RESUMEN
Reactive oxidative species (ROS) generation triggers pyroptosis and induces development of inflammatory osteolysis. Hecogenin (HG) has anti-inflammatory and antioxidative property, but its effects on inflammatory osteolysis remains unclear. In our study, we investigated the mechanism of HG on pyroptosis and its effect on inflammatory osteolysis in vitro and in vivo. The impact of HG on osteoclastogenesis was evaluated using cytotoxicity, TRAcP staining and bone resorption assays. The RNA-sequencing was employed to identify potential signaling pathways, and then RT-qPCR, western blot, immunofluorescence, and ELISA were used to verify. To determine the protective effect of HG in vivo, Lipopolysaccharide (LPS)-induced animal models were utilized, along with micro-CT and histological examination. HG suppressed RANKL-induced osteoclast differentiation, bone resorption, NFATc1 activity and downstream factors. RNA-sequencing results showed that HG inhibited osteoclastogenesis by modulating the inflammatory response and macrophage polarization. Furthermore, HG inhibited the NF-κB pathway, and deactivated the NLRP3 inflammasome. HG activated the expression of nuclear factor E2-related factor 2 (Nrf2) to eliminate ROS generation. Importantly, the inhibitory effect of HG on NLRP3 inflammasome could be reversed by treatment with the Nrf2 inhibitor ML385. In vivo, HG prevented the mice against LPS-induced osteolysis by suppressing osteoclastogenesis and inflammatory factors. In conclusion, HG could activate Nrf2 to eliminate ROS generation, inactivate NLRP3 inflammasome and inhibit pyroptosis, thereby suppressing osteoclastogenesis in vitro and alleviating inflammatory osteolysis in vivo, which indicating that HG might be a promising candidate to treat inflammatory osteolysis.
Asunto(s)
Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , Proteína con Dominio Pirina 3 de la Familia NLR , Osteoclastos , Osteólisis , Piroptosis , Especies Reactivas de Oxígeno , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteoclastos/patología , Osteogénesis/efectos de los fármacos , Osteólisis/inducido químicamente , Osteólisis/tratamiento farmacológico , Osteólisis/metabolismo , Osteólisis/patología , Piroptosis/efectos de los fármacos , Ligando RANK/metabolismo , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Periprosthetic osteolysis and subsequent aseptic loosening are the primary causes of failure following total joint arthroplasty. Wear particle-induced osteogenic impairment is recognized as an important contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress emerging as a pivotal underlying mechanism. Hence, searching for potential therapeutic targets and agents capable of modulating ER stress in osteoblasts is crucial for preventing aseptic loosening. Kaempferol (KAE), a natural flavonol compound, has shown promising osteoprotective effects and anti-ER stress properties in diverse diseases. However, the influence of KAE on ER stress-mediated osteogenic impairment induced by wear particles remains unclear. In this study, we observed that KAE effectively relieved TiAl6V4 particles-induced osteolysis by improving osteogenesis in a mouse calvarial model. Furthermore, we demonstrated that KAE could attenuate ER stress-mediated apoptosis in osteoblasts exposed to TiAl6V4 particles, both in vitro and in vivo. Mechanistically, our results revealed that KAE mitigated ER stress-mediated apoptosis by upregulating the IRE1α-XBP1s pathway while concurrently partially inhibiting the IRE1α-regulated RIDD and JNK activation. Collectively, our findings suggest that KAE is a prospective therapeutic agent for treating wear particle-induced osteolysis and highlight the IRE1α-XBP1s pathway as a potential therapeutic target for preventing aseptic loosening.
Asunto(s)
Estrés del Retículo Endoplásmico , Endorribonucleasas , Quempferoles , Osteoblastos , Osteogénesis , Osteólisis , Proteínas Serina-Treonina Quinasas , Proteína 1 de Unión a la X-Box , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Quempferoles/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genética , Ratones , Osteogénesis/efectos de los fármacos , Endorribonucleasas/metabolismo , Endorribonucleasas/genética , Osteoblastos/metabolismo , Osteoblastos/efectos de los fármacos , Osteólisis/metabolismo , Osteólisis/inducido químicamente , Osteólisis/patología , Osteólisis/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Masculino , Humanos , Ratones Endogámicos C57BLRESUMEN
Periprosthetic osteolysis (PPO) caused by wear particles is one of the leading causes of implant failure after arthroplasty. Macrophage polarization imbalance and subsequent osteogenic inhibition play a crucial role in PPO. Calycosin (CA) is a compound with anti-inflammatory and osteoprotective properties. This study aimed to evaluate the effects of CA on titanium (Ti) particle-induced osteolysis, Ti particle-induced macrophage polarization and subsequent osteogenic deficits, and explore the associated signalling pathways in a Ti particle-stimulated calvarial osteolysis mouse model using micro-CT, ELISA, qRT-PCR, immunofluorescence and western blot techniques. The results showed that CA alleviated inflammation, osteogenic inhibition and osteolysis in the Ti particle-induced calvarial osteolysis mouse model in vivo. In vitro experiments showed that CA suppressed Ti-induced M1 macrophage polarization, promoted M2 macrophage polarization and ultimately enhanced osteogenic differentiation of MC3T3-E1 cells. In addition, CA alleviated osteogenic deficits by regulating macrophage polarization homeostasis via the NF-κB signalling pathway both in vivo and in vitro. All these findings suggest that CA may prove to be an effective therapeutic agent for wear particle-induced osteolysis.
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Isoflavonas , Osteogénesis , Osteólisis , Ratones , Animales , Osteólisis/inducido químicamente , Osteólisis/tratamiento farmacológico , Osteólisis/metabolismo , Titanio/toxicidad , Macrófagos/metabolismoRESUMEN
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.
Asunto(s)
Péptidos y Proteínas de Señalización Intercelular , Osteoclastos , Osteólisis , Animales , Ratones , Inflamasomas/efectos adversos , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteólisis/inducido químicamente , Osteólisis/metabolismo , Piroptosis/efectos de los fármacos , Ligando RANK/metabolismo , Titanio/farmacologíaRESUMEN
Forsythia suspensa tea is a popular traditional Chinese medicine decoction for its healthy and therapeutic benefits. However, its effects in bone metabolism were not clear. In recent study, we uncovered anti-osteoclastogenesis property of Phillygenin (Phi), a compound abundant in Forsythia suspensa leaves, and aimed to investigate the effect and mechanism of Phi on bone metabolism in vivo and in vitro. Lipopolysaccharides-induced murine calvaria osteolysis and ovariectomy-induced bone loss animal models were used to identify the bone-protective effect of Phi in vivo and micro-CT, pQCT, and TRAP staining were applied. We used CCK8, TUNEL, BrdU, and TRAP staining to evaluate the efficacy of Phi on the proliferation and formation of OCs in primary mBMMs. RNA sequence, activity-based protein profiling, molecular docking, G-LISA, and WB were used to inspect the target and underlying mechanism of Phi's actions in mBMMs. We found Phi significantly inhibited bone resorption in vivo and inhibited mBMMs osteoclastogenesis in vitro. Ras homolog gene family member A (RhoA) was identified as the direct target of Phi. It counteracted the effects of RhoA activator and acted as a RhoA inhibitor. By targeting RhoA, Phi modulated Rho-associated coiled-coil containing protein kinase 1 (ROCK1) activity and regulated its downstream NF-κB/NFATc1/c-fos pathway. Furthermore, Phi depressed the disassembling of F-actin ring through cofilin and myosin1a. Our findings provided Phi as a potential option for treating bone loss diseases by targeting RhoA and highlighted the importance of F. suspensa as a preventive approach in bone disorders.
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Enfermedades Óseas Metabólicas , Resorción Ósea , Lignanos , Osteólisis , Animales , Femenino , Ratones , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/prevención & control , Diferenciación Celular , Lignanos/farmacología , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/farmacología , Osteoclastos , Osteogénesis , Osteólisis/inducido químicamenteRESUMEN
Wear particles generated from the surface of implanted prostheses can lead to peri-implant osteolysis and subsequent aseptic loosening. In the inflammatory environment, extensive formation and activation of osteoclasts are considered the underlying cause of peri-implant osteolysis. Current medications targeting osteoclasts for the treatment of particle-induced bone resorption are not ideal due to significant side effects. Therefore, there is an urgent need to develop more effective drugs with fewer side effects. Norcantharidin (NCTD), a derivative of cantharidin extracted from blister beetles, is currently primarily used for the treatment of solid tumors in clinical settings. However, the potential role of NCTD in treating aseptic loosening of the prosthesis has not been reported. In this study, the in vitro results demonstrated that NCTD could effectively inhibit the formation of osteoclasts and bone resorption induced by the RANKL. Consistently, NCTD strongly inhibited RANKL-induced mRNA and protein levels of c-Fos and NFATc1, concomitant with reduced expression of osteoclast specific genes including TRAP, CTR and CTSK. The in vivo data showed that NCTD exerted significant protective actions against titanium particle-induced inflammation and subsequent osteolysis. The molecular mechanism investigation revealed that NCTD could suppress the activations of RANKL-induced MAPK (p38, ERK). Overall, these findings support the potential use of NCTD for the treatment of aseptic loosening following total joint arthroplasty.
Asunto(s)
Resorción Ósea , Compuestos Bicíclicos Heterocíclicos con Puentes , Osteólisis , Animales , Ratones , Osteoclastos , Osteólisis/inducido químicamente , Osteólisis/tratamiento farmacológico , Osteólisis/metabolismo , Titanio/efectos adversos , FN-kappa B/metabolismo , Resorción Ósea/inducido químicamente , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/patología , Ligando RANK/metabolismo , Osteogénesis , Ratones Endogámicos C57BLRESUMEN
BACKGROUND AND AIM: Several studies reported osteolysis around polyethylene glycol/polybutylene terephthalate (PEG/PBT) based femoral cement restrictors. Our goal was to evaluate and compare osteolysis around 3 different plug designs: the slow biodegradable PEG/PBT cement restrictor; the fast biodegradable gelatin cement restrictor; and the non-biodegradable polyethylene plug. PATIENTS AND METHODS: In a retrospective multicentre cohort study chart data were extracted of patients who received a total hip arthroplasty between 2008 and 2012. A total of 961 hips were included. Cortical ratio between inner and outer cortices at the centre of the plug was measured on routine postoperative follow-up moments. Median follow up of all 3 hospitals was 3.5 years (1.4-7.3). The primary outcome was evidence of osteolysis (i.e. the difference in cortical ratio [CR]) on anteroposterior (AP) radiographs at final follow-up. RESULTS: Progressive osteolysis was found around the PEG/PBT cement restrictor represented by a significantly increasing cortical ratio (ΔCR 0.067 (95% CI, 0.063-0.071). Distance from tip prosthesis to plug and size of the plug were found to be independent factors in predicting increased cortical ratio. CONCLUSIONS: Our multicentre cohort shows increase of cortical ratio around the PEG/PBT cement restrictor which progresses over time. Physicians should be aware of this fact and are advised to intensify follow-up of patients who received this cement restrictor.
Asunto(s)
Artroplastia de Reemplazo de Cadera , Prótesis de Cadera , Osteólisis , Humanos , Artroplastia de Reemplazo de Cadera/efectos adversos , Estudios de Cohortes , Osteólisis/inducido químicamente , Osteólisis/diagnóstico por imagen , Cementación , Polietileno , Cementos para Huesos/efectos adversos , Prótesis de Cadera/efectos adversos , Estudios de Seguimiento , Falla de Prótesis , Diseño de PrótesisRESUMEN
Periprosthetic osteolysis (PPO) induced by wear particles is considered the primary cause of titanium prosthesis failure and revision surgery. The specific molecular mechanisms involve titanium particles inducing multiple intracellular pathways, which impact disease prevention and the targeted therapy of PPO. Notably, N6methyladenosine (m6A) serves critical roles in epigenetic regulation, particularly in bone metabolism and inflammatory responses. Thus, the present study aimed to determine the role of RNA methylation in titanium particleinduced osteolysis. Results of reverse transcriptionquantitative PCR (RTqPCR), western blotting, ELISA and RNA dot blot assays revealed that titanium particles induced osteogenic inhibition and proinflammatory responses, accompanied by the reduced expression of methyltransferaselike (Mettl) 3, a key component of m6A methyltransferase. Specific lentiviruses vectors were employed for Mettl3 knockdown and overexpression experiments. RTqPCR, western blotting and ELISA revealed that the knockdown of Mettl3 induced osteogenic inhibition and proinflammatory responses comparable with that induced by titanium particle, while Mettl3 overexpression attenuated titanium particleinduced cellular reactions. Methylated RNA immunoprecipitationqPCR results revealed that titanium particles mediated the methylation of two inhibitory molecules, namely Smad7 and SMAD specific E3 ubiquitin protein ligase 1, via Mettl3 in bone morphogenetic protein signaling, leading to osteogenic inhibition. Furthermore, titanium particles induced activation of the nucleotide binding oligomerization domain 1 signaling pathway through methylation regulation, and the subsequent activation of the MAPK and NFκB pathways. Collectively, the results of the present study indicated that titanium particles utilized Mettl3 as an upstream regulatory molecule to induce osteogenic inhibition and inflammatory responses. Thus, the present study may provide novel insights into potential therapeutic targets for aseptic loosening in titanium prostheses.
Asunto(s)
Osteólisis , Humanos , Osteólisis/inducido químicamente , Osteólisis/genética , Titanio/toxicidad , Metilación de ARN , Epigénesis Genética , ARN/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismoRESUMEN
INTRODUCTION: Surgery is the standard treatment for medication-related osteonecrosis of the jaw (MRONJ). This study reviewed patients with mandibular MRONJ who underwent surgical treatment, and in particular the characteristics of non-osteolytic MRONJ with no evidence of osteolysis on CT were described. MATERIALS AND METHODS: We conducted a retrospective study of patients with mandibular MRONJ who underwent surgery between January 2016 and September 2022. Various clinical and imaging factors regarding treatment outcomes were investigated and analyzed. Additionally, the disease course of non-osteolytic MRONJ was examined in detail. RESULTS: This study included 55 patients (66 surgeries) with a mean age of 74.7. The primary disease was osteoporosis (24 patients) and malignancy (31 patients); the type of antiresorptive agent was bisphosphonate (BP) in 21 patients and denosumab (DMB) in 26. BP was initially administered; however, it was changed to DMB in eight patients. Preoperatively, the cumulative cure rates for all 66 surgeries were 72.8% at 1 year and 77.3% at 2 years. Cure rates were significantly lower in patients with malignancy, those without osteolysis, and those who underwent sequestrum removal or marginal mandibulectomy than those with osteoporosis, osteolysis, and segmental mandibulectomy. Non-osteolytic MRONJ was observed in eight patients, all with malignancy and receiving high-dose DMB. Only two patients were cured after the initial surgery, and most patients ultimately underwent segmental mandibulectomy. CONCLUSIONS: Surgical treatment yielded good treatment outcomes in most patients with mandibular MRONJ; however, the cure rate was lower in patients with malignancy who showed no osteolysis on CT images.
Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos , Conservadores de la Densidad Ósea , Neoplasias , Osteólisis , Osteoporosis , Humanos , Anciano , Osteonecrosis de los Maxilares Asociada a Difosfonatos/diagnóstico por imagen , Osteonecrosis de los Maxilares Asociada a Difosfonatos/cirugía , Osteonecrosis de los Maxilares Asociada a Difosfonatos/tratamiento farmacológico , Estudios Retrospectivos , Osteólisis/diagnóstico por imagen , Osteólisis/inducido químicamente , Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/uso terapéutico , Tomografía Computarizada por Rayos X , Osteoporosis/tratamiento farmacológicoRESUMEN
Wear particles generated from total joint replacements induce chronic osteolysis mediated by inflammatory upregulation, which leads to implant failure. Recent studies have suggested an important role of the gut microbiota in modulating the host's metabolism and immune system, leading to alterations in bone mass. Following gavage with P. histicola, micro-CT and HE staining revealed that osteolysis was significantly reduced in titanium (Ti)-treated mice. Immunofluorescence analysis revealed an increased macrophage (M)1/M2 ratio in the guts of Ti-treated mice, which decreased when P. histicola was added. P. histicola was also found to upregulate the tight junction proteins ZO-1, occludin, claudin-1, and MUC2 in the gut, reduce the levels of inflammatory factors IL-1ß, IL-6, IL-8, and TNF-α, primarily in the ileum and colon, and decrease the expression of IL-1ß and TNF-α and increase the level of IL-10 in the serum and cranium. Furthermore, P. histicola treatment resulted in a significant downregulation of CTX-1, RANKL, and RANKL/OPG. These findings demonstrate that P. histicola significantly mitigates osteolysis in Ti-treated mice by improving intestinal microbiota that repairs intestinal leakage and reduces systemic and local inflammation which in turn inhibits RANKL expression for bone resorption. P. histicola treatment may thus be therapeutically beneficial for particle-induced osteolysis.
Asunto(s)
Microbioma Gastrointestinal , Osteólisis , Prevotella , Ratones , Animales , Osteólisis/inducido químicamente , Osteólisis/metabolismo , Osteólisis/prevención & control , Factor de Necrosis Tumoral alfa , Osteoclastos/metabolismo , Titanio/efectos adversos , Titanio/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismoRESUMEN
OBJECTIVES: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of antiresorptive and/or antiangiogenic agents. As the treatment application for MRONJ is controversial, we aimed to identify the risk factors for poor prognosis and to help determine appropriate management. METHODS: This study included 119 patients. Relevant clinical data were obtained for all the patients. In computed tomography images, osteosclerosis, osteolysis, cortical perforation (buccal or lingual), periosteal reaction, and sequestration were evaluated. RESULTS: Multivariate analyses showed statistically significant associations between poor prognosis in patients with MRONJ and conservative treatment alone (hazard ratio [HR] 1.89), osteolysis (HR 4.67), and the absence of sequestration (HR 5.33). CONCLUSIONS: Conservative treatment alone without clear objectives needs to be avoided, and osteolytic change could be the criteria for surgical intervention. As the boundary between the lesion and vital bone is indistinct, we recommend extensive surgery in cases with unpredictable sequestration.
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Osteonecrosis de los Maxilares Asociada a Difosfonatos , Conservadores de la Densidad Ósea , Osteólisis , Humanos , Osteonecrosis de los Maxilares Asociada a Difosfonatos/diagnóstico por imagen , Osteonecrosis de los Maxilares Asociada a Difosfonatos/etiología , Osteonecrosis de los Maxilares Asociada a Difosfonatos/terapia , Conservadores de la Densidad Ósea/efectos adversos , Osteólisis/inducido químicamente , Osteólisis/tratamiento farmacológico , Pronóstico , Factores de Riesgo , Difosfonatos/efectos adversos , MaxilaresRESUMEN
Infection by bacterial products in the implant and endotoxin introduced by wear particles activate immune cells, enhance pro-inflammatory cytokines production, and ultimately promote osteoclast recruitment and activity. These factors are known to play an important role in osteolysis as well as potential targets for the treatment of osteolysis. Sesamin has been shown to have a variety of biological functions, such as inhibiting inflammation, anti-tumour and involvement in the regulation of fatty acid and cholesterol metabolism. However, the therapeutic effect of sesamin on osteolysis and its mechanism remain unclear. Present studies shown that in the condition of in vitro, sesamin could inhibit osteoclastogenesis and bone resorption, as well as suppressing the expression of osteoclast-specific genes. Further studies on the mechanism suggest that the effect of sesamin on human osteoclasts was mediated by blocking the ERK and NF-κB signalling pathways. Besides, sesamin was found to be effective in treating LPS-induced osteolysis by decreasing the production of pro-inflammatory cytokines and inhibiting osteoclastogenesis in vivo. Sesamin was non-toxic to heart, liver, kidney, lung and spleen. Therefore, sesamin is a promising phytochemical agent for the therapy of osteolysis-related diseases caused by inflammation and excessive osteoclast activation.
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Resorción Ósea , Dioxoles , Lignanos , Osteólisis , Humanos , Animales , Ratones , Osteólisis/inducido químicamente , Osteólisis/tratamiento farmacológico , FN-kappa B/metabolismo , Osteogénesis , Lipopolisacáridos/metabolismo , Osteoclastos/metabolismo , Resorción Ósea/patología , Inflamación/patología , Citocinas/metabolismo , Ligando RANK/metabolismo , Ratones Endogámicos C57BLRESUMEN
Periodontal disease and arthroplasty prosthesis loosening and destabilization are both associated with osteolysis, which is predominantly caused by abnormal bone resorption triggered by pro-inflammatory cytokines. Osteoclasts (OCs) are critical players in the process. Concerns regarding the long-term efficacy and side effects of current frontline therapies, however, remain. Alternative therapies are still required. The aim of this work was to investigate the involvement of Tenacissoside H (TDH) in RANKL-mediated OC differentiation, as well as inflammatory osteolysis and associated processes. In vitro, bone marrow-derived macrophages (BMMs) cultured with RANKL and M-CSF were used to detect TDH in the differentiation and function of OCs. Real-time quantitative PCR was used to measure the expression of specific genes and inflammatory factors in OCs. Western blot was used to identify NFATc1, IKK, NF-κB, MAPK pathway, and oxidative stress-related components. Finally, an LPS-mediated calvarial osteolysis mouse model was employed to explore TDH's role in inflammatory osteolysis. The results showed that in vivo TDH inhibited the differentiation and resorption functions of OCs and down-regulated the transcription of osteoclast-specific genes, as well as Il-1ß, Il-6 and Tnf-α. In addition, TDH inhibited the IKK and NF-κB signalling pathways and down-regulated the level of ROS. In vivo studies revealed that TDH improves the bone loss caused by LPS. TDH may be a new candidate or treatment for osteoclast-associated inflammatory osteolytic disease.
Asunto(s)
Osteólisis , Animales , Ratones , Osteólisis/inducido químicamente , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Osteoclastos/metabolismo , Ligando RANK/metabolismo , Diferenciación Celular , Factores de Transcripción NFATC/metabolismoRESUMEN
OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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Resorción Ósea , Osteólisis , Animales , Ratones , Osteogénesis , Osteólisis/inducido químicamente , Osteólisis/tratamiento farmacológico , Osteólisis/metabolismo , Osteoclastos/metabolismo , Titanio , Sistema de Señalización de MAP Quinasas , Resorción Ósea/metabolismo , Ligando RANK/farmacología , Ratones Endogámicos C57BLRESUMEN
Kaempferol has demonstrated notable positive effects on the osteogenic differentiation of mesenchymal stem cells (MSC) and osteoblasts. A substantial body of research has emphasized the role of dislodged titanium particles in aseptic loosening following joint replacement surgery. This study predominantly investigates the suppressive influence of Kaempferol on osteolysis induced by titanium (Ti) alloy particles. In vitro investigations disclosed that Kaempferol effectively enhanced mineralization and alkaline phosphatase (ALP) activity in bone-marrow mesenchymal stem cells exposed to Ti particles. In addition, we conducted a comprehensive analysis of osteogenic differentiation microarray data_sets (GSE37676, GSE79814, and GSE114474) to identify differentially expressed genes. Significantly, Kaempferol upregulated the expression of critical osteogenic markers, including Runt-related transcription factor 2 (Runx2), osteocalcin (OCN), osterix/Sp-7, and ß-catenin. In vivo experiments, including H&E staining and Immunohistochemistry, provided compelling evidence that Kaempferol exerted a robust inhibitory effect on periprosthetic osteolysis in mice, with particularly pronounced results at higher doses. Moreover, it elevated the expression levels of osteogenic factors and Wnt/ß-catenin signaling components. These findings collectively indicate that Kaempferol mitigates the hindrance to osteogenesis posed by titanium particles by activating the Runx2 and Wnt/ß-catenin signaling pathways. This research lays a solid foundation for the prospective utilization of Kaempferol in the management of aseptic loosening following arthroplasty, offering promising therapeutic potential.
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Osteólisis , beta Catenina , Animales , Ratones , beta Catenina/genética , beta Catenina/metabolismo , Diferenciación Celular , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/farmacología , Quempferoles/farmacología , Osteogénesis/genética , Osteólisis/prevención & control , Osteólisis/inducido químicamente , Osteólisis/metabolismo , Estudios Prospectivos , Titanio/farmacología , Vía de Señalización WntRESUMEN
Peri-implantitis is one of the most important biological complications in the field of oral implantology. Identifying the causative factors of peri-implant inflammation and osteolysis is crucial for the disease's prevention and treatment. The underlying risk factors and detailed pathogenesis of peri-implantitis remain to be elucidated. Titanium-based implants as the most widely used implant inevitably release titanium particles into the surrounding tissue. Notably, the concentration of titanium particles increases significantly at peri-implantitis sites, suggesting titanium particles as a potential risk factor for the condition. Previous studies have indicated that titanium particles can induce peripheral osteolysis and foster the development of aseptic osteoarthritis in orthopedic joint replacement. However, it remains unconfirmed whether this phenomenon also triggers inflammation and bone resorption in peri-implant tissues. This review summarizes the distribution of titanium particles around the implant, the potential roles in peri-implantitis and the prevalent prevention strategies, which expects to provide new directions for the study of the pathogenesis and treatment of peri-implantitis.
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Implantes Dentales , Osteólisis , Periimplantitis , Humanos , Periimplantitis/inducido químicamente , Periimplantitis/patología , Titanio/farmacología , Implantes Dentales/efectos adversos , Osteólisis/inducido químicamente , Osteólisis/complicaciones , Osteólisis/patología , Inflamación/inducido químicamenteRESUMEN
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.
Asunto(s)
Exosomas , Células Madre Mesenquimatosas , Nanopartículas , Osteólisis , Humanos , Osteogénesis , Osteólisis/inducido químicamente , Osteólisis/terapia , Polietileno/efectos adversos , Glicoles/efectos adversos , Cordón UmbilicalRESUMEN
BACKGROUND: The development and maintenance of normal bone tissue is maintained by balanced communication between osteoblasts and osteoclasts. The invasion of cancer cells disrupts this balance, leading to osteolysis. As the only bone resorbing cells in vivo, osteoclasts play important roles in cancer-induced osteolysis. However, the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in osteoclast resorption remains unclear. METHODS: In our study, we used a receptor activator of nuclear factor-kappa B (RANK) promoter-driven Cre-LoxP system to conditionally delete the PDK1 gene in osteoclasts in mice. We observed the effect of osteoclast-specific knockout of PDK1 on prostate cancer-induced osteolysis. Bone marrow-derived macrophage cells (BMMs) were extracted and induced to differentiate osteoclasts in vitro to explore the role of PDK1 in osteoclasts. RESULTS: In this study, we found that PDK1 conditional knockout (cKO) mice exhibited smaller body sizes when compared to the wild-type (WT) mice. Moreover, deletion of PDK1 in osteoclasts ameliorated osteolysis and rPDK1educed bone resorption markers in the murine model of prostate cancer-induced osteolysis. In vivo, we discovered that osteoclast-specific knockout of suppressed RANKL-induced osteoclastogenesis, bone resorption function, and osteoclast-specific gene expression (Ctsk, TRAP, MMP-9, NFATc1). Western blot analyses of RANKL-induced signaling pathways showed that conditional knockout of PDK1 in osteoclasts inhibited the early nuclear factor κB (NF-κB) activation, which consequently suppressed the downstream induction of NFATc1. CONCLUSION: These findings demonstrated that PDK1 performs an important role in osteoclastogenesis and prostate cancer-induced osteolysis by modulating the PDK1/AKT/NF-κB signaling pathway.
Asunto(s)
Osteólisis , Neoplasias de la Próstata , Masculino , Animales , Ratones , Humanos , Osteoclastos/metabolismo , Osteogénesis/genética , Osteólisis/genética , Osteólisis/inducido químicamente , Osteólisis/metabolismo , FN-kappa B/metabolismo , Proteínas Quinasas/efectos adversos , Proteínas Quinasas/metabolismo , Modelos Animales de Enfermedad , Diferenciación Celular/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Ratones Endogámicos C57BLRESUMEN
Our previous data have revealed TCP particles caused cell death of osteocytes, comprising over 95 % of all bone cells, which contribute to periprosthetic osteolysis, joint loosening and implant failure, but its mechanisms are not fully understood. Here, we reported that TCP particles inhibited cell viability of osteocytes MLO-Y4, and caused cell death. TCP particles caused mitochondrial impairment and increased expressions of LC-3 II, Parkin and PINK 1, accompanied by the elevation of autophagy flux and intracellular acidic components, the accumulation of LC-3II, PINK1 and Parkin in damaged mitochondria, and p62 reduction. The increased LC-3II expression and cell death extent were significantly enhanced by the autophagy inhibitor Baf A1, compared with Baf A1 (or TCP particles) alone, indicating that TCP particles increase autophagic flux and lead to cell even death of MLO-Y4 cells, closely associated with mitophagy. Furthermore, TCP particles induced propidium iodide (PI) uptake and the phosphorylation of RIP1, RIP3 and MLKL, thereby increasing necroptosis in MLO-Y4 cells. The pro-necroptotic effect was alleviated by the RIP1 inhibitor Nec-1 or the MLKL inhibitor NSA. Additionally, TCP particles promoted the production of intracellular reactive oxygen species (ROS) and mitochondrial ROS (mtROS), and increased TXNIP expression, but decreased protein levels of TRX1, Nrf2, HO-1 and NQO1, leading to oxidative stress. The ROS scavenger NAC remarkably reversed mitophagy and necroptosis caused by TCP particles, suggesting that ROS is responsible for mitophagy and necroptosis. Collectively, ROS-mediated mitophagy and necroptosis regulate osteocytes death caused by TCP particles in MLO-Y4 cells, which enhances osteoclastogenesis and periprosthetic osteolysis.
Asunto(s)
Mitofagia , Osteólisis , Humanos , Especies Reactivas de Oxígeno , Necroptosis , Osteocitos , Osteólisis/inducido químicamenteRESUMEN
Osteoblast dysfunction plays a crucial role in periprosthetic osteolysis and aseptic loosening, and endoplasmic reticulum (ER) stress is recognized as an important causal factor of wear particle-induced osteolysis. However, the influence of ER stress on osteoblast activity during osteolysis and its underlying mechanisms remain elusive. This study aims to investigate whether ER stress is involved in the detrimental effects of wear particles on osteoblasts. Through our investigation, we observed elevated expression levels of ER stress and apoptosis markers in particle-stimulated bone specimens and osteoblasts. To probe further, we employed the ER stress inhibitor, 4-PBA, to treat particle-stimulated osteoblasts. The results revealed that 4-PBA effectively alleviated particle-induced osteoblast apoptosis and mitigated osteogenic reduction. Furthermore, our study revealed that wear particle-induced ER stress in osteoblasts coincided with mitochondrial damage, calcium overload, and oxidative stress, all of which were effectively alleviated by 4-PBA treatment. Encouragingly, 4-PBA administration also improved bone formation and attenuated osteolysis in a mouse calvarial model. In conclusion, our results demonstrate that ER stress plays a crucial role in mediating wear particle-induced osteoblast apoptosis and impaired osteogenic function. These findings underscore the critical involvement of ER stress in wear particle-induced osteolysis and highlight ER stress as a potential therapeutic target for ameliorating wear particle-induced osteogenic reduction and bone destruction.