Particle-induced Inflammatory Osteolysis Research Articles

The JNK signaling pathway against titanium-particle-induced osteoclastogenesis and bone resorption in vivo.

The c-Jun N-terminal kinases (JNK) signaling pathway may be involved in the regulation of osteoclast development. The purpose of this investigation was to investigate whether SB600125, a JNK inhibitor, could attenuate titanium-particle-induced inflammatory osteolysis in vivo. A total of 45 mice were randomly divided into a Sham group, a Titanium group, and a Titanium + JNK inhibitor group, 15 mice per group. After establishing an air pouch bone graft model, we injected phosphate-buffered saline (PBS), titanium particles, or titanium particles + JNK inhibitor into the air pouch of the three groups. The pouch membranes containing bone implants were taken for morphological and molecular analysis 14 days after the mice were sacrificed. General morphological structure observation results, Hematoxylin and Eosin (H&E)-Stained Sections, anti-tartaric acid phosphatase (TRAP) staining, and the transmission electron microscope showed that SB600125, by inhibiting the expression of JNK, attenuated titanium particle-induced inflammatory osteolysis (p<0.05). Immunohistochemical appearance results and reverse transcription-polymerase chain reaction (RT-PCR) results showed SB600125 reduced expression of IL-6, and TNF-α in osteolytic sites stimulated with wear debris (p<0.05). The Western blot results showed the expression of the p-JNK protein in the titanium particle + SB600125 group was significantly reduced compared to the titanium particle stimulation group (p<0.05). Interfering with the JNK signaling pathway may be beneficial in reducing osteolysis, providing a therapeutic target for preventing and treating aseptic loosening caused by debris-induced inflammatory osteolysis.

Kaempferol attenuates wear particle-induced inflammatory osteolysis via JNK and p38-MAPK signaling pathways

Ethnopharmacological relevanceWear particle-induced inflammatory osteoclast activation is a master contributor to periprosthetic osteolysis, which can cause pathological bone loss and destruction. Hence, inhibiting inflammation and osteoclastogenesis is an important strategy for preventing wear particle-induced osteolysis. To date, there are no FDA-approved non-surgical pharmacotherapies for arresting periprosthetic osteolysis. Kaempferol (KAE), a natural flavonol abundant in many traditional Chinese herbal medicines, has been shown to have protective effects against inflammatory bone diseases such as rheumatoid arthritis, but no previous study has evaluated the effects of KAE on wear particle-induced osteolysis. Aim of the studyThe study aimed to investigate the effects of KAE on wear particle-induced inflammatory osteolysis and osteoclast activation, and further explore the underlying mechanisms. Materials and methodsTiAl6V4 metal particles (TiPs) were retrieved from the prosthesis of patients who underwent revision hip arthroplasty due to aseptic loosening. A mouse calvarial osteolysis model was used to investigate the effects of KAE on wear particle-induced inflammatory osteolysis in vivo. Primary bone marrow-derived macrophages (BMMs) were used to explore the effects of KAE on osteoclast differentiation and bone-resorbing activity as well as the underlying mechanisms in vitro. ResultsIn the present study, we found that KAE alleviated wear particle-induced inflammatory bone loss in vivo and inhibited osteoclast differentiation and function in vitro. Furthermore, we revealed that KAE exerted anti-osteoclastogenic effects by downregulating JNK and p38-MAPK signaling as well as the downstream NFATc1 expression. ConclusionsKAE is an alternative therapeutic agent for preventing and treating periprosthetic osteolysis and aseptic loosening.

Zingerone attenuates Ti particle-induced inflammatory osteolysis by suppressing the NF-κB signaling pathway in osteoclasts.

Aseptic loosening caused by inflammatory osteolysis is one of the most frequent and serious long-term complications after total joint arthroplasty (TJA). Development of a new therapeutic drug is required due to the lack of effective therapy and serious adverse effects. This study aimed to explore the pharmacological properties of zingerone (ZO) in attenuating osteoclast-mediated periprosthetic osteolysis and how ZO modulates osteoclastogenesis. The nontoxic concentration of ZO was clarified by the CCK-8 method. Then, we explored the efficacy of ZO on suppressing osteoclast differentiation, F-actin ring formation, bone resorption, and NF-κB luciferase activity in vitro as well as osteoprotection in vivo. Polymerase chain reaction and western blotting were applied to detect the underlying mechanisms involved in osteoclastogenesis. ZO showed an obvious inhibitory effect on osteoclastogenesis and bone resorption in a dose-dependent manner by mainly suppressing the activation of NF-κB signaling pathways. Furthermore, ZO administration successfully attenuated titanium (Ti) particle-stimulated periprosthetic osteolysis and osteoporosis by regulating osteoclast formation. Our findings demonstrated the pharmacological properties of ZO in inhibiting osteoclast formation and function by downregulation of NF-κB signaling activation. As a result, these findings could be expected to provide a novel reagent for regulating inflammatory osteolysis caused by prosthetic loosening.

Novel alendronate-CGS21680 conjugate reduces bone resorption and induces new bone formation in post-menopausal osteoporosis and inflammatory osteolysis mouse models.

Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and μCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.

LY450139 Inhibited Ti-Particle-Induced Bone Dissolution via Suppressing Notch and NF-κB Signaling Pathways

Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint implants. The primary cause of aseptic loosening of the prosthesis is overactive bone resorption caused by wear-particle-activated osteoclasts in both direct and indirect ways. Therefore, drugs that can inhibit differentiation and bone resorption of osteoclasts need investigation as a potential therapeutic strategy to prevent and treat peri-prosthetic osteolysis and thereby prolong the service life of the prosthesis. This study has verified the potential inhibitory effect of LY450139 on inflammatory osteolysis induced by titanium particles in a mice skull model. In addition, we found that LY450139 inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, bone resorption, and podosomal actin belt formation in a dose-dependent manner without evidence of cytotoxicity in vitro. In addition, LY450139 significantly decreased the expression of osteoclast-specific markers, including TRAP, CTSK, V-ATPase d2, CTR, DC-STAMP, NFATc1, and the downstream target gene Hes1 in Notch signaling pathway. Further investigation of the molecular mechanism demonstrated that LY450139 inhibited the formation of osteoclasts via inhibition of the NF-κB and Notch signaling pathways. In summary, LY450139 inhibited the formation of RANKL-mediated osteoclasts via NF-κB and Notch signaling and inhibited Ti particle-induced inflammatory osteolysis in vivo. LY450139 is a potential targeted drug for the treatment of peri-prosthetic osteolysis and other osteolytic disease associated with overactive osteoclasts.

ZnO nanoparticles attenuate polymer-wear-particle induced inflammatory osteolysis by regulating the MEK-ERK-COX-2 axis

Background/ObjectivesAdvanced thermoplastic materials, such as polyether-ether-ketone (PEEK) and highly cross-linked polyethylene (HXLPE), have been increasingly used as orthopaedic implant materials. Similar to other implants, PEEK-on-HXLPE prostheses produce debris from polymer wear that may activate the immune response, which can cause osteolysis, and ultimately implant failure. In this study, we examined whether the anti-inflammatory properties of zinc oxide nanoparticles (ZnO NPs) could attenuate polymer wear particle-induced inflammation.MethodsRAW264.7 ​cells were cultured with PEEK or PE particles and gradient concentrations of ZnO NPs. Intracellular mRNA expression and protein levels of pro-inflammatory factors TNF-α, IL-1β, and IL-6 were detected. An air pouch mouse model was constructed to examine the inflammatory response and expression of pro-inflammatory factors in vivo. Furthermore, an osteolysis rat model was used to evaluate the activation of osteoclasts and destruction of bone tissue induced by polymer particles with or without ZnO NPs. Protein expression of the MEK-ERK-COX-2 pathway was also examined by western blotting to elucidate the mechanism underlying particle-induced anti-inflammatory effects.ResultsZnO NPs (≤50 ​nm, 5 ​μg/mL) showed no obvious cytotoxicity and attenuated PEEK or PE particle-induced inflammation and inflammatory osteolysis by reducing MEK and ERK phosphorylation and decreasing COX-2 expression.ConclusionZnO NPs (≤50 ​nm, 5 ​μg/mL) attenuated polymer wear particle-induced inflammation via regulation of the MEK-ERK-COX-2 axis. Further, ZnO NPs reduced bone tissue damage caused by particle-induced inflammatory osteolysis.The translational potential of this articlePolymer wear particles can induce inflammation and osteolysis in the body after arthroplasty. ZnO NPs attenuated polymer particle-induced inflammation and inflammatory osteolysis. Topical use of ZnO NPs and blended ZnO NP/polymer composites may provide promising approaches for inhibiting polymer wear particle-induced inflammatory osteolysis, thus expanding the range of polymers used in joint prostheses.

LY450139 Inhibited Ti-Particle-Induced Bone Dissolution via Suppressing Notch and NF-κB Signaling Pathways

Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint implants. The primary cause of aseptic loosening of the prosthesis is overactive bone resorption caused by wear-particle-activated osteoclasts in both direct and indirect ways. Therefore, drugs that can inhibit differentiation and bone resorption of osteoclasts need investigation as a potential therapeutic strategy to prevent and treat periprosthetic osteolysis and thereby prolong the service life of the prosthesis. This study has verified the potential inhibitory effect of LY450139 on inflammatory osteolysis induced by titanium particles in a mouse skull model. In addition, we found that LY450139 inhibited receptor activator of NF-κB ligand(RANKL)-induced osteoclast differentiation, bone resorption, and podosomal actin belt formation in a dose-dependent manner without evidence of cytotoxicity in vitro. In addition, LY450139 significantly decreased the expression of osteoclast-specific markers, including TRAP, CTSK, V-ATPase d2, CTR, DC-STAMP, NFATc1 and downstream target gene Hes1 in the Notch signaling pathway. Further investigation of the molecular mechanism demonstrated that LY450139 inhibited the formation of osteoclasts via inhibition of the NF-κB and Notch signaling pathways. In summary, LY450139 inhibited the formation of RANKL-mediated osteoclasts via NF-κB and Notch signaling and inhibited Ti particle-induced inflammatory osteolysis in vivo. LY450139 is a potential targeted drug for treatment of periprosthetic osteolysis and other osteolytic diseases associated with over-active osteoclasts.

Tetrandrine Inhibits Titanium Particle-Induced Inflammatory Osteolysis through the Nuclear Factor-κB Pathway.

Peri-implant osteolysis (PIO) and the subsequent aseptic loosening are the main reasons for artificial joint implant failure. Existing methods for treating aseptic loosening are far from satisfactory, necessitating advanced drug exploration. This study is aimed at investigating the effect and underlying mechanism of tetrandrine (Tet) on inflammatory osteolysis. We established a Ti particle-induced inflammatory osteolysis mouse model and administered Tet or an equal volume of phosphate-buffered saline (PBS). Two weeks later, specimens were collected. Histological staining showed that Tet administration inhibited Ti-stimulated osteolysis. Tartrate-resistant acid phosphate (TRAP) staining and transmission electron microscopy (TEM) demonstrated that osteoclast formation was remarkably inhibited in the groups treated with Tet in a dose-dependent manner. In addition, relevant inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) were also significantly reduced in the calvaria of the Tet-treated groups. Exposure of receptor activator for nuclear factor-κB ligand- (RANKL-) induced bone marrow-derived macrophages (BMMs) and RAW264.7 cells to Tet significantly reduced osteoclast formation, F-actin ring formation, bone resorption, and the expression of relevant genes (matrix metallopeptidase 9 (MMP-9), TRAP, and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1)) during osteoclastogenesis in vitro. Mechanistic studies using Western blotting demonstrated that Tet inhibited the nuclear factor (NF)-κB signaling pathway by decreasing the phosphorylation of inhibitor of NF-κB α (IκBα) and p65, which play important roles in osteoclast formation. Collectively, our data indicate that Tet suppressed Ti-induced inflammatory osteolysis and osteoclast formation in mice, suggesting that Tet has the potential to be developed to treat and prevent wear particle-induced inflammatory osteolysis.

Nepetin inhibits osteoclastogenesis by inhibiting RANKL-induced activation of NF-κB and MAPK signalling pathway, and autophagy.

Aseptic prosthetic loosening due to wear particle–induced inflammatory osteolysis is the main cause of failure for artificial joint replacement. The inflammatory response and the production of pro‐osteoclastic factors lead to elevation of osteoclast formation and excessive activity results in extensive bone destruction around the bone‐implant interface. Here we showed that Nepetin, a natural bioactive flavonoid with proven anti‐inflammatory and anti‐proliferative properties, potently inhibited RANKL‐induced osteoclast differentiation, formation and bone resorption in vitro, and protected mice against the deleterious effects of titanium particle–induced calvarial osteolysis in vivo. Mechanistically, Nepetin attenuated RANKL‐induced activation of NF‐κB and MAPK signalling pathways and TRAF6‐dependent ubiquitination of Beclin 1 which is necessary for the induction of autophagy. In brief, our study demonstrates the potential therapeutic application of Nepetin against osteoclast‐mediated osteolytic diseases.

ZBTB20 positively regulated titanium particle-induced macrophage inflammatory response and osteolysis

ZBTB20 positively regulated titanium particle-induced macrophage inflammatory response and osteolysis

Puerarin inhibits titanium particle-induced osteolysis and RANKL-induced osteoclastogenesis via suppression of the NF-κB signaling pathway.

Osteolysis around the prosthesis and subsequent aseptic loosening are the main causes of prosthesis failure. Inflammation due to wear particles and osteoclast activation are the key factors in osteolysis and are also potential targets for the treatment of osteolysis. However, it is not clear whether puerarin can inhibit chronic inflammation and alleviate osteolysis. In this study, we investigated the effect of puerarin on Ti particle‐induced inflammatory osteolysis in vivo in rat femoral models and in vitro in receptor activator of nuclear factor kappa‐B ligand (RANKL)‐induced osteoclast activation models. Our in vivo results showed that puerarin significantly inhibited Ti particle‐induced osteolysis and the expression of matrix metallopeptidase 9 (MMP‐9), nuclear factor of activated T cells 1 (NFATc1), tumour necrosis factor (TNF)‐α and interleukin (IL)‐6. In vitro, puerarin prevented RANKL‐induced osteoclast differentiation, bone resorption and F‐actin ring formation in a concentration‐dependent manner. Furthermore, puerarin decreased the phosphorylation of p65 and prevented p65 moving from the cytoplasm to the nucleus. Puerarin also reduced the expression of osteoclast‐specific factors and inhibited the inflammatory response. In conclusion, our study proves that puerarin can block the NF‐κB signalling pathway to inhibit osteoclast activation and inflammatory processes, which provides a new direction for the treatment of osteolysis‐related diseases.

Enalapril inhibits inflammatory osteolysis induced by wear debris in a mouse model.

ObjectiveAseptic loosening, the most frequent complication after total joint replacement, is probably caused by an inflammatory response to the shedding of wear debris from the implant. The only effective treatment is surgical revision. Using a mouse model, we investigated whether enalapril inhibits wear debris-induced inflammatory osteolysis.MethodsTitanium (Ti) alloy particles were introduced, and calvarial bone from syngeneic mice was implanted into air pouches established in BALB/c mice. Histological and molecular analyses were performed with inflammatory tissue samples obtained from mice treated with and without enalapril.ResultsEnalapril inhibited tissue inflammation and inflammatory osteolysis induced by Ti particles, reducing pouch membrane thickness and decreasing inflammatory cell infiltration. In addition, enalapril inhibited the expression of the inflammatory cytokines vascular endothelial growth factor and tumor necrosis factor-α.ConclusionsOur study provides evidence that enalapril inhibits Ti particle-induced inflammatory osteolysis, and it may be a potentially useful treatment for aseptic loosening.

Correction to: Ghrelin Fights against Titanium Particle-Induced Inflammatory Osteolysis through Activation of β-Catenin Signaling Pathway

The original version of this article was published with incorrect Fig.1B. The correct Fig.1B is now presented in Fig.1 shown at the next page.

Lithium chloride with immunomodulatory function for regulating titanium nanoparticle-stimulated inflammatory response and accelerating osteogenesis through suppression of MAPK signaling pathway.

BackgroundWear particle-induced inflammatory osteolysis and the consequent aseptic loosening constitute the leading reasons for prosthesis failure and revision surgery. Several studies have demonstrated that the macrophage polarization state and immune response play critical roles in periprosthetic osteolysis and tissue repair, but the immunomodulatory role of lithium chloride (LiCl), which has a protective effect on wear particle-induced osteolysis by suppressing osteoclasts and attenuating inflammatory responses, has never been investigated.MethodsIn this work, the immunomodulatory capability of LiCl on titanium (Ti) nanoparticle-stimulated transformation of macrophage phenotypes and the subsequent effect on osteogenic differentiation were investigated. We first speculated that LiCl attenuated Ti nanoparticle-stimulated inflammation responses by driving macrophage polarization and generating an immune micro-environment to improve osteogenesis. Furthermore, a metal nanoparticle-stimulated murine air pouch inflammatory model was applied to confirm this protective effect in vivo.ResultsThe results revealed that metal nanoparticles significantly activate M1 phenotype (proinflammatory macrophage) expression and increase proinflammatory cytokines secretions in vitro and in vivo, whereas LiCl drives macrophages to the M2 phenotype (anti-inflammatory macrophage) and increases the release of anti-inflammatory and bone-related cytokines. This improved the osteogenic differentiation capability of rat bone marrow mesenchymal stem cells (rBMSCs). In addition, we also provided evidence that LiCl inhibits the phosphorylation of the p38 mitogen-activated protein kinase (p38) and extracellular signal-regulated kinase (ERK) pathways in wear particle-treated macrophages.ConclusionLiCl has the immunomodulatory effects to alleviate Ti nanoparticle-mediated inflammatory reactions and enhance the osteogenic differentiation of rBMSCs by driving macrophage polarization. Thus, LiCl may be an effective therapeutic alternative for preventing and treating wear debris-induced inflammatory osteolysis.

Crocin inhibits titanium particle-induced inflammation and promotes osteogenesis by regulating macrophage polarization

Wear particle-induced periprosthetic inflammatory osteolysis and resultant aseptic loosening are major causes of orthopedic implant failure, for which there are no effective treatments other than revision surgery. Crocin, a carotenoid compound derived from crocus flowers, has anti-inflammatory properties, but its immunomodulatory function and role in particle-induced osteolysis are not well characterized. Here we report the effect of crocin on titanium (Ti) particle-induced macrophage polarization and osteogenic differentiation. We found that crocin induced anti-inflammatory (M2) macrophage polarization and attenuated Ti particle-induced inflammation by promoting the expression of anti-inflammatory cytokines in vitro as well as in vivo in a mouse air-pouch model. Additionally, crocin pre-treated macrophages promoted osteogenic differentiation of co-cultured mouse bone mesenchymal stem cells (BMSCs). These effects were mediated via inhibition of p38 and c-Jun N-terminal kinase signaling. Our results indicate that crocin suppresses Ti particle-induced inflammation and enhances osteogenic differentiation of BMSCs by inducing M2 macrophage polarization, highlighting its therapeutic potential for preventing wear particle-induced osteolysis.

Targeting vascular endothelial growth factor ameliorates PMMA-particles induced inflammatory osteolysis in murine calvaria.

Cytokines and growth factors mediate inflammatory osteolysis in response to particles released from bone implants. However, the mechanism by which this process develops is not entirely clear. Blood vessels and related factors may be required to deliver immune cells and soluble factors to the injury site. Therefore, in the current study we investigated if, vascular endothelial growth factor (VEGF), which is required for angiogenesis, mediates polymethylmethacrylate (PMMA) particles-induced osteolysis. Using bone marrow derived macrophages (BMMs) and ST2 stromal cell line, we show that PMMA particles increase VEGF expression. Further, using a murine calvarial osteolysis model, we found that PMMA injection over calvaria induce significant increase in VEGF expression as well as new vessel formation, represented by von Willebrand factor (vWF) staining. Co-treatment using a VEGF-neutralizing antibody abrogated expression of vWF, indicating decreased angiogenesis. Finally, VEGF neutralizing antibody reduced expression of Tumor necrosis factor (TNF) and decreased osteoclastogenesis induced by PMMA particles in calvariae. This work highlights the significance of angiogenesis, specifically VEGF, as key driver of PMMA particle-induced inflammatory osteolysis, inhibition of which attenuates this response.

Protection Effect of Curcumin for Macrophage-Involved Polyethylene Wear Particle-Induced Inflammatory Osteolysis by Increasing the Cholesterol Efflux.

BackgroundPeriprosthetic osteolysis, induced by wear particles and inflammation, is a common reason for failure of primary arthroplasty. Curcumin, a nature phenol from plants, has been reported to reduce the inflammation in macrophages. This study aimed to investigate the potential effect of curcumin on macrophage involved, wear particle-induced osteolysis and its mechanism.Material/MethodsRAW264.7 macrophages were used to test the effects of polyethylene (PE) particles and curcumin on macrophage cholesterol efflux and phenotypic changes. A mouse model of PE particle-induced calvarial osteolysis was established to test the effects of curcumin in vivo. After 14 days of treatment, the bone quality of the affected areas was analyzed by micro-computed tomography (micro-CT) and histology, and the bone surrounding soft tissues were analyzed at the cellular and molecular levels.ResultsWe found that PE particles can stimulate osteoclastogenesis and produce an M1-like phenotype in macrophages in vitro. Curcumin enhanced the cholesterol efflux in macrophages, and maintained the M0-like phenotype under the influence of PE particles in vitro. Additionally, the cholesterol transmembrane regulators ABCA1, ABCG1, and CAV1 were enhanced by curcumin in vivo. We also found enhanced bone density, reduced osteoclastogenesis, and fewer inflammatory responses in the curcumin treated groups in our mouse osteolysis model.ConclusionsOur study findings indicated that curcumin can inhibit macrophage involved osteolysis and inflammation via promoting cholesterol efflux. Maintaining the cholesterol efflux might be a potential strategy to prevent periprosthetic osteolysis after total joint arthroplasty surgery.

Inhibitory effects of melatonin on titanium particle-induced inflammatory bone resorption and osteoclastogenesis via suppression of NF-κB signaling.

Wear debris-induced chronic inflammation, osteoclastic activation and osteoblastic inhibition have been identified as critical factors of peri-implant bone loss. We previously demonstrated that melatonin, a bioactive indolamine secreted mainly by the pineal gland, activates Wnt/β-catenin signaling pathway and enhances bone regeneration at osteolytic site in vivo. In the current study, we further demonstrated that melatonin significantly suppresses wear debris-induced bone resorption and inflammatory cytokine expression in vivo. In addition, melatonin inhibits receptor activator of nuclear factor kappa-B ligand induced osteoclast formation and osteoclastic bone resorption in vitro. Meanwhile, we found that melatonin mediates its anti-inflammation and anti-bone resorption effects by abrogating nuclear factor kappa-B activation. These results further support the protective effects of melatonin on wear debris-induced peri-implant bone loss, and strongly suggest that melatonin could be considered as a potential candidate for the prevention and treatment of wear debris-induced osteolysis and subsequent aseptic loosening.

Probiotics protect mice from CoCrMo particles-induced osteolysis.

Wear particle-induced inflammatory osteolysis is the primary cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure in the med- and long term. Recent studies have suggested an important role of gut microbiota (GM) in modulating the host metabolism and immune system, leading to alterations in bone mass. Probiotic bacteria administered in adequate amounts can alter the composition of GM and confer health benefits to the host. Given the inflammatory osteolysis that occurs in wear debris-induced prosthesis loosening, we examined whether the probiotic Lactobacillus casei could reduce osteolysis in a mouse calvarial resorption model. In this study, L. casei markedly protected mice from CoCrMo particles (CoPs)-induced osteolysis. Osteoclast gene markers and the number of osteoclasts were significantly decreased in L. casei-treated mice. Probiotic treatment decreased the M1-like macrophage phenotype indicated by downregulation of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) and increased the M2-like macrophage phenotype indicated by upregulation of IL-4, IL-10 and arginase. Collectively, these results indicated that the L. casei treatment modulated the immune status and suppressed wear particle-induced osteolysis in vivo. Thus, probiotic treatment may represent a potential preventive and therapeutic approach to reduced wear debris-induced osteolysis.

Anthocyanin suppresses CoCrMo particle-induced osteolysis by inhibiting IKKα/β mediated NF-κB signaling in a mouse calvarial model

Wear particle-induced osteolysis and bone resorption have been identified as critical factors of implant failure and total joint revision, in which nuclear factor kappa B (NF-κB) signaling and chronic inflammation have been shown to play key roles. Although anthocyanin is known to have anti-inflammatory function via blocking NF-κB pathway, it is still unclear whether anthocyanin has a protective effect on particle-induced osteolysis. In the present study, we aimed to investigate the detailed effects and the underlying mechanism of anthocyanin on CoCrMo particle-induced osteolysis in a mouse calvavial model. One hundred and twelve male BALB/c mice were divided randomly into four groups: sham group (sham operation and injection with PBS), vehicle group (CoCrMo particle treatment and injection with PBS), low-dose anthocyanin group (CoCrMo particle treatment and injecting anthocyanin with 0.1mg/g/day), and high-dose anthocyanin group (CoCrMo particle treatment and injecting anthocyanin with 0.4mg/g/day). Mice were sacrificed after two weeks, harvesting the calvariae tissue for in depth analysis by micro-CT, histomorphometry, immunohistochemical and molecular biology analysis. As expected, anthocyanin markedly inhibited CoCrMo particle-induced inflammatory infiltration and decreased bone loss in vivo. Anthocyanin also reversed the increase in the ratio of receptor activator of nuclear factor kappa B ligand (RANKL)/osteoproteger (OPG) and suppressed osteoclast formation in CoCrMo particle-stimulated calvaria. Additionally, anthocyanin significantly reduced the expression and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the calvaria of CoCrMo-stimulated mice. Furthermore, we confirmed that anthocyanin attenuated osteolysis by blocking NF-κB pathway via inhibiting inhibitor of nuclear factor kappa-B kinase α/β (IKKα/β) phosphorylation. In conclusion, our study demonstrated that anthocyanin can protect against CoCrMo particle-induced inflammatory osteolysis via inhibiting the IKKα/β-NF-κB pathway, and have a potential therapeutic effect on the treatment of wear particle-induced osteolysis.