful for identification of osteolysis and studying pathogenesis, but interpretation of biomarker data could be confounded if local osteolysis engenders systemic bone remodeling. Our goal was to determine if remote bone remodeling contributes to biomarker levels. Serum concentrations of eight biomarkers and bone remodeling rates at local (femur), contiguous (tibia), and remote (humerus and lumbar vertebra) sites were evaluated in a rat model of particle‐induced osteolysis. Serum CTX‐1, cathepsin K, PINP, and OPG were elevated and osteocalcin was suppressed in the osteolytic group, but RANKL, TRAP 5b, and sclerostin were not affected at the termination of the study at 12 weeks. The one marker tested longitudinally (CTX‐1) was elevated by 3 weeks. We found increased bone resorption and decreased bone formation locally, subtle differences in contiguous sites, but no differences remotely at 12 weeks. Thus, the skeletal response to local particle challenge was not systemic, implying that the observed differences in serum biomarker levels reflect differences in local remodeling. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:967–973, 2014. 相似文献
17.
Lyndsey Burton Daniel Paget Nikolaus B. Binder Krista Bohnert Bryan J. Nestor Thomas P. Sculco Laura Santambrogio F. Patrick Ross Steven R. Goldring P. Edward Purdue 《Journal of orthopaedic research》2013,31(1):73-80
Activation of myeloid cells by orthopedic particulate debris is a key event in the pathogenesis of periprosthetic osteolysis and implant loosening after total joint replacement (TJR). Several lines of evidence implicate NACHT, LRR, and PYD domains‐containing protein 3 (NALP3) inflammasome‐mediated production of interleukin 1 beta (IL‐1β) in the pathogenesis of clinical disorders ascribable to foreign particulate materials, including asbestos, silica, and urate crystals. Recent reports indicate that orthopedic polymer products and metallic particulates and ions may activate the same pathway. Here, we investigated the contribution of the NALP3 inflammasome to the pathogenesis of peri‐implant osteolysis. Pharmaceutical and genetic perturbations of caspase‐1 and inflammasome components were used to assess the role of the NALP3 inflammasome in IL‐1β production and osteoclast formation by human monocytes and mouse macrophages in response to polymethylmethacrylate (PMMA) particle phagocytosis. The role of caspase‐1 in a mouse calvarial model of particle‐mediated osteolysis was assessed using µCT. Phagocytosis of PMMA particles induces caspase‐1 dependent release of IL‐1β from human monocytes and mouse macrophages. Importantly, using macrophages from mice deficient in components of the NALP3 inflammasome, we show PMMA‐induced IL‐1β production is strictly dependent on these components. Mice lacking caspase‐1, the sole effector of the NALP3 inflammasome, show reduced orthopedic wear particle‐induced calvarial osteolysis compared to wild‐type controls. Absence of NALP3 inflammasome components fails to alter osteoclast formation in vitro. Our findings identify the NALP3 inflammasome as a critical mediator of orthopedic wear‐induced osteolysis and as a viable therapeutic target for the treatment of periprosthetic osteolysis. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:73–80, 2012 相似文献
18.
Enhanced Immunoprotective Effects by Anti‐IL‐17 Antibody Translates to Improved Skeletal Parameters Under Estrogen Deficiency Compared With Anti‐RANKL and Anti‐TNF‐α Antibodies
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Abdul M Tyagi Mohd N Mansoori Kamini Srivastava Mohd P Khan Jyoti Kureel Manisha Dixit Priyanka Shukla Ritu Trivedi Naibedya Chattopadhyay Divya Singh 《Journal of bone and mineral research》2014,29(9):1981-1992
Activated T cell has a key role in the interaction between bone and immune system. T cells produce proinflammatory cytokines, including receptor activator of NF‐κB ligand (RANKL), tumor necrosis factor α (TNF‐α), and interleukin 17 (IL‐17), all of which augment osteoclastogenesis. RANKL and TNF‐α are targeted by inhibitors such as denosumab, a human monoclonal RANKL antibody, and infliximab, which neutralizes TNF‐α. IL‐17 is also an important mediator of bone loss, and an antibody against IL‐17 is undergoing phase II clinical trial for rheumatoid arthritis. Although there are a few studies showing suppression of Th17 cell differentiation and induction of regulatory T cells (Tregs) by infliximab, the effect of denosumab remains poorly understood. In this study, we investigated the effects of anti‐TNF‐α, anti‐RANKL, or anti‐IL‐17 antibody administration to estrogen‐deficient mice on CD4+ T‐cell proliferation, CD28 loss, Th17/Treg balance and B lymphopoesis, and finally, the translation of these immunomodulatory effects on skeletal parameters. Adult Balb/c mice were treated with anti‐RANKL/‐TNF‐α/‐IL‐17 subcutaneously, twice a week, postovariectomy (Ovx) for 4 weeks. Animals were then autopsied; bone marrow cells were collected for FACS and RNA analysis and serum collected for ELISA. Bones were dissected for static and dynamic histomorphometry studies. We observed that although anti‐RANKL and anti‐TNF‐α therapies had no effect on Ovx‐induced CD4+ T‐cell proliferation and B lymphopoesis, anti‐IL‐17 effectively suppressed both events with concomitant reversal of CD28 loss. Anti‐IL‐17 antibody reduced proinflammatory cytokine production and induced Tregs. All three antibodies restored trabecular microarchitecture with comparable efficacy; however, cortical bone parameters, bone biomechanical properties, and histomorphometry were best preserved by anti‐IL‐17 antibody, likely attributable to its inhibitory effect on osteoblast apoptosis and increased number of bone lining cells and Wnt10b expression. Based on the superior immunoprotective effects of anti‐IL‐17, which appears to translate to a better skeletal preservation, we propose beginning clinical trials using a humanized antibody against IL‐17 for treatment of postmenopausal osteoporosis. © 2014 American Society for Bone and Mineral Research. 相似文献
19.
Kambiz Sarahrudi Mehdi Mousavi Karl Grossschmidt Nezir Sela Franz König Vilmos Vécsei Seyedhossein Aharinejad 《Journal of orthopaedic research》2008,26(6):759-763
Anorganic bovine‐derived hydroxyapatite (ABM) in combination with binding peptid (P‐15) has demonstrated the capacity to improve the healing of periodontal defects. This study evaluated the benefit of ABM/P‐15 to promote healing of cortical long bone defects in a rabbit model. A 5‐mm segmental bone defect was created in the femur and fixed with a plate. There were two treatment groups: no implant (n = 12) and ABM/P‐15 (n = 12). At 4, 8, and 12 weeks, healing of the defect was evaluated with radiographs and histomorphometric examination of the treated femora. After 4 weeks, radiographs showed bone formation without signs of complete consolidation in three of four animals in the control group and two of four ABM/P‐15 treated animals. At the later course of the treatment, no radiologic difference was evident between the treatment groups. Histomorphometric evaluation revealed an area of 1.29 ± 0.11 mm2 and 0.97 ± 0.21 mm2 of newly produced bone in animals of the control group and ABM/P‐15 group after 4 weeks. After 8 and 12 weeks, animals in the control group had an area of 2.44 ± 0.62 mm2 and 2.5 ± 0.2 mm2 of newly produced bone within the osteotomy gap compared to 1.6 ± 0.65 mm2 and 1.56 ± 0.27 mm2 in the ABM/P‐15 group (p = 0.0004). An enhanced or accelerated ingrowth of bone, as reported in previous studies, was not observed. Our results imply that the ABM/P‐15 is not a suitable graft for the treatment of critical‐sized segmental defects in long bones. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:759–763, 2008 相似文献
20.
Derek C. Lacey Bernard De Kok Felix I. Clanchy Mark J. Bailey Kathy Speed David Haynes Stephen E. Graves John A. Hamilton 《Journal of orthopaedic research》2009,27(11):1481-1486
Aseptic loosening results in pain, loss of function, and ultimately prosthetic joint failure and revision surgery. The generation of wear particles from the prosthesis is a major factor in local osteolysis. We investigated the effects of such wear particles on the survival of monocytes and macrophages, populations implicated in wear particle‐driven pathology. Particles from titanium aluminum vanadium (TiAlV) and cobalt chromium (CoCr) alloys were generated in‐house and were equivalent in size (0.5–3 µm) to those seen in patients. Human CD14+ monocytes and murine bone marrow‐derived macrophages (BMM) were treated with TiAlV and CoCr particles in vitro, and cell survival was assayed. Both particles increased monocyte and macrophage survival in a dose‐dependent manner, with an optimal concentration of around 107 particles/mL. Conditioned media from particle‐treated BMM also increased macrophage survival. Studies with antibody blockade and gene‐deficient mice suggest that particle‐induced BMM survival is independent of endogenous CSF‐1 (M‐CSF), GM‐CSF, and TNFα. These data indicate that wear particles can promote monocyte/macrophage survival in vitro possibly via an endogenous mediator. If this phenomenon occurs in vivo, it could mean that increased numbers of macrophages (and osteoclasts) would be found at a site of joint implant failure, which could contribute to the local inflammatory reaction and osteolysis. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1481–1486, 2009 相似文献