Calycosin alleviates titanium particle-induced osteolysis by modulating macrophage polarization and subsequent osteogenic differentiation.

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.

Inhibitory effects of norcantharidin on titanium particle-induced osteolysis, osteoclast activation and bone resorption via MAPK pathways.

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.

Apelin-13 alleviates osteoclast formation and osteolysis through Nrf2-pyroptosis pathway.

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.

Mettl3­mediated m6A RNA methylation regulates osteolysis induced by titanium particles.

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.

Medication-related osteonecrosis of the lower jaw without osteolysis on computed tomography images.

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.

IKK/NF-κB and ROS signal axes are involved in Tenacissoside H mediated inhibitory effects on LPS-induced inflammatory osteolysis.

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.

Risk factors associated with prognosis of patients with medication-related osteonecrosis of the jaw.

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.

Prevotella histicola Prevented Particle-Induced Osteolysis via Gut Microbiota-Dependent Modulation of Inflammation in Ti-Treated Mice.

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.

Sesamin inhibits RANKL-induced osteoclastogenesis and attenuates LPS-induced osteolysis via suppression of ERK and NF-κB signalling pathways.

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.

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

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.

Kaempferol prevents aseptic loosening via enhance the Wnt/ß-catenin signaling pathway in vitro and in vivo.

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.

PLGA nanoparticles engineering extracellular vesicles from human umbilical cord mesenchymal stem cells ameliorates polyethylene particles induced periprosthetic osteolysis.

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.

Conditional knockout of PDK1 in osteoclasts suppressed osteoclastogenesis and ameliorated prostate cancer-induced osteolysis in murine model.

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.

Morphine-induced osteolysis and hypersensitivity is mediated through toll-like receptor-4 in a murine model of metastatic breast cancer.

ABSTRACT: The propensity for breast cancer to metastasize to bone is coupled to the most common complaint among breast cancer patients: bone pain. Classically, this type of pain is treated using escalating doses of opioids, which lack long-term efficacy due to analgesic tolerance, opioid-induced hypersensitivity, and have recently been linked to enhanced bone loss. To date, the molecular mechanisms underlying these adverse effects have not been fully explored. Using an immunocompetent murine model of metastatic breast cancer, we demonstrated that sustained morphine infusion induced a significant increase in osteolysis and hypersensitivity within the ipsilateral femur through the activation of toll-like receptor-4 (TLR4). Pharmacological blockade with TAK242 (resatorvid) as well as the use of a TLR4 genetic knockout ameliorated the chronic morphine-induced osteolysis and hypersensitivity. Genetic MOR knockout did not mitigate chronic morphine hypersensitivity or bone loss. In vitro studies using RAW264.7 murine macrophages precursor cells demonstrated morphine-enhanced osteoclastogenesis that was inhibited by the TLR4 antagonist. Together, these data indicate that morphine induces osteolysis and hypersensitivity that are mediated, in part, through a TLR4 receptor mechanism.

STING/TBK1 Regulates Inflammation in Macrophages and Titanium Particles-Induced Osteolysis.

Inflammatory response in macrophages on account of prostheses-derived wear particles is the leading cause of artificial joint failure. However, the mechanism by which wear particles initiate macrophage inflammation has not been fully elucidated. Previous research studies have identified TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING) as potential factors in inflammation and autoimmune diseases. Here, we found that both TBK1 and STING were increased in synovium from aseptic loosening (AL) patients and were activated in titanium particles (TiPs)-stimulated macrophages. Lentivirus-mediated knockdown of TBK or STING significantly inhibited the inflammatory effects of macrophages, while overexpression of TBK or STING exerted opposite results. In concrete, STING/TBK1 promoted the activation of NF-κB and IRF3 pathways and macrophage M1 polarization. For further validation, a mice cranial osteolysis model was constructed for in vivo assays, and we found that STING-overexpressed lentivirus injection exacerbated osteolysis and inflammation, which was counteracted by TBK1-knockdown injection. In conclusion, STING/TBK1 enhanced TiP-induced macrophage inflammation and osteolysis via orchestrating the activation of NF-κB and IRF3 pathways and M1 polarization, which suggested STING/TBK1 as potential therapeutic targets for preventing AL of prostheses.

Quercetin alleviates nanoparticle-induced osteolysis via deactivating pyroptosis.

As one of the most successful stories in modern medicine, total joint arthroplasty (TJA) is performed several million times worldwide every year. However, more than 20% of patients will suffer from aseptic loosening (AL) following periprosthetic osteolysis (PPO) in the next few years. Unfortunately, the only effective treatment for PPO, i.e., revision surgery, can cause great surgical trauma. It has been reported that the accumulation of reactive oxidative species (ROS) generated by exposure to wear particles could activate NLRP3 inflammasome in macrophages and accelerate the progress of osteolysis. Given that the conservative treatment is not effective and can be accompanied by apparent side effects, we, therefore, investigated the therapeutic effect of the natural compound quercetin (Que) on wear particle-induced osteolysis. Our results showed that Que could activate nuclear factor erythroid 2-related factor 2 (Nrf2) to remove ROS and deactivate inflammasome activation. Besides, the imbalance between osteoclastogenesis and osteogenesis induced by inflammatory cytokines was also rescued by Que. Collectively, our work demonstrates that Que may be a qualified candidate for the conservative treatment of wear particle-induced osteolysis.

Targeted therapy for peri-prosthetic osteolysis using macrophage membrane-encapsulated human urine-derived stem cell extracellular vesicles.

Aseptic loosening of the prosthesis is a severe complication after joint replacement. It is of great practical significance and social value to discover the prevention and treatment strategies for this condition. Exosomes from urine-derived stem cells (Exos) have great potential in promoting bone repair, reconstruction, and regulating bone metabolism. However, they are easily eliminated by macrophages and incapable of targeting the osteolysis zone. In this study, based on macrophage "homing" into periprosthetic osteolysis region and cell membrane encapsulating nanotechnology, exosomes from urine-derived stem cells were encapsulated with macrophage membrane (MM) to prevent periprosthetic osteolysis. We found that macrophage membrane encapsulated urine-derived stem cell-derived exosomes (MM-Exos) can be targeted delivery to the osteolysis zone and enhance the therapeutic effectiveness of Exos, which alleviated wear particles-induced calvarial osteolysis. Furthermore, MM-Exos could provide immunological camouflage and allow the Exos to avoid phagocytosis by macrophages and stimulate cellular uptake by bone marrow-derived stem cells (BMSCs). Therefore, we demonstrated the unique ability of the macrophage membrane as a targeted transport of exosomes from urine-derived stem cells for the prevention and treatment of periprosthetic osteolysis. These biomimetic nanoparticles provided a new therapeutic exosome delivery system for preventing wear particles-induced osteolysis. STATEMENT OF SIGNIFICANCE: Macrophage membrane encapsulated urine-derived stem cell-derived exosomes (MM-Exos) can be targeted delivery to the osteolysis zone and enhance the therapeutic effect of Exos on peri­prosthetic osteolysis prevention. MM-Exos could allow the Exos to avoid phagocytosis by macrophages and promote the uptake of Exos by BMSCs.

Ultrasmall PtAu2 nanoclusters activate endogenous anti-inflammatory and anti-oxidative systems to prevent inflammatory osteolysis.

Rationale: Inflammatory osteolysis, characterized by abundant immune cell infiltration and osteoclast (OC) formation, is a common complication induced by bacterial products and/or wear particles at the bone-prosthesis interface that severely reduces long-term stability after implantation. Molecular nanoclusters are ultrasmall particles with unique physicochemical and biological properties that have great potential as theranostic agents for treating inflammatory diseases. Methods: In this study, heterometallic PtAu2 nanoclusters with sensitive nitric oxide-responsive phosphorescence turn-on characteristics and strong binding interactions with cysteine were designed, making them desirable candidates for the treatment of inflammatory osteolysis. Results: PtAu2 clusters exhibited satisfactory biocompatibility and cellular uptake behavior, with potent anti-inflammatory and anti-OC activities in vitro. In addition, PtAu2 clusters alleviated lipopolysaccharide-induced calvarial osteolysis in vivo and activated nuclear factor erythroid 2-related factor 2 (Nrf2) expression by disrupting its association with Kelch-like ECH-associated protein 1 (Keap1), thereby upregulating the expression of endogenous anti-inflammatory and anti-oxidative products. Conclusion: Through the rational design of novel heterometallic nanoclusters that activate the endogenous anti-inflammatory system, this study provides new insights into the development of multifunctional molecular therapeutic agents for inflammatory osteolysis and other inflammatory diseases.

Postoperative Lumbar Fusion Bone Morphogenic Protein-Related Epidural Cyst Formation.

Bone morphogenetic protein is broadly used in spinal surgery to enhance fusion rates. Several complications have been associated with the use of bone morphogenetic protein, including postoperative radiculitis and pronounced bone resorption/osteolysis. Bone morphogenetic protein-related epidural cyst formation may represent another complication that has not been described aside from limited case reports. In this case series, we retrospectively reviewed imaging and clinical findings of 16 patients with epidural cysts on postoperative MR imaging following lumbar fusion. In 8 patients, mass effect on the thecal sac or lumbar nerve roots was noted. Of these, 6 patients developed new postoperative lumbosacral radiculopathy. During the study period, most patients were managed conservatively, and 1 patient required revision surgery with cyst resection. Concurrent imaging findings included reactive endplate edema and vertebral bone resorption/osteolysis. Epidural cysts had characteristic findings on MR imaging in this case series and may represent an important postoperative complication in patients following bone morphogenetic protein-augmented lumbar fusion.

Titanium dioxide nanoparticles affect osteoblast-derived exosome cargos and impair osteogenic differentiation of human mesenchymal stem cells.

Titanium (Ti) and its alloys are the most widely used metallic biomaterials in total joint replacement; however, increasing evidence supports the degradation of its surface due to corrosion and wear processes releasing debris (ions, and micro and nanoparticles) and contribute to particle-induced osteolysis and implant loosening. Cell-to-cell communication involving several cell types is one of the major biological processes occurring during bone healing and regeneration at the implant-bone interface. In addition to the internal response of cells to the uptake and intracellular localization of wear debris, a red flag is the ability of titanium dioxide nanoparticles (mimicking wear debris) to alter cellular communication with the tissue background, disturbing the balance between osseous tissue integrity and bone regenerative processes. This study aims to understand whether titanium dioxide nanoparticles (TiO2 NPs) alter osteoblast-derived exosome (Exo) biogenesis and whether exosomal protein cargos affect the communication of osteoblasts with human mesenchymal stem/stromal cells (HMSCs). Osteoblasts are derived from mesenchymal stem cells coexisting in the bone microenvironment during development and remodelling. We observed that TiO2 NPs stimulate immature osteoblast- and mature osteoblast-derived Exo secretion that present a distinct proteomic cargo. Functional tests confirmed that Exos derived from both osteoblasts decrease the osteogenic differentiation of HMSCs. These findings are clinically relevant since wear debris alter extracellular communication in the bone periprosthetic niche, contributing to particle-induced osteolysis and consequent prosthetic joint failure.