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Background/Objectives: Periprosthetic osteolysis is the primary cause of arthroplasty failure in the majority of patients. Mechanistically, wear debris released from the articulating surfaces of a prosthesis initiates local inflammation and several modes of regulated cell death programs, such as ferroptosis, which represents a promising therapeutic target in various chronic inflammatory diseases. Thus, the current study aimed at exploring the therapeutic potential of targeting ferroptosis in a polyethylene-wear-debris-induced osteolysis model. Methods: Inverted cell culture model was used for stimulating the cells with wear debris in vitro, and calvarial osteolysis model was used for evaluating the therapeutic effects of inhibitors in vivo. Results: The immunostaining of periprosthetic bone tissues demonstrated a number of osteocytes expressing ferroptosis markers. Likewise, the expressions of ferroptosis markers were confirmed in polyethylene-wear-debris-stimulated osteocyte-like cells and primary osteoblasts in a direct stimulation model but not in an indirect stimulation model. Furthermore, polyethylene wear debris was implanted onto calvarial bone and mice were treated with the ferroptosis inhibitors DFO and Fer-1. These treatments alleviated the inflammatory and pathological bone resorption induced by the wear debris implantation. Conclusions: Our data broaden the knowledge of the pathogenesis of periprosthetic osteolysis and highlight ferroptosis as a promising therapeutic target. [ABSTRACT FROM AUTHOR]

BACKGROUND: Linagliptin exhibits the capacity to regulate macrophage polarization, shifting them from the pro-inflammatory M1 phenotype towards the antiinflammatory M2 phenotype. This alteration results in a dampened release of inflammatory mediators, thereby mitigating local inflammation. OBJECTIVE: To explore the effects of linagliptin on macrophage polarization, osteoclast activation, and inflammatory osteolysis elicited by wear particles. METHODS: (1) Cell experiments: For macrophage polarization, RAW264.7 cells were cultured and divided into four groups: the control group received highglucose culture medium; the M1-induced group received M1-inducing culture medium (high-glucose culture medium containing 100 ng/mL lipopolysaccharide and 20 ng/mL interferon-γ) to simulate an inflammatory environment; the low- and high-dose linagliptin groups were treated with 50 and 200 nmol/L linagliptin, respectively, for 4 hours before exposure to M1-inducing culture medium. After 24 hours of macrophage polarization induction, immunofluorescence staining and RT-PCR were performed. For osteoclast activation, RAW264.7 cells were cultured and divided into four groups: the control group was cultured with high-glucose culture medium, the osteoclast-induced group and low- and high-dose linagliptin groups were subjected to osteoclast induction. After osteoclast formation, cells were treated with linagliptin (50 and 200 nmol/L) for 3 days. Subsequently, cell tartrate-resistant acid phosphatase staining and RT-PCR were performed. (2) Animal experiments: Twenty-four male C57BL/6J mice were randomly divided into four groups: sham operation group, model group, low-dose linagliptin group, and high-dose linagliptin group. The model group, low-dose linagliptin group, and high-dose linagliptin group were induced to establish a cranial bone resorption model by injecting titanium particle suspension onto the surface of the skull. Starting from the 2nd day after modeling, the low- and high-dose linagliptin groups were orally administered linagliptin (2 and 10 mg/kg, respectively) once daily. After modeling for 3 weeks, serum macrophage polarization marker protein and inflammatory factor levels were detected; skull samples were collected for micro-CT scanning, bone parameter analysis, and hematoxylin-eosin staining to evaluate osteolysis and morphological changes. RESULTS AND CONCLUSION: (1) Cell experiments: Both low and high doses of linagliptin significantly suppressed M1 polarization while promoting M2 polarization compared to the M1-induced group (P < 0.01). Notably, the high-dose group exhibited a more pronounced inhibitory effect (P < 0.01). Inflammatory factor mRNA expression was elevated in the M1-induced group compared with the control group (P < 0.01), whereas inflammatory factor mRNA expression was significantly lower in the low- and high-dose linagliptin groups compared with the M1-induced group (P < 0.01). There was a significant upregulation of mRNA expression of osteoclast functional markers in the osteoclast-induced group compared with the control group (P < 0.01). Conversely, both low and high doses of linagliptin led to a substantial downregulation of mRNA expression of these markers compared with the osteoclast-induced group (P < 0.01), with the high-dose group exhibiting a more pronounced reduction. (2) Animal experiments: Titanium particle implantation induced cranial bone resorption damage in mice. Treatment with linagliptin effectively mitigated this bone resorption, with the high-dose group showing superior efficacy. To conclude, linagliptin has been shown to modulate macrophage polarization, inhibit osteoclast activation, and have a protective effect on the skeletal system. [ABSTRACT FROM AUTHOR]

The development of strategies for the prevention and treatment of aseptic loosening of prostheses stands as a critical area of global research interest. The pyroptosis of local macrophages triggered by wear particles plays a pivotal role in the onset of periprosthetic osteolysis and subsequent loosening. Extracellular vesicles, carrying the surface components and regulatory molecules of their parent cells, embody the cellular characteristics and biological functions of these progenitors. In a pioneering approach to precisely inhibit the pyroptosis of local macrophages induced by wear particles, we have engineered fused extracellular vesicles (fEV) from M2 macrophages and human umbilical cord mesenchymal stem cells. These fEV boast the distinctive capability for targeted transport and immune evasion, collectively enhancing the anti‐pyroptosis effect of the therapeutic extracellular vesicles. Our research demonstrates the targeted, significant preventive and therapeutic potential of fEVs against periprosthetic osteolysis prompted by wear particles, highlighting its crucial clinical significance and application prospects. These findings suggest that extracellular vesicle fusion technology heralds a novel paradigm in the design and development of targeted extracellular vesicle‐based drug delivery systems. [ABSTRACT FROM AUTHOR]

The scientific literature suggests that, if periprosthetic osteolysis (PPO) is not treated, it may have a negative impact on the results of a total hip replacement and possibly result in failure. This systematic review aimed to determine the efficacy of using bisphosphonates preventatively to limit PPO after a total hip arthroplasty (THA). Methods: A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PICOS template was developed to ensure a structured approach. A search for relevant studies was performed across four databases, including Pubmed, Scopus, Embase, and Cochrane. They were all last searched on March 1st and were assessed using the Cochrane risk of bias tool for randomised studies. Results: The final analysis included seven studies with a total of 126 study group participants and 144 control group participants. The studies looked at Bony Mass Density in terms of bone loss on Gruen's femoral zones after THA in a bisphosphonate (treatment) and control group (placebo/no treatment). The analysis revealed a statistically significant difference (p < 0.05) in favour of the bisphosphonate group in many of the included studies at 6, 12, and 24 postoperative months. Conclusions: This systematic review and meta-analysis, using the most recent applicable studies, showed the efficacy of bisphosphonates in limiting periprosthetic osteolysis after THA in a period between 6 and 24 postoperative months. Future studies should focus increasing group sizes and collecting results beyond the 2-year mark. [ABSTRACT FROM AUTHOR]

BACKGROUND: In addition to apoptosis, recent studies have discovered novel forms of programmed cell death in periprosthetic osteolysis, which is involved in regulating local chronic inflammation and the outcome of osteoblast and osteoclast under pathological conditions. This has an important value for the treatment and prognosis of periprosthetic osteolysis. OBJECTIVE: To provide new ideas and strategies for the prevention and treatment of periprosthetic osteolysis by summarizing studies on the novel forms of programmed cell death. METHODS: The first author used the computer to search the articles published from 2005 to 2022. Chinese search terms “wear particles, periprosthetic osteolysis, programmed cell death, apoptosis, autophagy, pyroptosis, necrotizing apoptosis, iron death” were used to search the databases of CNKI, WanFang and VIP. English search terms “osteolysis, wear debris, wear particles, peri*prosthetic osteolysis, PPOL, aseptic loosening, autophagy, regulated cell death, programmed cell death, apoptosis, pyroptosis, autophagic cell death, autophagy, necroptosis, ferroptosis” were used for search in PubMed and Web of Science databases. A total of 68 articles were finally included according to the inclusion criteria. RESULTS AND CONCLUSION: (1) Inadequate or excessive activation of autophagy can cause cell death, inhibit bone formation, and promote bone resorption, leading to bone metabolism disorders and osteolysis. (2) Recent studies have paid close attention to pyroptosis in periprosthetic osteolysis, where the Nod-like receptor, pyrin containing 3 inflammasome plays an important role in local inflammation. Inhibiting pyroptosis can effectively alleviate osteolysis. (3) In vitro studies have shown that necroptosis can inhibit the formation and function of osteoblasts and osteoclasts, affecting the process of osteolysis and destruction. (4) Ferroptosis is the newest form of programmed cell death, which is regulated by complex signaling pathways and mechanisms, but is not yet fully understood. (5) Autophagy, pyroptosis, necroptosis, and ferroptosis play important roles in the development of periprosthetic osteolysis, and their associated signaling pathways and genes require further investigation. [ABSTRACT FROM AUTHOR]

Aseptic loosening around the prosthesis is a common cause of failure in total joint arthroplasty. Polyethylene wear particles trigger the release of inflammatory factors by macrophages. Key mediators involved in osteoclastogenesis include interleukin-6, tumor necrosis factor-α, receptor activator of nuclear factor kappa B (RANK), RANK ligand (RANKL), and bone protection hormone (Osteoprotegerin [OPG]). The purpose of our experiment was to see whether melittin can slow down the release of inflammatory mediators through the NF-kB pathway, regulate the RANKL/OPG ratio, reduce osteoclast formation, and delay the onset of arthritis in rats. A total of 20 male Sprague-Dawley rats (10 months, Specific Pathogen Free, 350 g ± 20 g) were randomly divided into 5 groups: sham group, model group, melittin concentration 1 group (0.2 mg/kg), concentration 2 group (0.4 mg/kg), and concentration 3 group (0.6 mg/kg). All rats were implanted with TA2 high-purity titanium rods. A drill was used to create a bone canal along the long axis of the femur in the intercondylar notch. The model group and experimental groups were exposed to polyethylene particles, while the sham group did not receive any particles. The melittin group exhibited significantly increased serum levels of serum P, calcium-phosphorus product, OPG, PINP, PINP/CTX-I, and OPG/RANKKL (P <.05). In the experimental group, micro computed tomography scanning results revealed a decrease in the amount of bone defect around the prosthesis. Immunofluorescence analysis demonstrated a decrease in the expression of IKKα and P65, while the expression of OPG showed an upward trend. Both Hematoxylin-Eosin and Tartrate-Resistant Acid Phosphatase staining revealed less osteoclast and inflammatory cell infiltration in bone resorption pits. Our study demonstrates that melittin has the ability to inhibit the NF-kB pathway in a rat model, and reduce the impact of RANKL/OPG, thereby delaying osteoclast activity and alleviating periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

Wear particles produced by joint replacements induce inflammatory responses that lead to periprosthetic osteolysis and aseptic loosening. However, the precise mechanisms driving wear particle-induced osteolysis are not fully understood. Recent evidence suggests that autophagy, a cellular degradation process, plays a significant role in this pathology. This study aimed to clarify the role of autophagy in mediating inflammation and osteolysis triggered by wear particles and to evaluate the therapeutic potential of zinc oxide nanoparticles (ZnO NPs).We incorporated ZnO into the prosthetic material itself, ensuring that the wear particles inherently carried ZnO, providing a targeted and sustained intervention. Our findings reveal that polymer wear particles induce excessive autophagic activity, which is closely associated with increased inflammation and osteolysis. We identified secretory autophagy as a key mechanism for IL-1β secretion, exacerbating osteolysis. Both in vitro and in vivo experiments demonstrated that ZnO-doped particles significantly inhibit autophagic overactivation, thereby reducing inflammation and osteolysis.In summary, this study establishes secretory autophagy as a critical mechanism in wear particle-induced osteolysis and highlights the potential of ZnO-doped prosthetic polymers for targeted, sustained mitigation of periprosthetic osteolysis.

Background/Objectives: Periprosthetic osteolysis is the primary cause of arthroplasty failure in the majority of patients. Mechanistically, wear debris released from the articulating surfaces of a prosthesis initiates local inflammation and several modes of regulated cell death programs, such as ferroptosis, which represents a promising therapeutic target in various chronic inflammatory diseases. Thus, the current study aimed at exploring the therapeutic potential of targeting ferroptosis in a polyethylene-wear-debris-induced osteolysis model. Methods: Inverted cell culture model was used for stimulating the cells with wear debris in vitro, and calvarial osteolysis model was used for evaluating the therapeutic effects of inhibitors in vivo. Results: The immunostaining of periprosthetic bone tissues demonstrated a number of osteocytes expressing ferroptosis markers. Likewise, the expressions of ferroptosis markers were confirmed in polyethylene-wear-debris-stimulated osteocyte-like cells and primary osteoblasts in a direct stimulation model but not in an indirect stimulation model. Furthermore, polyethylene wear debris was implanted onto calvarial bone and mice were treated with the ferroptosis inhibitors DFO and Fer-1. These treatments alleviated the inflammatory and pathological bone resorption induced by the wear debris implantation. Conclusions: Our data broaden the knowledge of the pathogenesis of periprosthetic osteolysis and highlight ferroptosis as a promising therapeutic target.

Wear particle‐induced periprosthetic osteolysis is the key to aseptic loosening after artificial joint replacement. Osteoclastogenesis plays a central role in this process. Apelin‐13 is a member of the adipokine family with anti‐inflammatory effects. Here, we report that apelin‐13 alleviates RANKL‐mediated osteoclast differentiation and titanium particle‐induced osteolysis in mouse calvaria. Mechanistically, apelin‐13 inhibits NLRP3 inflammasome‐mediated pyroptosis by activating the nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway. In summary, apelin‐13 is expected to be a potential drug for relieving aseptic osteolysis. Research Highlights: This study reveals the molecular mechanism by which apelin‐13 inhibits NLRP3 inflammasome activation and pyroptosis by promoting Nrf2.This study confirms that apelin‐13 alleviates osteoclast activation by inhibiting pyroptosis.In vivo studies further confirmed that apelin‐13 alleviated mouse skull osteolysis by inhibiting the activation of NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

BACKGROUND: Tabersonine has shown good therapeutic effects in diseases such as myocardial remodeling, acute kidney injury and lung injury due to its an inflammatory biological activity. Prosthetic wear particles often lead to aseptic inflammation, and the massive release of inflammatory factors further promotes periprosthetic bone destruction and bone loss; however, there are no basic studies on the efficacy of tabersonine on periprosthetic osteolysis. OBJECTIVE: To investigate the effects of tabersonine on osteoclast activation, expression of inflammatory factors and inflammatory osteolysis induced by wear particles. METHODS: (1) Cell experiment: RAW264.7 cells were divided into four groups for culture. A complete medium was added in the control group. Osteoclast induction medium (50 ng/mL RANKL+complete medium) was added to the osteoclast induction group. 1 and 5 μmol/L tabersonine was added for 4 hours, and then osteoclast induction medium was added to the low- and high-dose tabersonine groups, respectively. After 5 days of induction, tartrate-resistant acid phosphatase staining, F-actin staining and RT-PCR were performed. (2) Animal experiments: Twenty C57BL/6J mice were randomly divided into sham operation group, osteolysis group, low-dose tabersonine group and high-dose tabersonine group (n=5 per group). Skull osteolysis model of the skull was established by injecting titanium pellets on the skull surface in the osteolysis group, low-dose tabersonine group and high-dose tabersonine group. On day 2 after model establishment, mice in the low-dose and high-dose tabersonine groups received intraperitoneal injections of 10 and 20 mg/kg tabersonine every 2 days, respectively. 2 weeks after surgery, mouse sera were collected for detecting inflammatory factors (interleukin 1β, interleukin 6, and tumor necrosis factor α), and cranial bones were collected for micro-CT scan and bone parameter analysis. RESULTS AND CONCLUSION: (1) Cellular experiments: Tartrate-resistant acid phosphatase staining and F-actin staining showed that compared with the osteoclast induction group, low-dose and high-dose tabersonine significantly inhibited osteoclast activation and bone resorption, and the inhibition was more significant in the high-dose tabersonine group. RT-PCR results showed that compared with the control group, the mRNA expressions of three kinds of inflammatory factors were increased in the osteoclast induction group (P < 0.01). Compared with the osteoclast induction group, the mRNA expressions of three kinds of inflammatory factors were decreased in low- and high-dose tabersonine groups (P < 0.01), and the decrease was more obvious in the highdose tabersonine group. (2) Animal experiments: Compared with the sham operation group, the levels of three kinds of inflammatory factors were increased in the osteolysis group (P < 0.01). Compared with the osteolysis group, the levels of three kinds of inflammatory factors were decreased in the low- and highdose tabersonine groups (P < 0.05, P < 0.01), and the decrease was more obvious in the high-dose tabersonine group. The micro-CT scan results revealed that titanium particles caused the destruction of cranial osteolysis, and tabersonine could inhibit the osteolysis induced by titanium particles, especially in the highdose tabersonine group. (3) The results confirm that tabersonine can enhance the osteolysis and bone destruction induced by titanium particles by inhibiting the release of inflammatory factors and down-regulating the bone absorption function of osteoclasts. [ABSTRACT FROM AUTHOR]

Abstract The wear particle-induced dissolution of bone around implants is a significant pathological factor in aseptic loosening, and controlling prosthetic aseptic loosening holds crucial social significance. While human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exos, Exos) have been found to effectively promote osteogenesis and angiogenesis, their role in periprosthetic osteolysis remains unexplored. To enhance their in vivo application, we engineered HucMSCs-Exos-encapsulated poly lactic-co-glycolic acid (PLGA) nanoparticles (PLGA-Exos). In our study, we demonstrate that PLGA-Exos stimulate osteogenic differentiation while inhibiting the generation of reactive oxygen species (ROS) and subsequent osteoclast differentiation in vitro. In vivo imaging revealed that PLGA-Exos released exosomes slowly and maintained a therapeutic concentration. Our in vivo experiments demonstrated that PLGA-Exos effectively suppressed osteolysis induced by polyethylene particles. These findings suggest that PLGA-Exos hold potential as a therapeutic approach for the prevention and treatment of periprosthetic osteolysis. Furthermore, they provide novel insights for the clinical management of osteolysis.

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The scientific literature suggests that, if periprosthetic osteolysis (PPO) is not treated, it may have a negative impact on the results of a total hip replacement and possibly result in failure. This systematic review aimed to determine the efficacy of using bisphosphonates preventatively to limit PPO after a total hip arthroplasty (THA). Methods: A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PICOS template was developed to ensure a structured approach. A search for relevant studies was performed across four databases, including Pubmed, Scopus, Embase, and Cochrane. They were all last searched on March 1st and were assessed using the Cochrane risk of bias tool for randomised studies. Results: The final analysis included seven studies with a total of 126 study group participants and 144 control group participants. The studies looked at Bony Mass Density in terms of bone loss on Gruen’s femoral zones after THA in a bisphosphonate (treatment) and control group (placebo/no treatment). The analysis revealed a statistically significant difference (p < 0.05) in favour of the bisphosphonate group in many of the included studies at 6, 12, and 24 postoperative months. Conclusions: This systematic review and meta-analysis, using the most recent applicable studies, showed the efficacy of bisphosphonates in limiting periprosthetic osteolysis after THA in a period between 6 and 24 postoperative months. Future studies should focus increasing group sizes and collecting results beyond the 2-year mark.

Classically, particle-induced periprosthetic osteolysis at the implant-bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3+, CD4+, and CD8+) and B cells (CD20+) coexisting with CD68+/TRAP- multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recent evidence suggests that autophagy, as a cell self-protection mechanism, plays an important role in regulating osteoblast function and maintaining osteoblast homeostasis. It has an important influence on the treatment and prognosis of periprosthetic osteolysis. OBJECTIVE: To provide new therapeutic ideas and potential therapeutic targets for periprosthetic osteolysis by summarizing previous studies on the autophagy mechanism of osteoblasts. METHODS: The first author used the computer to search the articles published from 2015 to 2022. In Chinese, the search terms “wear particles, periprosthetic osteolysis, osteoblasts, signal pathways, autophagy” were used to search the databases of CNKI, WanFang, and VIP. In English, the PubMed and Web of Science databases were retrieved with “wear debris, wear particles, peri*prosthetic osteolysis, PPOL, aseptic loosening, osteoblast, OB, signal path, autophagy”. A total of 98 articles were included according to the inclusion criteria. RESULTS AND CONCLUSION: In periprosthetic osteolysis, the changes in the autophagy ability of osteoblasts induced by wear particles play a key role in the development and outcome of the disease. A variety of signaling pathways jointly mediate autophagy in osteoblasts, among which the key pathways include AMPK/ULK1/mTOR, nuclear factor-κB, Pink1/Parkin, etc. AMPK, mTOR, and ULK1 can regulate each other and jointly maintain the stability of the autophagy level. There is a complex crosstalk between the nuclear factor-κB pathway and autophagy. PINK1 and Parkin are accumulated on the surface of the damaged mitochondrial membrane, inducing autophagy. There is crosstalk among multiple signaling pathways, which form a complex autophagy network under their mutual influence. Moreover, the activation of the same autophagy pathway in different cells may bring about completely opposite effects. Moderate autophagy induced by wear particles can reduce the apoptosis of osteoblasts, enhance their differentiation and mineralization ability, and improve the prognosis of osteolysis around the prosthesis. On the contrary, insufficient or excessive activation of autophagy will cause damage to osteoblasts and promote the progress of osteolysis. Therefore, targeting the level of autophagy of osteoblasts induced by wear particles through drugs or genes may be one of the directions for the treatment of periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

The wear particle-induced dissolution of bone around implants is a significant pathological factor in aseptic loosening, and controlling prosthetic aseptic loosening holds crucial social significance. While human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exos, Exos) have been found to effectively promote osteogenesis and angiogenesis, their role in periprosthetic osteolysis remains unexplored. To enhance their in vivo application, we engineered HucMSCs-Exos-encapsulated poly lactic-co-glycolic acid (PLGA) nanoparticles (PLGA-Exos). In our study, we demonstrate that PLGA-Exos stimulate osteogenic differentiation while inhibiting the generation of reactive oxygen species (ROS) and subsequent osteoclast differentiation in vitro. In vivo imaging revealed that PLGA-Exos released exosomes slowly and maintained a therapeutic concentration. Our in vivo experiments demonstrated that PLGA-Exos effectively suppressed osteolysis induced by polyethylene particles. These findings suggest that PLGA-Exos hold potential as a therapeutic approach for the prevention and treatment of periprosthetic osteolysis. Furthermore, they provide novel insights for the clinical management of osteolysis. [ABSTRACT FROM AUTHOR]

Classically, particle-induced periprosthetic osteolysis at the implant–bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3+, CD4+, and CD8+) and B cells (CD20+) coexisting with CD68+/TRAP− multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants.

BACKGROUND: Theaflavin-3,3'-digallate has shown a good therapeutic effect in animal models of osteoporosis by inhibiting osteoclast formation, but there are few studies on osteogenesis. OBJECTIVE: To investigate the effect of theaflavin-3,3'-digallate on periprosthetic osteolysis. METHODS: (1) In vitro test: The MC3T3-E1 cells with good growth status were selected and cultured in four groups. The control group was added with osteogenic differentiation medium; the titanium particle group was added with titanium particles + osteogenic differentiation medium; the low-dose group was added with titanium particles + theaflavin-3,3'-digallate (1 mg/L) + osteogenic differentiation medium; high-dose group was added with titanium particles + theaflavin-3,3'-digallate (10 mg/L) + osteogenic differentiation medium. After 2 weeks of osteogenic induction, alkaline phosphatase staining was performed; after 3 weeks of osteogenic induction, alizarin red staining was performed. (2) In vivo experiment: 32 C57BL/6J mice were randomly divided into 4 groups. The blank control group did not receive any treatment. In the model group, sterile titanium particles were evenly placed on the surface of the skull to establish an osteolysis model. The low-dose group and high-dose group were injected intraperitoneally with 1, 10 mg/(kg·d) theaflavin-3,3'-digallate into osteolysis model mice. The mouse skull was analyzed by micro-CT 2 weeks after operation. RESULTS AND CONCLUSION: (1) In vitro experiments: alkaline phosphatase and alizarin red staining showed that titanium particles could inhibit alkaline phosphatase activity and mineralized nodule formation in MC3T3-E1 cells, and theaflavins-3,3'-bisgallate could inhibit the effect of titanium particles and was dose-dependent. (2) In vivo experiments: micro-CT scans showed that titanium particles could induce osteolysis around the skull, and high-dose theaflavin3,3'-digallate could inhibit the osteolysis caused by titanium particles. (3) The results showed that theaflavin-3,3'-digallate could promote the osteogenic differentiation of MC3T3-E1 and inhibit periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

Periprosthetic osteolysis (PPO) induced by wear particles is the most severe complication of total joint replacement; however, the mechanism behind PPO remains elusive. Previous studies have shown that osteocytes play important roles in wear-particle-induced osteolysis. In this study, we investigated the effects of connexin 43 (Cx43) on the regulation of osteocyte-to-osteoblast differentiation. We established an in vivo murine model of calvarial osteolysis induced by titanium (Ti) particles. The osteolysis characteristic and osteogenesis markers in the osteocyte-selective Cx43 (CKO)-deficient and wild-type (WT) mice were observed. The calvarial osteolysis induced by Ti particles was partially attenuated in CKO mice. The expression of β-catenin and osteogenesis markers increased significantly in CKO mice. In vitro, the osteocytic cell line MLO-Y4 was treated with Ti particles. The co-culturing of MLO-Y4 cells with MC3T3-E1 osteoblastic cells was used to observe the effects of Ti-treated osteocytes on osteoblast differentiation. When Cx43 of MLO-Y4 cells was silenced or overexpressed, β-catenin was detected. Additionally, co-immunoprecipitation detection of Cx43 and β-catenin binding in MLO-Y4 cells and MC3T3-E1 cells was performed. Finally, β-catenin expression in MC3T3-E1 cells and osteoblast differentiation were evaluated after 18α-glycyrrhetinic acid (18α-GA) was used to block the intercellular communication of Cx43 between MLO-Y4 and MC3T3-E1 cells. Ti particles increased Cx43 expression and decreased β-catenin expression in MLO-Y4 cells. The silencing of Cx43 increased the β-catenin expression, and the over-expression of Cx43 decreased the β-catenin expression. In the co-culture model, Ti treatment of MLO-Y4 cells inhibited the osteoblastic differentiation of MC3T3-E1 cells and Cx43 silencing in MLO-Y4 cells attenuated the inhibitory effects on osteoblastic differentiation. With Cx43 silencing in the MLO-Y4 cells, the MC3T3-E1 cells, co-cultured alongside MLO-Y4, displayed decreased Cx43 expression, increased β-catenin expression, activation of Runx2, and promotion of osteoblastic differentiation in vitro co-culture. Finally, Cx43 expression was found to be negatively correlated to the activity of the Wnt signaling pathway, mostly through the Cx43 binding of β-catenin from its translocation to the nucleus. The results of our study suggest that Ti particles increased Cx43 expression in osteocytes and that osteocytes may participate in the regulation of osteoblast function via the Cx43 during PPO. [ABSTRACT FROM AUTHOR]

The most common cause for prosthetic revision surgery is wear particle-induced periprosthetic osteolysis, which leads to aseptic loosening of the prosthesis. Both SOST gene and its synthetic protein, sclerostin, are hallmarks of osteocytes. According to our previous findings, blocking SOST induces bone formation and protects against bone loss and deformation caused by titanium (Ti) particles by activating the Wnt/β-catenin cascade. Although SOST has been shown to influence osteoblasts, its ability to control wear-particle-induced osteolysis via targeting osteoclasts remains unclear. Mice were subjected to development of a cranial osteolysis model. Micro CT, HE staining, and TRAP staining were performed to evaluate bone loss in the mouse model. Bone marrow-derived monocyte-macrophages (BMMs) made from the C57BL/6 mice were exposed to the medium of MLO-Y4 (co-cultured with Ti particles) to transform them into osteoclasts. Bioinformatics methods were used to predict and validate the interaction among SOST, Wnt/β-catenin, RANKL/OPG, TNF-α, and IL-6. Local bone density and bone volume improved after SOST inhibition, both the number of lysis pores and the rate of skull erosion decreased. Histological research showed that β-catenin and OPG expression were markedly increased after SOST inhibition, whereas TRAP and RANKL levels were markedly decreased. In-vitro, Ti particle treatment elevated the expression of sclerostin, suppressed the expression of β-catenin, and increased the RANKL/OPG ratio in the MLO-Y4 cell line. TNF-α and IL-6 also elevated after treatment with Ti particles. The expression levels of NFATc1, CTSK, and TRAP in osteoclasts were significantly increased, and the number of positive cells for TRAP staining was increased. Additionally, the volume of bone resorption increased at the same time. In contrast, when SOST expression was inhibited in the MLO-Y4 cell line, these effects produced by Ti particles were reversed. All the results strongly show that SOST inhibition triggered the osteocyte Wnt/β-catenin signaling cascade and prevented wear particle-induced osteoclastogenesis, which might reduce periprosthetic osteolysis. Key messages: SOST is a molecular regulator in maintaining bone homeostasis. SOST plays in regulating bone homeostasis through the Wnt/β-catenin signaling pathway. SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis. [ABSTRACT FROM AUTHOR]

Background Periprosthetic osteolysis is a serious complication following total hip arthroplasty (THA). However, most orthopedic surgeons only focus on bone loss and hip reconstruction. Thus, it was required to understand the treatment algorithm for periprosthetic osteolysis integrally. Case Presentation A 52‐year‐old Asian male presented with chronic hip pain. A mass appeared on the medial side of the proximal left thigh at more than 20 years after bilateral THA. Radiographs revealed catastrophic periprosthetic osteolysis, especially on the acetabular side. Large amounts of necrotic tissue and bloody fluids were thoroughly debrided during revision THA. A modular hemipelvic prosthesis was used for revision of the left hip. Four years later, the patient presented with right hip pain, where a mass appeared on the medial side of the proximal right thigh. A primary acetabular implant with augment was used for revision of the right hip. Laboratory evaluation of bloody fluid retrieved from surgery revealed elevated levels of inflammatory markers. Conclusion Inflammatory responses to polyethylene wear debris can lead to severe bone resorption and aseptic loosening in the long‐term following THA. Therefore, in spite of revision THA, interrupting the cascade inflammatory might be the treatment principle for periprosthetic osteolysis.

Abstract Periprosthetic osteolysis (PPO) triggered by wear particles is the most severe complication of total joint replacement (TJR) surgeries, representing the major cause of implant failure, which is public health concern worldwide. Previous studies have confirmed the specialized role of osteoclast-induced progressive bone destruction in the progression of PPO. Additionally, the reactive oxygen species (ROS) induced by wear particles can promote excessive osteoclastogenesis and bone resorption. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), a cellular enzyme, is considered to be responsible for the production of ROS and the formation of mature osteoclasts. However, NOX4 involvement in PPO has not yet been elucidated. Therefore, we investigated the mechanism by which NOX4 regulates osteoclast differentiation and the therapeutic effects on titanium nanoparticle-induced bone destruction. We found that NOX4 blockade suppressed osteoclastogenesis and enhanced the scavenging of intracellular ROS. Our rescue experiment revealed that nuclear factor-erythroid 2-related factor 2 (Nrf2) silencing reversed the effects of NOX4 blockade on ROS production and osteoclast differentiation. In addition, we found increased expression levels of NOX4 in PPO tissues, while NOX4 inhibition in vivo exerted protective effects on titanium nanoparticle-induced osteolysis through antiosteoclastic and antioxidant effects. Collectively, these findings suggested that NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway and that NOX4 blockade may be an attractive therapeutic approach for preventing PPO. Graphical Abstract

Circular RNAs (circRNAs) are often found in eukaryocyte and have a role in the pathogenesis of a variety of human disorders. Our related research has shown the differential expression of circRNAs in periprosthetic osteolysis (PPOL). However, the involvement of circRNAs in the exact process is yet unknown. CircSLC8A1 expression was evaluated in clinical samples and human bone marrow mesenchymal stem cells (hBMSCs) in this investigation using quantitative real‐time PCR. In vitro and in vivo studies were conducted to explicate its functional role and pathway. We demonstrated CircSLC8A1 is involved in PPOL using gain‐ and loss‐of‐function methods. The association of CircSLC8A1 and miR‐144‐3p, along with miR‐144‐3p and RUNX1, was predicted using bioinformatics. RNA pull‐down and luciferase assays confirmed it. The impact of CircSLC8A1 in the PPOL‐mouse model was also investigated using adeno‐associated virus. CircSLC8A1 was found to be downregulated in PPOL patients' periprosthetic tissues. Overexpression of CircSLC8A1 promoted osteogenic differentiation (OD) and inhibited apoptosis of hBMSCs in vitro. The osteogenic markers of RUNX1, osteopontin (OPN) and osteocalcin (OCN) were significantly upregulated in hBMSCs after miR‐144‐3p inhibitor was transferred. Mechanistic analysis demonstrated that CircSLC8A1 directly bound to miR‐144‐3p and participated in PPOL through the miR‐144‐3p/RUNX1 pathway in hBMSCs. Micro‐CT and quantitative analysis showed that CircSLC8A1 markedly inhibited PPOL, and osteogenic markers (RUNX1, OPN and OCN) were significantly increased (P<0.05) in the mice model. Our findings prove that CircSLC8A1 exerted a regulatory role in promoting osteogenic differentiation in hBMSCs, and CircSLC8A1/miR‐144‐3p/RUNX1 pathway may provide a potential target for prevention of PPOL. [ABSTRACT FROM AUTHOR]

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Abstract Background Mitochondrial calcium uniporter (MCU) is an important ion channel regulating calcium transport across the mitochondrial membrane. Calcium signaling, particularly via the Ca2+/NFATc1 pathway, has been identified as an important mediator of the osteoclast differentiation that leads to osteolysis around implants. The present study aimed to investigate whether down-regulation of MCU using microRNA-25 (miR-25) mimics could reduce osteoclast differentiation induced upon exposure to titanium (Ti) particles. Methods Ti particles were prepared. Osteoclast differentiation of RAW264.7 cells was induced by adding Ti particles and determined by TRAP staining. Calcium oscillation was determined using a dual-wavelength technique. After exposure of the cells in each group to Ti particles or control medium for 5 days, relative MCU and NFATc1 mRNA expression levels were determined by RT-qPCR. MCU and NFATc1 protein expression was determined by western blotting. NFATc1 activation was determined by immunofluorescence staining. Comparisons among multiple groups were conducted using one-way analysis of variance followed by Tukey test, and differences were considered significant if p

Abstract Wear particle-induced periprosthetic osteolysis (PPO) have become a major reason of joint arthroplasty failure and secondary surgery following joint arthroplasty and thus pose a severe threat to global public health. Therefore, determining how to effectively suppress particle-induced PPO has become an urgent problem. The pathological mechanism involved in the PPO signaling cascade is still unclear. Recently, the interaction between osteogenic inhibition and wear particles at the implant biological interface, which has received increasing attention, has been revealed as an important factor in pathological process. Additionally, Hedgehog (Hh)-Gli1 is a crucial signaling cascade which was regulated by multiple factors in numerous physiological and pathological process. It was revealed to exert a crucial part during embryonic bone development and metabolism. However, whether Hh-Gli1 is involved in wear particle-induced osteogenic inhibition in PPO remains unknown. Our present study explored the mechanism by which the Hh-Gli1 signaling cascade regulates titanium (Ti) nanoparticle-induced osteolysis. We found that Hh-Gli1 signaling was dramatically downregulated upon Ti particle treatment. Mechanistically, glycogen synthesis kinase 3β (GSK-3β) activation was significantly increased in Ti particle-induced osteogenic inhibition via changes in GSK-3β phosphorylation level and was found to participate in the posttranslational modification and degradation of the key transcription factor Gli1, thus decreasing the accumulation of Gli1 and its translocation from the cytoplasm to the nucleus. Collectively, these findings suggest that the Hh-Gli1 signaling cascade utilizes a GSK3β-mediated mechanism and may serve as a rational new therapeutic target against nanoparticle-induced PPO. Graphical Abstract

Joint replacement surgery is one of the orthopedic surgeries with high successful rates; however, wear debris generated from prostheses can ultimately lead to periprosthetic osteolysis and failure of the implant. The implant-derived particulate debris such as ultrahigh molecular weight polyethylene (UHMWPE) can initiate the local immune response and recruit monocytic cells to phagocytose particles for generating reactive oxygen species (ROS). ROS induces osteoclastogenesis and macrophages to secrete cytokines which ultimately promote the development of osteolysis. In this work, we develop the few-layered Nb2C (FNC) as an antioxidant which possesses the feature of decreasing the production of cytokines and inhibiting osteoclastogenesis by its ROS adsorption. Moreover, local injection of FNC attenuates the UHMWPE-induced osteolysis in a mouse calvarial model. In sum, our results suggest that FNC can be used for treating osteolytic bone disease caused by excessive osteoclastogenesis.

Periprosthetic osteolysis (PPO) induced by wear particles is an important cause of aseptic loosening after artificial joint replacement, among which the imbalance of osteogenesis and osteoclastic processes occupies a central position. The cells involved in PPO mainly include osteoclasts (macrophages), osteoblasts, osteocytes, and fibroblasts. RANKL/RANK/OGP axis is a typical way for osteolysis. Autophagy, a mode of regulatory cell death and maintenance of cellular homeostasis, has a dual role in PPO. Although autophagy is activated in various periprosthetic cells and regulates the release of inflammatory cytokines, osteoclast activation, and osteoblast differentiation, its beneficial or detrimental role remains controversy. In particular, differences in the temporal control and intensity of autophagy may have different effects. This article focuses on the role of autophagy in PPO, and expects the regulation of autophagy to become a powerful target for clinical treatment of PPO.

Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and subsequent revision surgery, however, the precise molecular mechanism underlying PPO remains unclear. Aseptic inflammation triggered by metal particles, resulting in the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts may be the decisive factor. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by gasdermins (GSDMs) family, among which GSDMD is the best characterized. Recent evidence indicates that activation of NLRP3 inflammasomes and pyroptosis play a pivotal role in the pathological process of PPO. Here, we review the pathological process of PPO, the molecular mechanism of pyroptosis and the interventions to inhibit the inflammation and pyroptosis of different cells during the PPO. Conclusively, this review provides theoretical support for the search for new strategies and new targets for the treatment of PPO by inhibiting pyroptosis and inflammation. [ABSTRACT FROM AUTHOR]

Periprosthetic osteolysis (PPO) remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles. Previous studies have shown that inhibition of osteoblastic differentiation is the most widespread incident affecting the interface of trabecular and loosening prostheses. Additionally, the NLRP3 inflammasome is activated by prosthetic particles. Sirtuin3, an NAD+-dependent deacetylase of mitochondria, regulates the function of mitochondria in diverse activities. However, whether SIRT3 can mitigate wear debris-induced osteolysis by inhibiting the NLRP3 inflammasome and enhancing osteogenesis has not been previously reported. Therefore, we investigated the role of SIRT3 during the process of titanium (Ti) particle-induced osteolysis. We revealed that upregulated SIRT3 dramatically attenuated Ti particle-induced osteogenic inhibition through suppression of the NLRP3 inflammasome and improvement of osteogenesis in vivo and in vitro. Moreover, we found that SIRT3 interference in the process of Ti particle-induced osteolysis relied on the GSK-3β/β-catenin signalling pathway. Collectively, these findings indicated that SIRT3 may serve as a rational new treatment against debris-induced PPO by deacetylase-dependent inflammasome attenuation.

Our research revealed that AKBA can reduce the oxidative stress injury of osteoblasts induced by Ti particles and reduce the apoptosis of osteoblasts by up-regulating the expression of Prdx3 and inhibiting the expression of Nox4. This protective effect may be related to AKBA's regulation of Foxo3 expression in osteoblasts. The antioxidation and anti-apoptosis effects of AKBA can alleviate the cranial osteolysis induced by Ti particles in mice. [Display omitted] • Ti particles exacerbate the oxidative stress injury of osteoblasts. • AKBA alleviates the oxidative stress induced by Ti particles. • AKBA alleviates oxidative stress by regulating FOXO3. Oxidative stress injury in osteoblasts is one of the leading causes of periprosthetic osteolysis (PPOL). Acetyl-11-keto-β-boswellia acid (AKBA) has been used as an antioxidant in the treatment of various diseases, but its antioxidant mechanism in osteolysis has yet to be elucidated. In this study, a mouse cranial osteolysis model was constructed, and MC3T3-E1 cells and bone marrow mesenchymal stem cells (BMSCs) were cultured in vitro. Western blotting and immunofluorescence staining revealed that titanium (Ti) particles aggravated osteoblast oxidative stress injury and apoptosis. Ti particles and hydrogen peroxide reduced the osteogenic ability of BMSCs. At a certain concentration, AKBA alleviated the oxidative stress injury of MC3T3-E1 cells induced by Ti particles and enhanced the osteogenic ability of BMSCs, and the expression of Forkhead box O3 (Foxo3) increased with increasing AKBA concentration. To verify the antioxidant mechanism of AKBA, we designed and synthesized Foxo3-targeting siRNAs. We found that after Foxo3 expression was inhibited, the protective effect of AKBA on osteoblasts decreased significantly. Moreover, AKBA treatment suppressed bone mass loss in the skull mediated by Ti particles in mice. Therefore, we suggest that AKBA alleviates the oxidative stress injury in osteoblasts induced by Ti particles, at least in part, by regulating the expression of Foxo3. In this study, the mechanism and biosafety of AKBA in treating PPOL were demonstrated to some extent. [ABSTRACT FROM AUTHOR]

Background: Periprosthetic osteolysis is a serious complication following total hip arthroplasty (THA). However, most orthopedic surgeons only focus on bone loss and hip reconstruction. Thus, it was required to understand the treatment algorithm for periprosthetic osteolysis integrally. Case Presentation: A 52‐year‐old Asian male presented with chronic hip pain. A mass appeared on the medial side of the proximal left thigh at more than 20 years after bilateral THA. Radiographs revealed catastrophic periprosthetic osteolysis, especially on the acetabular side. Large amounts of necrotic tissue and bloody fluids were thoroughly debrided during revision THA. A modular hemipelvic prosthesis was used for revision of the left hip. Four years later, the patient presented with right hip pain, where a mass appeared on the medial side of the proximal right thigh. A primary acetabular implant with augment was used for revision of the right hip. Laboratory evaluation of bloody fluid retrieved from surgery revealed elevated levels of inflammatory markers. Conclusion: Inflammatory responses to polyethylene wear debris can lead to severe bone resorption and aseptic loosening in the long‐term following THA. Therefore, in spite of revision THA, interrupting the cascade inflammatory might be the treatment principle for periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

Periprosthetic osteolysis (PPO) triggered by wear particles is the most severe complication of total joint replacement (TJR) surgeries, representing the major cause of implant failure, which is public health concern worldwide. Previous studies have confirmed the specialized role of osteoclast-induced progressive bone destruction in the progression of PPO. Additionally, the reactive oxygen species (ROS) induced by wear particles can promote excessive osteoclastogenesis and bone resorption. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), a cellular enzyme, is considered to be responsible for the production of ROS and the formation of mature osteoclasts. However, NOX4 involvement in PPO has not yet been elucidated. Therefore, we investigated the mechanism by which NOX4 regulates osteoclast differentiation and the therapeutic effects on titanium nanoparticle-induced bone destruction. We found that NOX4 blockade suppressed osteoclastogenesis and enhanced the scavenging of intracellular ROS. Our rescue experiment revealed that nuclear factor-erythroid 2-related factor 2 (Nrf2) silencing reversed the effects of NOX4 blockade on ROS production and osteoclast differentiation. In addition, we found increased expression levels of NOX4 in PPO tissues, while NOX4 inhibition in vivo exerted protective effects on titanium nanoparticle-induced osteolysis through antiosteoclastic and antioxidant effects. Collectively, these findings suggested that NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway and that NOX4 blockade may be an attractive therapeutic approach for preventing PPO. [ABSTRACT FROM AUTHOR]

Introduction Osteolysis is a common problem in the long-term outcome after total hip arthroplasty, since the wear of a polyethylene liner is an inevitable process. However, its pace depends on many factors and not all of them have been proven. In particular, many studies do not find a connection between the wear rate of the liner and the position of the acetabular component. The purpose of this publication is to demonstrate the importance of correct acetabular component positioning. Methods A clinical case of bilateral total hip arthroplasty with follow-ups after 17 and 19 years is presented. The patient was operated being 31 and 33 years old, respectively, by one surgeon. The same type of the acetabular component was installed with the same type of polyethylene and friction pair diameter. It eliminates implant or surgical approach factors and patient characteristics. The position of the implant components is then remains the most important factor. For analysis, there were radiographs before the operation, at different times after it, CT data and intraoperative photos during the revision surgery. Results At the time of the last examination, there were minor manifestations of retroacetabular osteolysis that were better seen in CT and were more pronounced on the right. CT radiometry data on the angles of inclination of the acetabular components were 50.6° and 46.7° on the right and left, respectively, and the anversion was 40.3° and 25.4°. Revision of the right total hip arthroplasty was performed and it was found that the liner wear extended till the metal layer. Given good fixation of the cup, only the liner was exchanged and osteolytic cavities were filled with allogenic bone chips. Discussion The case can be considered a very good result of primary arthroplasty as revision surgery in this young patient was performed only after 17 years. However, in the contralateral joint the implant with the same pair of friction has survived for 19 years and at the moment it is early to decide on its revision. In our opinion, this case is an excellent illustration of the importance of the correct positioning of implant components.

Wear particulate debris-induced osteoclast over-activation is a major causative factor in periprosthetic osteolysis and aseptic loosening, resulting in the non-infectious failure of total joint arthroplasty. To mitigate such pathological bone loss, various therapeutic targets have been identified. Oxidative stress is one of the main contributing factors in the promotion of osteoclastogenesis. Herein, using a template-assisted approach, hollow ruthenium oxide (RuO 2 ) nanospheres are synthesized as an effective antioxidant for the treatment of CoCrMo alloy particles-induced osteolysis. Hollow RuO 2 significantly suppressed receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis, bone resorption, and the expression of specific markers (including NFATc1, c-Fos, MMP9, CTSK, and DC-STAMP) of bone marrow-derived macrophages via inhibition of the nuclear factor kappa-B (NF-κB) and tumor necrosis factor (TNF)-α pathways. In mouse calvaria, hollow RuO 2 nanozymes demonstrate an appreciable attenuation in osteoclast differentiation, bone loss, and soft tissue malformations induced by CoCrMo alloy particles. This study envisions that the antioxidant nanozymes may be further applied as a therapeutic entity in the prevention and treatment of other inflammatory and oxidative stress-related ailments., (© 2024 Wiley‐VCH GmbH.)

Introduction: Total hip arthroplasty (THA) is one of the most successful and effective surgeries for the treatment of hip osteoarthritis, with good rates in terms of survival, pain relief, and patient functional recovery. Aseptic loosening (AL) accompanied by periprosthetic osteolysis (PPOL) is the most frequent late complication, accounting for almost 50% of all revision surgeries. The primary purpose of this observational, cross-sectional study is to identify alterations in small, non-coding RNAs, miRNAs, that could be involved in the pathogenesis of AL and PPOL following THA., Methods/design: Sixty-three patients will be included in this study and will be divided into three groups (21 in each group): Group A (control group), including patients undergoing primary THA due to degenerative hip osteoarthritis, Group B including patients without clinical and radiological evidence of PPOL/AL following primary THA, and Group C including patients with clinical and radiological evidence of PPOL and AL undergoing revision surgery following primary THA. Blood samples will be collected from all patients. Peripheral blood samples from Group A and C patients will be collected prior to surgery while synovial membrane samples will also be collected intraoperatively. Synovial membrane samples will not be collected from Group B patients since they are not candidates for any surgical intervention. The relative expression of miRNAs let-7i-5p, let-7e-5p, miR-15a-5p, miR-30a-3p, and miR-130a-3p, will be measured using real-time quantitative PCR (qRT-PCR) at baseline from all patients., Conclusion: The primary goal is to identify the expression of inflammation-related miRNAs that could play a role in the pathophysiology of AL and highlight the differences among patients with confirmed AL, patients with degenerative hip disease, and patients with no signs of AL following THA. The secondary goal is to use these miRNAs as biomarkers to estimate the possibility for a patient to develop AL after total hip replacement, and also as possible treatment targets. Our study has been registered with an International Standard Randomized Controlled Trial Number ID: ISRCTN25839413., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Research and Ethics Committee of University Hospital of Patras (Rion, Patras, 26500, Greece) issued approval 164/20.04.2021. This study was approved by the Research and Ethics Committee of University Hospital of Patras (Rion, Patras, 26500, Greece), on 22/03/2021, with reference number: 164/20.04.2021. All participants provided written informed consent prior to enrollment. This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Papagiannis et al.)

Background: Inflammatory osteolysis induced by wear particles is the major cause of prosthetic loosening after artificial joint replacement, and its prevention and treatment are difficult worldwide. Our previous study confirmed that sphingosine kinases (SPHKs) are important mediators regulating the wear particle-induced macrophage inflammatory response. However, it is unclear whether SPHKs can modulate chronic inflammation and alleviate osteolysis. Zoledronic acid (ZA), an imidazole-containing bisphosphonate, directly affects osteoclasts and prevents bone mineral-related diseases. However, the effects of SPHK inhibitors and ZA used to treat periprosthetic osteolysis are unknown.Methods: We applied tartrate-resistant acid phosphatase (TRAP) staining to evaluate bone destruction in the interface membranes of patients with aseptic loosening and a control group. A murine calvarial osteolysis model was used to examine the preventative effect of SPHK inhibitors and ZA on osteolysis. Micro-CT scanning, immunohistochemistry (IHC), and histomorphometric analysis were conducted to determine the variations in inflammatory osteolysis. The effects of different drug concentrations on cell viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to confirm the reduced expression of osteoclast-specific genes after drug and titanium treatment. The osteoclast formation and functions of the drugs were analyzed using TRAP staining in vivo and in vitro. The effect of SPHKs/S1P-TRAF2-BECN1 signaling pathways was verified via RT-qPCR and tissue IHC.Results: In this study, we found that SPHK inhibitors (ABC294640 and FTY720) combined with ZA decreased the degree of inflammatory osteolysis in vivo. However, ABC294640 and ZA suppressed osteoclast differentiation and osteoclast-specific genes in vitro. SPHKs regulate the inflammatory osteolysis induced by wear particles by increasing the expression of SPHKs/S1P-TRAF2-BECN1.Conclusion: Our study revealed that wear particles could induce inflammatory osteolysis by upregulating SPHKs/S1P-TRAF2-BECN1 and SPHK inhibitors/ZA inhibit osteoclastogenesis in vitro and prevent inflammatory osteolysis in vivo, suggesting that SPHK inhibitors and ZA can be a new perspective and scientific basis for the prevention and treatment of prosthesis loosening.

Wear particle-induced periprosthetic osteolysis (PPO) have become a major reason of joint arthroplasty failure and secondary surgery following joint arthroplasty and thus pose a severe threat to global public health. Therefore, determining how to effectively suppress particle-induced PPO has become an urgent problem. The pathological mechanism involved in the PPO signaling cascade is still unclear. Recently, the interaction between osteogenic inhibition and wear particles at the implant biological interface, which has received increasing attention, has been revealed as an important factor in pathological process. Additionally, Hedgehog (Hh)-Gli1 is a crucial signaling cascade which was regulated by multiple factors in numerous physiological and pathological process. It was revealed to exert a crucial part during embryonic bone development and metabolism. However, whether Hh-Gli1 is involved in wear particle-induced osteogenic inhibition in PPO remains unknown. Our present study explored the mechanism by which the Hh-Gli1 signaling cascade regulates titanium (Ti) nanoparticle-induced osteolysis. We found that Hh-Gli1 signaling was dramatically downregulated upon Ti particle treatment. Mechanistically, glycogen synthesis kinase 3β (GSK-3β) activation was significantly increased in Ti particle-induced osteogenic inhibition via changes in GSK-3β phosphorylation level and was found to participate in the posttranslational modification and degradation of the key transcription factor Gli1, thus decreasing the accumulation of Gli1 and its translocation from the cytoplasm to the nucleus. Collectively, these findings suggest that the Hh-Gli1 signaling cascade utilizes a GSK3β-mediated mechanism and may serve as a rational new therapeutic target against nanoparticle-induced PPO. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial calcium uniporter (MCU) is an important ion channel regulating calcium transport across the mitochondrial membrane. Calcium signaling, particularly via the Ca2+/NFATc1 pathway, has been identified as an important mediator of the osteoclast differentiation that leads to osteolysis around implants. The present study aimed to investigate whether down-regulation of MCU using microRNA-25 (miR-25) mimics could reduce osteoclast differentiation induced upon exposure to titanium (Ti) particles. Methods: Ti particles were prepared. Osteoclast differentiation of RAW264.7 cells was induced by adding Ti particles and determined by TRAP staining. Calcium oscillation was determined using a dual-wavelength technique. After exposure of the cells in each group to Ti particles or control medium for 5 days, relative MCU and NFATc1 mRNA expression levels were determined by RT-qPCR. MCU and NFATc1 protein expression was determined by western blotting. NFATc1 activation was determined by immunofluorescence staining. Comparisons among multiple groups were conducted using one-way analysis of variance followed by Tukey test, and differences were considered significant if p < 0.05. Results: MCU expression was reduced in response to miR-25 overexpression during the process of RAW 264.7 cell differentiation induced by Ti particles. Furthermore, osteoclast formation was inhibited, as evidenced by the low amplitude of calcium ion oscillation, reduced NFATc1 activation, and decreased mRNA and protein expression levels of nuclear factor-κB p65 and calmodulin kinases II/IV. Conclusions: Regulation of MCU expression can impact osteoclast differentiation, and the underlying mechanism likely involves the Ca2+/NFATc1 signal pathway. Therefore, MCU may be a promising target in the development of new strategies to prevent and treat periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

Background: Inflammatory osteolysis induced by wear particles is the major cause of prosthetic loosening after artificial joint replacement, and its prevention and treatment are difficult worldwide. Our previous study confirmed that sphingosine kinases (SPHKs) are important mediators regulating the wear particle-induced macrophage inflammatory response. However, it is unclear whether SPHKs can modulate chronic inflammation and alleviate osteolysis. Zoledronic acid (ZA), an imidazole-containing bisphosphonate, directly affects osteoclasts and prevents bone mineral-related diseases. However, the effects of SPHK inhibitors and ZA used to treat periprosthetic osteolysis are unknown. Methods: We applied tartrate-resistant acid phosphatase (TRAP) staining to evaluate bone destruction in the interface membranes of patients with aseptic loosening and a control group. A murine calvarial osteolysis model was used to examine the preventative effect of SPHK inhibitors and ZA on osteolysis. Micro-CT scanning, immunohistochemistry (IHC), and histomorphometric analysis were conducted to determine the variations in inflammatory osteolysis. The effects of different drug concentrations on cell viability were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to confirm the reduced expression of osteoclast-specific genes after drug and titanium treatment. The osteoclast formation and functions of the drugs were analyzed using TRAP staining in vivo and in vitro. The effect of SPHKs/S1P-TRAF2-BECN1 signaling pathways was verified via RT-qPCR and tissue IHC. Results: In this study, we found that SPHK inhibitors (ABC294640 and FTY720) combined with ZA decreased the degree of inflammatory osteolysis in vivo. However, ABC294640 and ZA suppressed osteoclast differentiation and osteoclast-specific genes in vitro. SPHKs regulate the inflammatory osteolysis induced by wear particles by increasing the expression of SPHKs/S1P-TRAF2-BECN1. Conclusion: Our study revealed that wear particles could induce inflammatory osteolysis by upregulating SPHKs/S1P-TRAF2-BECN1 and SPHK inhibitors/ZA inhibit osteoclastogenesis in vitro and prevent inflammatory osteolysis in vivo, suggesting that SPHK inhibitors and ZA can be a new perspective and scientific basis for the prevention and treatment of prosthesis loosening. [ABSTRACT FROM AUTHOR]

Purpose of Review: Joint replacement has revolutionized the treatment of end-stage arthritis. We highlight the key role of macrophages in the innate immune system in helping to ensure that the prosthesis-host interface remains biologically robust. Recent Findings: Osteoimmunology is of great interest to researchers investigating the fundamental biological and material aspects of joint replacement. Constant communication between cells of the monocyte/macrophage/osteoclast lineage and the mesenchymal stem cell-osteoblast lineage determines whether a durable prosthesis-implant interface is obtained, or whether implant loosening occurs. Tissue and circulating monocytes/macrophages provide local surveillance of stimuli such as the presence of byproducts of wear and can quickly polarize to pro- and anti-inflammatory phenotypes to re-establish tissue homeostasis. When these mechanisms fail, periprosthetic osteolysis results in progressive bone loss and painful failure of mechanical fixation. Summary: Immune modulation of the periprosthetic microenvironment is a potential intervention to facilitate long-term durability of prosthetic interfaces. [ABSTRACT FROM AUTHOR]

Aseptic loosening due to periprosthetic osteolysis has been accepted as one of the leading causes of revision procedures in patients with previous joint arthroplasty. Recently, several strategies for suppression of osteolysis were proposed, mostly based on biological treatment such as mitigation of chronic inflammatory reactions. However, these biological treatments do not stop the debris migration but only reduce the inflammatory reaction. To address this shortcoming, we propose the concept of ultrahigh molecular weighted polyethylene particles filtration storage by electrospun membranes. Firstly, the surface tension of synovial fluid (SF) is obtained by use of a pendant droplet. Secondly, the contact angle of the electrospun membranes wetted by two different liquids is measured to obtain the free surface energy using of the Owens–Wendt model. Additionally, the wettability of electrospun membranes by SF as a function of technology parameters is studied.

The success of implant performance and arthroplasty is based on several factors, including oxidative stress-induced osteolysis. Oxidative stress is a key factor of the inflammatory response. Implant biomaterials can release wear particles which may elicit adverse reactions in patients, such as local inflammatory response leading to tissue damage, which eventually results in loosening of the implant. Wear debris undergo phagocytosis by macrophages, inducing a low-grade chronic inflammation and reactive oxygen species (ROS) production. In addition, ROS can also be directly produced by prosthetic biomaterial oxidation. Overall, ROS amplify the inflammatory response and stimulate both RANKL-induced osteoclastogenesis and osteoblast apoptosis, resulting in bone resorption, leading to periprosthetic osteolysis. Therefore, a growing understanding of the mechanism of oxidative stress-induced periprosthetic osteolysis and anti-oxidant strategies of implant design as well as the addition of anti-oxidant agents will help to improve implants' performances and therapeutic approaches. [ABSTRACT FROM AUTHOR]