Autophagy mediated CoCrMo particle-induced peri-implant osteolysis by promoting osteoblast apoptosis

Wear particle-induced osteolysis is the leading cause of aseptic loosening, which is the most common reason for THA (total hip arthroplasty) failure and revision surgery. Although existing studies suggest that osteoblast apoptosis induced by wear debris is involved in aseptic loosening, the underlying mechanism linking wear particles to osteoblast apoptosis remains almost totally unknown. In the present study, we investigated the effect of autophagy on osteoblast apoptosis induced by CoCrMo metal particles (CoPs) in vitro and in a calvarial resorption animal model. Our study demonstrated that CoPs stimulated autophagy in osteoblasts and PIO (particle-induced osteolysis) animal models. Both autophagy inhibitor 3-MA (3-methyladenine) and siRNA of Atg5 could dramatically reduce CoPs-induced apoptosis in osteoblasts. Further, inhibition of autophagy with 3-MA ameliorated the severity of osteolysis in PIO animal models. Moreover, 3-MA also prevented osteoblast apoptosis in an antiautophagic way when tested in PIO model. Collectively, these results suggest that autophagy plays a key role in CoPs-induced osteolysis and that targeting autophagy-related pathways may represent a potential therapeutic approach for treating particle-induced peri-implant osteolysis.     

A comparison of the antiresorptive effects of bisphosphonates and statins on polyethylene particle-induced osteolysis]

An ongoing unraveling of the molecular mechanisms in aseptic loosening of hip arthroplasty has opened up novel potential pharmacological interventions. In this study the antiresorptive effects of the bisphosphonate zoledronate and the statin simvastatin on ultra high molecular weighted polyethylene (UHMWPE) particle-induced osteolysis were compared. Two previous studies of our group based on the murine calvarial model of UHWMPE particle-induced osteolysis were pooled to form four study groups. Animals in group I (n=14) underwent sham surgery only. In groups II (n=14), III (n=7) and IV (n=7) UHMWPE particles were implanted on the calvariae. Animals in groups III and IV were additionally treated with zoledronate (single 25 microg/kg s.c. injection) and simvastatin (120 mg/day p.o. for 14 days), respectively. After two weeks, calvaria were processed for undecalcified histomorphometry. Bone resorption was measured using Giemsa staining. Osteoclast numbers were determined using TRAP-staining. UHMWPE particle implantation resulted in a grossly pronounced osteolytic activity with significantly increased values of bone resorption (p < 0.001) and osteoclast numbers (p < 0.001). Additional treatment with zoledronate or simvastatin counteracted the particle-induced effects. A comparison of the two medical treatments revealed no statistically significant differences in bone resorption (p = 0.63) and osteoclast numbers (p = 0.41). A single dose of the bisphosphonate zoledronate decreased UHMWPE particle-induced osteolysis in a murine calvarial model as effectively as a daily treatment with simvastin. Both drug groups may have a preventive and therapeutic role as antiresorptive agents in wear particle-induced bone resorption following total joint replacement.     

Association between Apoptotis and CD4+/CD8+ T-Lymphocyte Ratio in Aseptic Loosening after Total Hip Replacement

Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. While the osteolytic cascade initiated by cytokine release from macrophages has been studied extensively, the involvement of T-lymphocytes in this context is controversial and has been addressed by only a few authors. In a former study we detected that the quantity of T-lymphocytes may be influenced by apoptosis in patients with aseptic loosening. In this study we intended to find out more details about the apoptosis-induced shifting of the T-cell number. We focused our interest on the CD4⁺ and CD8⁺ T-cells and their relative ratio. Caspase-3 cleaved was evaluated immunohistochemically to detect apoptotic T-cells in capsules and interface membranes from patients with aseptic hip implant loosening and a varying degree of caspase-3 cleaved expression in CD4⁺ and CD8⁺ T-lymphocytes was detected. Moreover, a relationship between the intensity of the apoptotic reactions and the radiological extent of osteolysis was observed. The number of CD4⁺ cells was decreased in the presence of strong apoptotic reactions, respectively extensive osteolysis, while CD8⁺ cells were affected to a much lower degree. Thus, the CD4⁺/CD8⁺ ratio changed from 1.0 in cases with only small areas of periprosthetic osteolysis and minimally intense apoptosis to 0.33 in cases with large areas of osteolysis. This may suggest a causal relationship between the apoptosis-induced shift in the CD4⁺/CD8⁺ ratio and the osteolysis respectively aseptic loosening. It is possible that these findings may lead to a new understanding of particle-induced osteolysis.     

Preparation of UHMWPE particles and establishment of inverted macrophage cell model to investigate wear particles induced bioactivites

Total joint replacement surgery has been widely applied to patients with severe osteoarthritis. Aseptic loosening induced by wear particles generated during joint movement is the major reason causing the failure of joint implants. Interaction of ultra-high molecular weight polyethylene (UHMWPE) wear particles with macrophages stimulates the release of inflammatory cytokines and leads to bone resorption and osteolysis. Effect of UHMWPE particle size and shape on the bioactivities remains unclear due to the lack of particles with controlled morphology as well as adequate in-vitro cell culture models for further investigations. We have developed a micro-cutting procedure to generate UHMWPE particles with desired sizes and shapes by rubbing UHMWPE with microfabricated surfaces. A narrow distribution and sterility of the generated particles was achieved. An inverted cell culturing apparatus and procedures were created and the contact between particles and macrophage cells was observed. No significant difference of the cell proliferations under normal and inverted positions further demonstrates the feasibility of the system. This newly developed platform can assist in the further understanding of the mechanism and therapy strategies of osteolysis induced by polyethylene particles.     

Prevention of wear particle-induced osteolysis by a novel V-ATPase inhibitor saliphenylhalamide through inhibition of osteoclast bone resorption

Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening) is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis) by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis.     

Titanium and zirconia particle-induced pro-inflammatory gene expression in cultured macrophages and osteolysis,inflammatory hyperalgesia and edema in vivo

Aims

The biological reaction to wear debris is critical to the osteolysis underlying aseptic loosening of joint prosthetic implants. In an attempt to reduce aseptic loosening, ceramics have been introduced. This study was designed to evaluate, compare and correlate the expression of Toll-like receptors (TLRs), their intracellular adaptors and proinflammatory cytokines in cultured macrophages challenged with titanium or zirconia particles, as well as particle-induced osteolysis in calvaria and hyperalgesia and edema in hind paw.

Main methods

TLRs and their adaptors were evaluated at the mRNA level by RT-PCR, and cytokine expression was evaluated at the mRNA and protein levels. Osteolysis and hyperalgesia and edema were evaluated in vivo, in calvaria and hind paw, respectively.

Key findings

Cultured macrophages challenged with zirconia or titanium particles expressed increased mRNA for TLRs 2, 3, 4 and 9, and their adaptors MyD88, TRIF and NF-κB and cytokines TNF-α, IL-1β and IL-6, which were also increased at protein level. Quantitative differences are evident and, in general, zirconia particle-induced pro-inflammatory gene expression was lower than that induced by titanium particles. In in vivo experiments, exposition to titanium or zirconia particles induced osteolysis in calvaria and hyperalgesia and edema in hind paw; however those induced by zirconia particles were significantly lower. There is a strong and positive correlation between the expressions of mRNA for TLR4, NF-κB, TNF-α, IL-1β and IL-6.

Significance

Collectively, our data suggest that zirconia ceramic particles are less bioactive than titanium particles.     

ER Stress Mediates TiAl6V4 Particle-Induced Peri-Implant Osteolysis by Promoting RANKL Expression in Fibroblasts

Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the synovial fibroblasts present in the periprosthetic membrane are important targets of wear debris during osteolysis. However, the interaction mechanisms between the wear debris and fibroblasts remain largely unknown. In the present study, we investigated the effect of ER (endoplasmic reticulum) stress induced by TiAl₆V₄ particles (TiPs) in human synovial fibroblasts and calvarial resorption animal models. The expression of ER stress markers, including IRE1-α, GRP78/Bip and CHOP, were determined by western blot in fibroblasts that had been treated with TiPs for various times and concentration. To address whether ER stress was involved in the expression of RANKL, the effects of ER stress blockers (including 4-PBA and TUDCA) on the expression of RANKL in TiPs-treated fibroblasts were examined by real-time PCR, western blot and ELISA. Osteoclastogenesis was assessed by tartrate resistant acid phosphatase (TRAP) staining. Our study demonstrated that ER stress markers were markedly upregulated in TiPs-treated fibroblasts. Blocking ER stress significantly reduced the TiPs-induced expression of RANKL both in vitro and in vivo. Moreover, the inhibition of ER stress ameliorated wear particle-induced osteolysis in animal models. Taken together, these results suggested that the expression of RANKL induced by TiPs was mediated by ER stress in fibroblasts. Therefore, down regulating the ER stress of fibroblasts represents a potential therapeutic approach for wear particle-induced periprosthetic osteolysis.     

Aspirin inhibits osteoclast formation and wear-debris-induced bone destruction by suppressing mitogen-activated protein kinases

Excessive osteoclast recruitment and activation is the chief cause of periprosthetic osteolysis and subsequent aseptic loosening, so blocking osteolysis may be useful for protecting against osteoclastic bone resorption. We studied the effect of aspirin on titanium (Ti)-particle-induced osteolysis in vivo and in vitro using male C57BL/6J mice randomized to sham (sham surgery), Ti (Ti particles), low-dose aspirin (Ti/5 mg·kg⁻¹·d⁻¹ aspirin), and high-dose aspirin (Ti/30 mg·kg⁻¹·d⁻¹ aspirin). After 2 weeks, a three-dimensional reconstruction evaluation using micro-computed tomography and histomorphology assessment were performed on murine calvariae. Murine hematopoietic macrophages and RAW264.7 lineage cells were studied to investigate osteoclast formation and function. Aspirin attenuated Ti-particle-induced bone erosion and reduced osteoclasts. In vitro, aspirin suppressed osteoclast formation, osteoclastic-related gene expression, and osteoclastic bone erosion in a dose-dependent manner. Mechanically, aspirin reduced osteoclast formation by suppressing receptor activator of nuclear factor kappa-B ligand-induced activation of extracellular signal-related kinase, p-38 mitogen-activated protein kinase, and c-Jun N-terminal kinase. Thus, aspirin may be a promising option for preventing and curing osteoclastic bone destruction, including peri-implant osteolysis.     

Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies

Total joint replacement, although considered an excellent surgical procedure, can be complicated by osteolysis induced by implant particles and subsequent aseptic loosening of the implant. The pathogenesis of implant-associated osteolysis includes inflammatory and osteolytic processes. The sustained chronic inflammatory response initiated by particulate debris at the implant-bone interface is manifested by recruitment of a wide array of cell types. These cells include macrophages, fibroblasts, giant cells, neutrophils, lymphocytes, and--most importantly--osteoclasts, which are the principal bone resorbing cells. The 'cellular response' entails secretion of osteoclastogenic and inflammatory cytokines that favor exacerbated osteoclast activity and enhanced osteolysis. An appreciation of the complex network that leads to these cellular and inflammatory responses will form a foundation on which to develop therapeutic interventions to combat inflammatory periprosthetic bone loss.     

人工关节假体无菌性松动动物模型的快速建立

目的:人工关节置换手术发展至今,取得了非常大的成功,已在临床解决了许多终末期的关节疾患。研究表明,假体无菌性松动的患者,其假体周围处于高骨更新状态。因此骨-假体界面的早期整合对于阻止磨屑颗粒和细胞因子的迁移至关重要,而限制人工关节假体使用寿命的一个主要原因是磨屑颗粒诱导的假体无菌性松动。在本研究中,我们旨在尝试使用107个UHMWPE颗粒快速建立人工关节假体无菌性松动的兔动物模型,以便为进一步探讨假体无菌性松动的机制及防治奠定实验基础。方法:我们用雌性新西兰大白兔建立动物模型,随机均分为实验组和对照组,在两组动物的左侧胫骨髓腔内植入羟基磷灰石(hydroxyapatite,HA)涂层假体。在实验组中,分别于假体表面和膝关节腔内植入0.5×10~7超高分子量聚乙烯(Ultra-high molecular weight polyethylene,UHMWPE)颗粒。结果:同对照组相比,实验组动物的关节内压力更高、骨组织形态学参数更差、假体生物力学固定强度更低,同时,促炎细胞因子和骨更新标志均显著高于对照组。结论:我们使用很少的UHMWPE颗粒成功快速地建立了人工关节假体无菌性松动的兔动物模型,从而为今后人工关节假体无菌性松动的进一步研究奠定了实验基础。     

Alpha-Calcitonin Gene-Related Peptide Can Reverse The Catabolic Influence Of UHMWPE Particles On RANKL Expression In Primary Human Osteoblasts

Background and purpose: A linkage between the neurotransmitter alpha-calcitonin gene-related peptide (alpha-CGRP) and particle-induced osteolysis has been shown previously. The suggested osteoprotective influence of alpha-CGRP on the catabolic effects of ultra-high molecular weight polyethylene (UHMWPE) particles is analyzed in this study in primary human osteoblasts. Methods: Primary human osteoblasts were stimulated by UHMWPE particles (cell/particle ratios 1:100 and 1:500) and different doses of alpha-CGRP (10^-7 M, 10^-9 M, 10^-11 M). Receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) mRNA expression and protein levels were measured by RT-PCR and Western blot. Results: Particle stimulation leads to a significant dose-dependent increase of RANKL mRNA in both cell-particle ratios and a significant down-regulation of OPG mRNA in cell-particle concentrations of 1:500. A significant depression of alkaline phosphatase was found due to particle stimulation. Alpha-CGRP in all tested concentrations showed a significant depressive effect on the expression of RANKL mRNA in primary human osteoblasts under particle stimulation. Comparable reactions of RANKL protein levels due to particles and alpha-CGRP were found by Western blot analysis. In cell-particle ratios of 1:100 after 24 hours the osteoprotective influence of alpha-CGRP reversed the catabolic effects of particles on the RANKL expression. Interpretation: The in-vivo use of alpha-CGRP, which leads to down-regulated RANKL in-vitro, might inhibit the catabolic effect of particles in conditions of particle induced osteolysis.     

Polyubiquitination events mediate polymethylmethacrylate (PMMA) particle activation of NF-kappaB pathway

The pathologic response to implant wear-debris constitutes a major component of inflammatory osteolysis and remains under intense investigation. Polymethylmethacrylate (PMMA) particles, which are released during implant wear and loosening, constitute a major culprit by virtue of inducing inflammatory and osteolytic responses by macrophages and osteoclasts, respectively. Recent work by several groups has identified important cellular entities and secreted factors that contribute to inflammatory osteolysis. In previous work, we have shown that PMMA particles contribute to inflammatory osteolysis through stimulation of major pathways in monocytes/macrophages, primarily NF-κB and MAP kinases. The former pathway requires assembly of large IKK complex encompassing IKK1, IKK2, and IKKγ/NEMO. We have shown recently that interfering with the NF-κB and MAPK activation pathways, through introduction of inhibitors and decoy molecules, impedes PMMA-induced inflammation and osteolysis in mouse models of experimental calvarial osteolysis and inflammatory arthritis. In this study, we report that PMMA particles activate the upstream transforming growth factor β-activated kinase-1 (TAK1), which is a key regulator of signal transduction cascades leading to activation of NF-κB and AP-1 factors. More importantly, we found that PMMA particles induce TAK1 binding to NEMO and UBC13. In addition, we show that PMMA particles induce TRAF6 and UBC13 binding to NEMO and that lack of TRAF6 significantly attenuates NEMO ubiquitination. Altogether, these observations suggest that PMMA particles induce ubiquitination of NEMO, an event likely mediated by TRAF6, TAK1, and UBC13. Our findings provide important information for better understanding of the mechanisms underlying PMMA particle-induced inflammatory responses.     

The role played by cell-substrate interactions in the pathogenesis of osteoclast-mediated peri-implant osteolysis

Prosthetic wear debris-induced peri-implant osteolysis is a major cause of aseptic loosening after total joint replacement. In this condition, wear particles released from the implant components induce a granulomatous inflammatory reaction at the interface between implant and adjacent bone, leading to progressive bone resorption and loss of fixation. The present study was undertaken to characterize definitively the phenotype of osteoclast-like cells associated with regions of peri-implant focal bone resorption and to compare the phenotypic features of these cells with those of mononucleated and multinucleated cells associated with polyethylene wear particles. Peri-implant tissues were obtained from patients undergoing hip revision surgery for aseptic loosening after total joint replacement. Cells were examined for the expression of several markers associated with the osteoclast phenotype using immunohistochemistry, histochemistry, and/or in situ hybridization. CD68 protein, a marker expressed by multiple macrophage lineage cell types, was detected in mononucleated and multinucleated cells associated with polyethylene particles and the bone surface. Cathepsin K and tartrate-resistant acid phosphatase were expressed highly in both mononucleated and multinucleated cells associated with the bone surface. Levels of expression were much lower in cells associated with polyethylene particles. High levels of β₃ integrin protein were detected in cells in contact with bone. Multinucleated cells associated with polyethylene particles exhibited faint positive staining. Calcitonin receptor mRNA expression was detected solely in multinucleated cells present in resorption lacunae on the bone surface and was absent in cells associated with polyethylene particles. Our findings provide further evidence that cells expressing the full repertoire of osteoclast phenotypic markers are involved in the pathogenesis of peri-implant osteolysis after total joint replacement. They also demonstrate that foreign body giant cells, although believed to be phenotypically and functionally distinct from osteoclasts, express many osteoclast-associated genes and gene products. However, the levels and patterns of expression of these genes in the two cell types differ. We speculate that, in addition to the role of cytokines and growth factors, the substrate with which these cells interact plays a critical role in their differential phenotypic and functional properties.     

Infiltration of neutrophils following injection of apoptotic cells into the peritoneal cavity

It has been assumed that apoptosis leads to no production of pro-inflammatory cytokines or the production of anti-inflammatory cytokines in vivo, although the response of macrophages following phagocytosis of apoptotic cells in vivo has not been examined. In this study we therefore examined the response to apoptotic cells in vivo. Injection of apoptotic cells into the peritoneal cavity of mice led to transient neutrophil infiltration and concomitant production of MIP-2, a mouse homologue of IL-8. Apoptotic cells were phagocytosed by macrophages, as revealed on two-color flow cytometric analysis and microscopic observation. When the mice were depleted of macrophages by pretreatment with liposome-encapsulated dichloromethylene bisphosphonate, both neutrophil infiltration and MIP-2 production were significantly suppressed, suggesting that macrophages are required for MIP-2 production in this in vivo response. These results support the hypothesis that extensive apoptosis occurring rapidly may induce an inflammatory response in vivo.     

Molecular pathways in aseptic loosening of orthopaedic endoprosthesis

Operative joint replacement to treat disabling joint conditions secondary to degenerative and inflammatory arthritides has become one of the most efficacious and cost-effective procedures to relieve pain and restore joint function. However, prosthetic implants are not built to last forever and osteolysis and aseptic loosening has been associated with prosthetic arthroplasties since their introduction. The functional life of a synthetic joint is influenced by many factors including the material of the implant, operation procedures and the surgeon involved, as well as patient-related factors. Although promising developments have been achieved in this field, more than 10% of all implants still have to undergo operative revision within 15 years after the initial operation. Failure due to sepsis, fractures and dislocations has become rare; premature loosening of implants on the other hand is becoming much more important. Prosthetic loosening without concurrent infection or trauma is called aseptic loosening. It is generally accepted that small particles ("wear debris") and activated macrophages play a key role in aseptic loosening. The pathophysiology of this condition, however, is still not very well characterized. In this article, we review the molecular mechanisms and signal pathways that were unravelled as responsible factors for loosening orthopaedic implants. Finally, we discuss possible novel strategies for future therapeutic approaches.     

磷酸三钙磨损颗粒诱导小鼠假体周围骨细胞损伤的作用

目的：研究磷酸三钙（TCP）磨损颗粒是否能诱导小鼠颅骨假体周围骨细胞损伤,并探讨其作用机制。方法：36只雄性ICR小鼠随机分为3组（n=12）：假手术组（Sham）、模型（TCP）组和3-甲基腺嘌呤（3-MA）组,采用TCP磨损颗粒30 mg置于小鼠颅骨中缝骨膜外缝合皮肤构建小鼠颅骨溶解模型。3-MA处理组小鼠于术后第2天颅顶皮下注射自噬的特异性抑制剂3-MA （1.0 mg/kg）,2 d 1次,2周后处死动物取血清和颅骨。Micro-CT分析各组小鼠颅骨骨密度（BMD）、骨体积分数（BVF）和骨吸收孔（porosity）数;HE染色和流式细胞术检测各组假体周围骨细胞活性及凋亡情况;ELISA法检测各组血清中骨细胞特征蛋白牙本质基质蛋白（DMP-1）和骨硬化蛋白（SOST）水平;Western blot法检测各组假体周围骨细胞中DMP-1、SOST和自噬关键分子Beclin-1及微管相关蛋白1轻链3（LC-3）等蛋白的表达。结果：与Sham组比较,TCP组假体周围骨细胞活性明显降低,骨细胞死亡及凋亡显著增加（P<0.05）,血清SOST水平及其蛋白表达明显增加,而血清DMP-1水平及其蛋白表达显著减少（P<0.05）,Beclin-1表达增加,LC-3I向LC-3Ⅱ转换明显增加;与TCP组比较,3-MA组假体周围骨细胞损伤明显加重,骨细胞凋亡显著增加（P<0.05）。结论：TCP磨损颗粒可通过激活凋亡和自噬而诱导假体周围骨细胞损伤,促进假体周围骨溶解和关节无菌性松动。     

Daphnetin attenuates LPS-induced osteolysis and RANKL mediated osteoclastogenesis through suppression of ERK and NFATc1 pathways

Aseptic prosthetic loosening and periprosthetic infection resulting in inflammatory osteolysis is a leading complication of total joint arthroplasty (TJA). Excessive bone destruction around the bone and prosthesis interface plays a key role in the loosening prostheses leading to revision surgery. The bacterial endotoxins or implant-derived wear particles-induced inflammatory response is the major cause of the elevated osteoclast formation and activity. Thus, agents or compounds that can attenuate the inflammatory response and/or inhibit the elevated osteoclastogenesis and excessive bone resorption would provide a promising therapeutic avenue to prevent aseptic prosthetic loosening in TJA. Daphnetin (DAP), a natural coumarin derivative, is clinically used in Traditional Chinese Medicine for the treatment of rheumatoid arthritis due to its anti-inflammatory properties. In this study, we report for the first time that DAP could protect against lipopolysaccharide-induced inflammatory bone destruction in a murine calvarial osteolysis model in vivo. This protective effect of DAP can in part be attributed to its direct inhibitory effect on RANKL-induced osteoclast differentiation, fusion, and bone resorption in vitro. Biochemical analysis found that DAP inhibited the activation of the ERK and NFATc1 signaling cascades. Collectively, our findings suggest that DAP as a natural compound has potential for the treatment of inflammatory osteolysis.     

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

The balance between bone formation and bone resorption is closely related to bone homeostasis. Osteoclasts, originating from the monocyte/macrophage lineage, are the only cell type possessing bone resorption ability. Osteoclast overactivity is thought to be the major reason underlying osteoclast‐related osteolytic problems, such as Paget's disease, aseptic loosening of prostheses and inflammatory osteolysis; therefore, disruption of osteoclastogenesis is considered a crucial treatment option for these issues. WKYMVm, a synthetic peptide, which is a potent FPR2 agonist, exerts an immunoregulatory effect. This peptide inhibits the production of inflammatory cytokines, such as (IL)‐1β and TNF‐α, thus regulating inflammation. However, there are only few reports on the role of WKYMVm and FPR2 in osteoclast cytology. In the current study, we found that WKYMVm negatively regulates RANKL‐ and lipopolysaccharide (LPS)‐induced osteoclast differentiation and maturation in vitro and alleviates LPS‐induced osteolysis in animal models. WKYMVm down‐regulated the expression of osteoclast marker genes and resorption activity. Furthermore, WKYMVm inhibited osteoclastogenesis directly through reducing the phosphorylation of STAT3 and NF‐kB and indirectly through the CD9/gp130/STAT3 pathway. In conclusion, our findings demonstrated the potential medicinal value of WKYMVm for the treatment of inflammatory osteolysis.     

RANK, RANKL and OPG in inflammatory arthritis and periprosthetic osteolysis

Elucidation of the receptor activator of nuclear factor kappa B (RANK), its ligand (RANKL) and osteoprotegerin (OPG) as the final effectors of bone resorption has transformed our understanding of metabolic bone diseases and revealed novel therapeutic targets. Activation of the RANK-RANKL signaling pathway is directly responsible for dramatic focal erosions that are observed in inflammatory arthritis and aseptic loosening of orthopaedic implants. While these conditions share many features common to all metabolic bone disorders (e.g., osteoclastic resorption), they exhibit several unique properties, which are highlighted in this review. Most important is the relative inability of bisphosphonate therapy to inhibit osteolysis in joint inflammation and periprosthetic joint loosening and the unexpected effectiveness of anti-cytokine therapy in both rheumatoid and psoriatic arthritis. Herein, we provide a review of the role of RANK, RANKL and OPG in erosive arthritis and periprosthetic osteolysis and discuss the potential of anti-RANKL therapy for these conditions.