DNA hypomethylation ameliorates erosive inflammatory arthritis by modulating interferon regulatory factor-8.

Epigenetic regulation plays a crucial role in the pathogenesis of autoimmune diseases such as inflammatory arthritis. DNA hypomethylating agents, such as decitabine (DAC), have been shown to dampen inflammation and restore immune homeostasis. In the present study, we demonstrate that DAC elicits potent anti-inflammatory effects and attenuates disease symptoms in several animal models of arthritis. Transcriptomic and epigenomic profiling show that DAC-mediated hypomethylation regulates a wide range of cell types in arthritis, altering the differentiation trajectories of anti-inflammatory macrophage populations, regulatory T cells, and tissue-protective synovial fibroblasts (SFs). Mechanistically, DAC-mediated demethylation of intragenic 5'-Cytosine phosphate Guanine-3' (CpG) islands of the transcription factor Irf8 (interferon regulatory factor 8) induced its re-expression and promoted its repressor activity. As a result, DAC restored joint homeostasis by resetting the transcriptomic signature of negative regulators of inflammation in synovial macrophages (MerTK, Trem2, and Cx3cr1), TREGs (Foxp3), and SFs (Pdpn and Fapα). In conclusion, we found that Irf8 is necessary for the inhibitory effect of DAC in murine arthritis and that direct expression of Irf8 is sufficient to significantly mitigate arthritis.

Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α-XBP1s pathway.

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.

NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis.

Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acro-osteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS.

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.

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.

Enhanced Osteolysis Targeted Therapy through Fusion of Exosomes Derived from M2 Macrophages and Bone Marrow Mesenchymal Stem Cells: Modulating Macrophage Polarization.

Aseptic loosening of prostheses is a highly researched topic, and wear particle-induced macrophage polarization is a significant cause of peri-prosthetic osteolysis. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs-Exos) promote M2 polarization and inhibit M1 polarization of macrophages. However, clinical application problems such as easy clearance and lack of targeting exist. Exosomes derived from M2 macrophages (M2-Exos) have good biocompatibility, immune escape ability, and natural inflammatory targeting ability. M2-Exos and BMSCs-Exos fused exosomes (M2-BMSCs-Exos) are constructed, which targeted the osteolysis site and exerted the therapeutic effect of both exosomes. M2-BMSCs-Exos achieved targeted osteolysis after intravenous administration inhibiting M1 polarization and promoting M2 polarization to a greater extent at the targeted site, ultimately playing a key role in the prevention and treatment of aseptic loosening of prostheses. In conclusion, M2-BMSCs-Exos can be used as a precise and reliable molecular drug for peri-prosthetic osteolysis. Fused exosomes M2-BMSCs-Exos  were originally proposed and successfully prepared, and exosome fusion technology provides a new theoretical basis and solution for the clinical application of therapeutic exosomes.

Treatment for Gorham-Stout syndrome with a combination of teriparatide and denosumab.

Gorham-Stout syndrome is an aggressive, non-hereditary, and rare disease affecting bone metabolism. Its etiology and pathogenesis remain elusive. The syndrome manifests with diverse clinical symptoms, often leading to frequent misdiagnoses and presenting challenges in treatment. In this study, we report a case of cranial and maxillary osteolysis in a 47-year-old female patient with somatic mutations in the VEGF-A, VEGF-B, and VEGF-C genes and the EPHB4 gene. After treatment with bisphosphonates, this patient still had persistent resorption of the mandible, but switching to a teriparatide and denosumab combination yielded substantial improvement. This study is the first report to show that teriparatide combined with denosumab can be used to treat Gorham-Stout syndrome.

The STING inhibitor C-176 attenuates osteoclast-related osteolytic diseases by inhibiting osteoclast differentiation.

Inflammatory osteolysis occurs primarily in the context of osteoarthritis, aseptic inflammation, prosthesis loosening, and other conditions. An excessive immune inflammatory response causes excessive activation of osteoclasts, leading to bone loss and bone destruction. The signaling protein stimulator of interferon gene (STING) can regulate the immune response of osteoclasts. C-176 is a furan derivative that can inhibit activation of the STING pathway and exert anti-inflammatory effects. The effect of C-176 on osteoclast differentiation is not yet clear. In this study, we found that C-176 could inhibit STING activation in osteoclast precursor cells and inhibit osteoclast activation induced by nuclear factor κB ligand receptor activator in a dose-dependent manner. After treatment with C-176, the expression of the osteoclast differentiation marker genes nuclear factor of activated T-cells c1(NFATc1), cathepsin K, calcitonin receptor, and V-ATPase a3 decreased. In addition, C-176 reduced actin loop formation and bone resorption capacity. The WB results showed that C-176 downregulated the expression of the osteoclast marker protein NFATc1 and inhibited activation of the STING-mediated NF-κB pathway. We also found that C-176 could inhibit the phosphorylation of mitogen-activated protein kinase signaling pathway factors induced by RANKL. Moreover, we verified that C-176 could reduce LPS-induced bone absorption in mice, reduce joint destruction in knee arthritis induced by meniscal instability, and protect against cartilage matrix loss in ankle arthritis induced by collagen immunity. In summary, our findings demonstrated that C-176 could inhibit the formation and activation of osteoclasts and could be used as a potential therapeutic agent for inflammatory osteolytic diseases.

A case report of multicentric carpotarsal osteolysis syndrome: Depiction of a debilitating disease course.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO. Here, we report a case of a male patient who presented with kidney failure in childhood with progressive disabling skeletal deformity. He was diagnosed with MCTO at 31-years-old, where a de novo pathogenic heterozygous variant in NM_005461.5:c.212C>A: p.(Pro71His) of the MAFB gene was identified. While there has been little data on the long-term prognosis and life expectancy of this disease, this case report sheds light on the debilitating disease course with multiple significant morbidities of a patient with MCTO throughout his lifetime of 33 years.

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.

Clinical management of bone loss in cervical total disc arthroplasty: literature review and treatment recommendations.

PURPOSE: Cervical total disc replacement (cTDR) has been established as an alternative treatment for degenerative cervical radiculopathy and myelopathy. While the rate of complications for cTDR is reasonably low, recent studies have focused on bone loss after cTDR. The purpose of this work is to develop a clinical management plan for cTDR patients with evidence of bone loss. To guide our recommendations, we undertook a review of the literature and aimed to determine: (1) how bone loss was identified/imaged, (2) whether pre- or intraoperative assessments of infection or histology were performed, and (3) what decision-making and revision strategies were employed. METHODS: We performed a search of the literature according to PRISMA guidelines. Included studies reported the clinical performance of cTDR and identified instances of cervical bone loss. RESULTS: Eleven case studies and 20 cohort studies were reviewed, representing 2073 patients with 821 reported cases of bone loss. Bone loss was typically identified on radiographs during routine follow-up or by computed tomography (CT) for patients presenting with symptoms. Assessments of infection as well as histological and/or explant assessment were sporadically reported. Across all reviewed studies, multiple mechanisms of bone loss were suspected, and severity and progression varied greatly. Many patients were reportedly asymptomatic, but others experienced symptoms like progressive pain and paresthesia. CONCLUSION: Our findings demonstrate a critical gap in the literature regarding the optimal management of patients with bone loss following cTDR, and treatment recommendations based on our review are impractical given the limited amount and quality evidence available. However, based on the authors' extensive clinical experience, close follow-up of specific radiographic observations and serial radiographs to assess the progression/severity of bone loss and implant changes are recommended. CT findings can be used for clinical decision-making and further follow-up care. The pattern and rate of progression of bone loss, in concert with patient symptomatology, should determine whether non-operative or surgical intervention is indicated. Future studies involving implant retrieval, histopathological, and microbiological analysis for patients undergoing cTDR revision for bone loss are needed.

Heterotopic ossification, osteolysis and implant failure following cervical total disc replacement with the M6-C™ artificial disc.

INTRODUCTION: A recent study reported a 34% mid-term revision rate after M6-C™ cervical total disc replacement (CTDR) for wear-related osteolysis. Here, we aim to investigate the prevalence, risk factors, and radiographic characteristics of periprosthetic bony changes and implant failure of the M6-C™ artificial disc. METHODS: We retrospectively analysed radiographic (conventional X-ray, CT scan) and clinical outcomes (EQ-5D-5L, Neck Disability Index (NDI), and Visual Analog Scale (VAS) for neck and arm pain) data collected during routine follow-up of patients who underwent CTDR with the M6-C™ between 2011 and 2015. RESULTS: In total, 85 patients underwent CTDR with the M6-C™. Follow-up data were available for 43 patients (54% female, mean age 44 years) with 50 implants and a mean follow-up of 8.1 years (6.5-11 years). Implant failure with the presence of severe osteolysis was identified in 5 (12%) patients who were all male (p = 0.016) and implanted at the C5/6 level (p = 0.11). All failed implants required revision surgery. The overall prevalence of osteolysis was 44% (22/50 implants) and 34% (17/50 implants) for significant heterotopic ossification. Patients with high-grade osteolysis showed higher VAS arm pain (p = 0.05) and lower EQ-5D-VAS health VAS (p = 0.03). CONCLUSION: We report a lower reoperation rate for failed M6-C™ implants than previously published, but confirmed that osteolysis and heterotopic ossification are common following CTDR with the M6-C™ and may be asymptomatic. Therefore, we strongly recommend ongoing clinical and radiographic monitoring after CTDR with the M6-C™, particularly for male patients implanted at the C5/6 level.

Disrupted osteocyte connectivity and pericellular fluid flow in bone with aging and defective TGF-ß signaling.

Skeletal fragility in the elderly does not simply result from a loss of bone mass. However, the mechanisms underlying the concurrent decline in bone mass, quality, and mechanosensitivity with age remain unclear. The important role of osteocytes in these processes and the age-related degeneration of the intricate lacunocanalicular network (LCN) in which osteocytes reside point to a primary role for osteocytes in bone aging. Since LCN complexity severely limits experimental dissection of these mechanisms in vivo, we used two in silico approaches to test the hypothesis that LCN degeneration, due to aging or an osteocyte-intrinsic defect in transforming growth factor beta (TGF-ß) signaling (TßRIIocy-/-), is sufficient to compromise essential osteocyte responsibilities of mass transport and exposure to mechanical stimuli. Using reconstructed confocal images of bone with fluorescently labeled osteocytes, we found that osteocytes from aged and TßRIIocy-/- mice had 33 to 45% fewer, and more tortuous, canaliculi. Connectomic network analysis revealed that diminished canalicular density is sufficient to impair diffusion even with intact osteocyte numbers and overall LCN architecture. Computational fluid dynamics predicts that the corresponding drop in shear stress experienced by aged or TßRIIocy-/- osteocytes is highly sensitive to canalicular surface area but not tortuosity. Simulated expansion of the osteocyte pericellular space to mimic osteocyte perilacunar/canalicular remodeling restored predicted shear stress for aged osteocytes to young levels. Overall, these models show how loss of LCN volume through LCN pruning may lead to impaired fluid dynamics and osteocyte exposure to mechanostimulation. Furthermore, osteocytes emerge as targets of age-related therapeutic efforts to restore bone health and function.

Phalangeal microgeodic syndrome: a paediatric case series.

We present the clinical and radiological characteristics of phalangeal microgeodic syndrome in a cluster of five children during the second peak of COVID-19 pandemic in the UK. Each child presented with phalangeal swelling and erythema, prompting a comprehensive multi-disciplinary team review to analyse the clinical presentation, blood test results and imaging. The cohort's average age was 14.1 years, ranging from 10.4 to 16.6 years, with two girls and three boys. Four children experienced phalangeal involvement in the hands, whilst one was affected solely in the feet. A rheumatological work-up was performed for all. Hand X-rays performed on three children revealed distinct radiographic features like microgeodes, subperiosteal bone resorption and rarefaction in two cases. However, further MRI showed extensive changes closely correlated with the clinical signs of cutaneous vasculopathic rashes. The MRI abnormalities were notable, encompassing marrow oedema primarily affecting metaphyses and epiphyses, displaying broad transition zones. Soft tissue swelling and cortical erosions were also observed. These MRI features proved more pathognomonic in the acute clinical context. The study concluded that phalangeal microgeodic syndrome, characterised by digital swelling and erythema, might not be adequately assessed by plain X-rays. The more comprehensive MRI features, including marrow oedema and soft tissue abnormalities, appeared to be more indicative in diagnosing the condition. Considering the rarity of this syndrome and its temporal association with the COVID-19 pandemic, the study hypothesised that COVID-related thrombophilia and immune-mediated vasculopathy might act as crucial triggers for the active bony manifestations seen in this syndrome. KEY POINTS: • PMS is a rare, predominantly paediatric condition, of unknown aetiology which affects the digits. • Laboratory investigations are generally negative; however, in the appropriate clinical context, the X-ray findings of microgeodes and pattern of bone marrow oedema seen on MRI are pathognomonic. • Considering the rarity of PMS and temporal association with the COVID-19 pandemic, COVID vasculopathy may represent a previously unrecognised aetiology for PMS.

Effects of apical periodontitis treatment on hyperglycaemia in diabetes: A prospective cohort study.

AIM: This prospective cohort study was undertaken to evaluate the success rate of root canal treatment (RCT) in type 2 diabetes mellitus (T2DM) patients with targeted level and unachieved targeted level of glycaemic control as well as the impact of RCT on the glucose blood level in T2DM patients. METHODOLOGY: Patients needing RCT were divided into three groups: these without T2DM, that is, the control group (CG), those with targeted level of glycated haemoglobin HbA1c < 7% (TL A1c) and the third ones with unachieved targeted level (UTL A1c), that is, with HbA1c ≥ 7%. Before RCT, HbA1c and the periapical index (PAI) score were assessed, as well as 1 year later. RESULTS: Our results showed less favourable treatment results of RCT such as a reduction of radiographic lesions in T2DM patients, particularly in subjects with UTL A1c. The intergroup analysis of PAI score at the 12-month follow-up revealed a significant difference in TL A1C (p = .022) and CG (p = .001) with respect to UTL A1c. Total number of healed teeth (PAI≤2) at the 12-month after RCT in UTL A1c was significantly lower in comparison to CG (p = .008). Contrariwise, RCT may improve the glycaemic control in diabetic patients with UTL A1c after 12 months of posttreatment. Regression analysis showed that UTL A1c patients were more likely to have AP persistence after endodontic treatment (OR = 4.788; CI: 1.157-19.816; p = .031). CONCLUSIONS: T2DM retards the AP healing and conversely AP contributes to increasing the inflammatory burden in T2DM. RCT reduces the cumulative inflammatory burden in T2DM and thus may contribute to improvement of glycaemic control particularly in patients with UTL A1c.

Nanoparticulate bioceramic putty suppresses osteoclastogenesis and inflammatory bone loss in mice via inhibition of TRAF6-mediated signalling pathways: A laboratory investigation.

AIM: This study aimed to determine the effects of iRoot BP Plus on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in vitro and inflammation-mediated bone resorption in vivo and investigated the underlying molecular mechanisms. METHODOLOGY: CCK-8 was performed to test cell viability in RANKL-induced RAW 264.7 cells and BMDMs in response to iRoot BP Plus. The effect of iRoot BP Plus on osteoclastogenesis was determined using TRAP staining and phalloidin staining, respectively. Pit formation assay was conducted to measure osteoclast resorptive capacity. Western blot and qPCR were performed to examine osteoclast-related proteins and gene expression, respectively. Western blot was also used to investigate the signalling pathways involved. For in vivo experiments, an LPS-induced mouse calvarial bone resorption model was established to analyse the effect of iRoot BP Plus on bone resorption (n = 6 per group). At 7 days, mouse calvaria were collected and prepared for histological analysis. RESULTS: We identified that iRoot BP Plus extracts significantly attenuated RANKL-induced osteoclastogenesis, reduced sealing zone formation, restrained osteolytic capacity and decreased osteoclast-specific gene expression (p < .01). Mechanistically, iRoot BP Plus extracts reduced TRAF6 via proteasomal degradation, then suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), blocked the nuclear translocation of c-Fos and diminished nuclear factor-κB (NF-κB) p65 and NFATc1 accumulation. Consistent with the in vitro results, iRoot BP Plus extracts attenuated osteoclast activity thus protecting against inflammatory bone resorption in vivo (p < .05), which was accompanied by a suppression of TRAF6, c-Fos, NFATc1 and cathepsin K expression. CONCLUSION: These findings provide valuable insights into the signalling mechanisms underlying nanoparticulate bioceramic putty-mediated bone homeostasis.

Trifolirhizin reduces osteoclast formation and prevents inflammatory osteolysis by inhibiting RANKL-induced activation of NF-κB and MAPK signaling pathways and ROS.

Inflammatory osteolysis is often caused by the excessive activation of osteoclasts stimulated by bacterial products such as lipopolysaccharide. The natural flavonoid trifolirhizin (TRI) has anti-inflammatory properties; however, its function in inflammatory bone lysis remains unclear. This study aimed to elucidate the potential regulatory mechanisms of TRI in osteoclasts.Tartrate-resistant acid phosphatase (TRAP) staining, acid secretion assays, podosomal actin belt fluorescence staining, and bone resorption assays were used to investigate the effects of TRI on osteoclast differentiation and bone resorption. A reactive oxygen species (ROS) measurement kit was used to detect the effect of TRI on ROS levels in osteoclasts. The effects of TRI on genes and signaling pathways related to osteoclast differentiation were determined by quantitative polymerase chain reaction (qPCR) and western blotting. A mouse model of lipopolysaccharide-mediated inflammatory osteolysis was established, and the effects of TRI treatment on bone mass were observed using micro-CT and histological examination. Mechanistically, TRI reduced ROS production by inhibiting receptor activator of nuclear factor-κB ligand (RANKL)-induced activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and by upregulating the expression levels of the anti-ROS enzymes heme oxygenase-1 (HO-1) and catalase (CAT), which contributed to the degradation of ROS, ultimately leading to a decrease in osteoclastogenesis. TRI inhibited osteoclast formation and ameliorated lipopolysaccharide (LPS)-mediated inflammatory osteolysis. Thus, TRI may be a candidate agent for anti-inflammatory osteolysis.

Germacrone alleviates breast cancer-associated osteolysis by inhibiting osteoclastogenesis via inhibition of MAPK/NF-κB signaling pathways.

Bone is one of the most frequent sites for metastasis in breast cancer patients. Bone metastasis significantly reduces the survival time and the life quality of breast cancer patients. Germacrone (GM) can serve humans as an anti-cancer and anti-inflammation agent, but its effect on breast cancer-induced osteolysis remains unclear. This study aims to investigate the functions and mechanisms of GM in alleviating breast cancer-induced osteolysis. The effects of GM on osteoclast differentiation, bone resorption, F-actin ring formation, and gene expression were examined in vitro. RNA-sequencing and Western Blot were conducted to explore the regulatory mechanisms of GM on osteoclastogenesis. The effects of GM on breast cancer-induced osteoclastogenesis, and breast cancer cell malignant behaviors were also evaluated. The in vivo efficacy of GM in the ovariectomy model and breast cancer bone metastasis model with micro-CT and histomorphometry. GM inhibited osteoclastogenesis, bone resorption and F-actin ring formation in vitro. Meanwhile, GM inhibited the expression of osteoclast-related genes. RNA-seq analysis and Western Blot confirmed that GM inhibited osteoclastogenesis via inhibition of MAPK/NF-κB signaling pathways. The in vivo mouse osteoporosis model further confirmed that GM inhibited osteolysis. In addition, GM suppressed the capability of proliferation, migration, and invasion and promoted the apoptosis of MDA-MB-231 cells. Furthermore, GM could inhibit MDA-MB-231 cell-induced osteoclastogenesis in vitro and alleviate breast cancer-associated osteolysis in vivo human MDA-MB-231 breast cancer bone metastasis-bearing mouse models. Our findings identify that GM can be a promising therapeutic agent for patients with breast cancer osteolytic bone metastasis.

Subacromial osteolysis following hook plate fixation for acromioclavicular dislocation: a systematic review and meta-analysis.

BACKGROUND: Clavicular hook plates are extensively used in the treatment of acromioclavicular dislocation. Subacromial osteolysis is a typical complication following hook plate fixation. We performed a systematic review and meta-analysis to determine the incidence of subacromial osteolysis and analyzed the associated characteristics of subacromial osteolysis to guide surgeons. METHODS: PubMed, EMBASE, and Cochrane Library databases were comprehensively searched for relevant literature. We screened the literature based on the eligibility criteria, extracted relevant data, and assessed the quality of the included studies. Pooled odds ratios or mean differences with 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model. Heterogeneity was evaluated by the chi-squared test and I2 statistics. A meta-regression analysis was performed to explore the potential source of heterogeneity. RESULTS: Thirty-two studies met the inclusion criteria. The total pooled incidence of subacromial osteolysis was 29% and the only covariate that could influence the incidence of subacromial osteolysis was the radiological measurement method (P = .017). Patients in the hook plate fixation with coracoclavicular ligament reconstruction group had lower odds of subacromial osteolysis (odds ratio, 2.54, 95% CI 1.54-4.18; P < .001). There were no significant differences in the Constant-Murley scores at the final follow-up between patients with and without subacromial osteolysis (standardized mean difference, -0.17; 95% CI, -0.50 to 0.15; P = .294). CONCLUSIONS: Subacromial osteolysis has a relatively high and variable incidence, and the primary factor influencing the reported incidence is the radiological assessment method. The current analysis suggests coracoclavicular ligament reconstruction as an effective surgical approach for decreasing the incidence of subacromial osteolysis. The presence or absence of subacromial osteolysis did not significantly impact the functional outcomes observed during the final follow-up period.

Clinical Results and CT Analysis of ISA Stemless at a Minimum Follow-up of 2 Years.

INTRODUCTION: The utilization of stemless anatomic total shoulder arthroplasty is on the rise. Epiphyseal fixation leads to radiological bone remodeling, which has been reported to exceed 40% in certain studies series. The aim of this study was to present the clinical and radiological outcomes of a stemless implant with asymmetric central epiphyseal fixation at an average follow-up of 31 months. MATERIALS: This retrospective multicenter study examined prospective data of patients undergoing total anatomic arthroplasty with ISA Stemless implant and followed up at least 2 years. Clinical assessment included preoperative and final follow-up measurements of active range of motion (ROM), Constant score, and Subjective Shoulder Value (SSV). Anatomical epiphyseal reconstruction and bone remodeling at the 2-year follow-up were assessed by standardized Computed Tomography Scanner (CT scan). Statistical analysis employed unpaired Student's t-test or chi-squared test depending on the variable type, conducted using EasyMedStat software (version 3.22; www.easymedstat.com). RESULTS: Fifty patients (mean age 68 years, 62% females) were enrolled, with an average follow-up of 31 months (24-44). Primary osteoarthritis (68%) with type A glenoid (78%) was the prevailing indication. The mean Constant score and SSV improved significantly from 38 ± 11 to 76 ± 11 (p<0.001) and from 31% ± 16 to 88% ± 15 (p<0.001) respectively at the last follow-up. Forward elevation, external rotation and internal rotation ROM increased by 39° ± 42, 28° ± 21 and 3,2 ± 2,5 points respectively, surpassing the Minimally Clinically Important Difference (MCID) after total shoulder arthroplasty. No revisions were necessary. CT scans identified 30% osteolysis in the posterior-medial calcar region, devoid of clinical repercussions. No risk factors were associated with bone osteolysis. CONCLUSION: At an average follow-up of 31 months, ISA Stemless implant provided favorable clinical results. CT analysis revealed osteolysis-like remodeling in the posterior-medial zone of the calcar (30%), without decline in clinical outcomes and revisions. Long-term follow-up studies are mandated to evaluate whether osteolysis is associated with negative consequences.