osteoarthritis is a chronic degenerative joint disease. long non-coding rna plasmacytoma variant translocation 1 (PVT1) is involved in the progression of osteoarthritis and exosomes serve a central role in intercellular communication. However, whether PVT1 can be mediated by exosomes in osteoarthritis has not been reported. Whole blood was drawn from osteoarthritis patients and healthy volunteers. lipopolysaccharide (lPS) was used to stimulate human normal chondrocytes (c28/i2) to construct a cell damage model in vitro. Protein levels were examined via western blot analysis. eThe expression of PVT1, microrna (mir)-93-5p and high mobility groupprotein B1 (HMGB1) was evaluated through reverse transcription-quantitative Pcr. cell viability and apoptosis were determined through ccK-8 or flow cytometric assay. inflammatory cytokines were measured via eliSa. The relationship between PVT1 or HMGB1 and miR-93-5p was confirmed by dual-luciferase reporter assay. PVT1, HMGB1 and exosomal PVT1 were upregulated while mir-93-5p was downregulated in osteoarthritis patient serum and lPS-induced c28/i2 cells. exosomes from osteoarthritis patient serum and lPS-treated c28/i2 cells increased PVT1 expression in c28/i2 cells. PVT1 depletion reversed the decrease of viability and the increase of apoptosis, inflammation responses and collagen degradation of C28/I2 cells induced by lPS. PVT1 regulated HMGB1 expression via sponging mir-93-5p. mir-93-5p inhibition abolished PVT1 silencing-mediated viability, apoptosis, inflammation responses and collagen degradation of lPS-stimulated c28/i2 cells. HMGB1 increase overturned mir-93-5p upregulation-mediated viability, apoptosis, inflammation responses and collagen degradation of lPS-stimulated c28/i2 cells. Furthermore, PVT1 modulated the Toll-like receptor 4/nF-κB pathway through an mir-93-5p/HMGB1 axis. in summary, exosome-mediated PVT1 regulated lPS-induced osteoarthritis progression by modulating the HMGB1/Tlr4/nF-κB pathway via mir-93-5p, providing a new route for possible osteoarthritis treatment.
The present study aimed to investigate the role of periostin (POSTN) and high melatonin concentrations in the apoptosis of hFOB 1.19 human normal fetal osteoblastic cells. hFOB 1.19 human osteoblastic cells were stably cultured and treated in different concentrations of melatonin for different durations of action. Apoptosis was assessed quantitatively using flow cytometric analysis. The results of western blot analysis demonstrated that the treatment of cells with different concentrations of melatonin for different durations of action revealed a positive association between melatonin and the expression levels of glucose‑regulated protein (GRP)78, GRP94, phosphorylated (p‑) eukaryotic initiation factor 2α (eIF2α), activating transcription factor (ATF)4, CCAAT/enhanced binding protein homologous protein (CHOP), cleaved caspase‑3, p‑c‑Jun N‑terminal kinase (JNK) and POSTN. When POSTN was inhibited, the levels of p‑JNK, CHOP, p‑eIF2α, ATF4 and cleaved caspase‑3 were significantly increased, whereas other proteins associated with the endoplasmic reticulum stress (ERS) pathways, including ATF6 and X‑box binding protein 1 (XBP1), were not significantly altered. Reverse transcription‑quantitative polymerase chain reaction analysis was also performed to assess the relative mRNA levels of ATF4, ATF6 and XBP1. The results of the present study are the first, to the best of our knowledge, to demonstrate that melatonin induced apoptosis in hFOB 1.19 human osteoblastic cells by activating the ERS‑associated eIF2α‑ATF4 pathway and subsequently triggered the cascade effects of CHOP, caspase‑3 and JNK. POSTN may function as a protective factor for osteoblasts during this process by inhibiting the eIF2α‑ATF4 pathway.
Background: As the most malignant bone tumor globally, osteosarcoma has drawn increased attention. However, no studies have focused on the association between marital status and survival rate. The objectives of this study were to determine the association between marital and survival rate of osteosarcoma patients based on the SEER database. Material/Methods: We enrolled a total of 2725 osteosarcoma patients between 1973 and 2015, including 1184 married, 154 divorced/separated, 136 widowed, and 1251 never-married patients. Survival rate was determined based on the Kaplan-Meier method in different marital subgroups. Multivariate Cox regression analysis was performed to explore independent prognostic factors. Results: The 5-year overall survival (OS) and cancer-specific survival (CSS) rates of the married, separated/divorced, widowed, and never-married subjects were 45.93%, 41.39%, 19.08%, and 57.21% (OS), and 49.97%, 45.85%, 22.14%, and 60.69% (CSS), respectively. The survival outcome among subgroups exhibited a clear difference, with a log-rank test p-value <0.0001. Multivariate Cox regression showed that widowhood served as the independent prognostic factor for decreased OS rather than marriage (HR, 1.246; 95% CI, 1.011-1.536; p-value=0.039) and CSS (HR, 1.34; 95% CI, 1.07-1.68; p-value=0.01). Moreover, the OS and CSS in widowed patients were lower. Additionally, based on the propensity score matching (PSM) method, the prognosis of married patients was better than that of unmarried subjects. Conclusions: Marital status was correlated with the survival rate, meaning that married patients had higher survival than widowed subjects, who had worse prognoses of osteosarcoma.
Rationale:Phosphaturic mesenchymal tumor (PMT) is a new tumor entity of soft tissue and bone tumor recently accepted by the World Health Organization, which typically causes the paraneoplastic syndrome of tumor-induced osteomalacia (TIO). The majority of PMTs follow a benign clinical course and local recurrence occurs in < 10% of cases, malignant PMTs with distant organ metastasis are extremely uncommon.Patient concerns:We reported a 41-year-old woman who was diagnosed with PMT 10 years ago with a repeated recurrence and pulmonary metastasis.Diagnoses:Based on clinical manifestations, MRI scan, serum biochemical indicators evaluation, followed by histopathological examination, the patient was diagnosed as malignant PMT with pulmonary metastasis.Interventions:The patient was treated with calcium, phosphorus, and vitamin D after surgical resection and measured the serum ion concentrations every 3 months.Outcomes:The patient had a favorable outcome for 10 months without recurrence.Lessons:PMTs lack of characteristic histological morphology, some recurrence cases may appear benign morphologically; the malignant PMTs are easily overlooked. Patients with PMT should be carefully evaluated and monitored, in order to early identify its malignant potential.
Osteoporosis is a common disease resulting in deteriorated microarchitecture and decreased bone mass. In type 2 diabetes patients, the incidence of osteoporosis is significantly higher accompanied by increased apoptosis of osteoblasts. In this study, using the osteoblastic cell line MC3T3-E1, we show that high glucose reduces cell viability and induces apoptosis. Also, high glucose leads to endoplasmic reticulum (ER) stress (ERS) via an increase in calcium flux and upregulation of the ER chaperone binding immunoglobulin protein (BiP). Moreover, it induces post-translational activation of eukaryotic initiation factor 2 alpha (eIF2α) which functions downstream of PKR-like ER kinase (PERK). This subsequently leads to post-translational activation of the transcription factor 4 (ATF4) and upregulation of C/EBP-homologous protein (CHOP) which is an ER stress-induced regulator of apoptosis, as well as downstream effectors DNAJC3, HYOU1, and CALR. Interestingly, melatonin treatment significantly alleviates the high-glucose induced changes in cell growth, apoptosis, and calcium influx by inhibiting the PERK-eIF2α-ATF4-CHOP signaling pathway. Additionally, the MC3T3-E1 cells engineered to express a phosphodead eIF2α mutant did not show high glucose induced ER stress, confirming that melatonin protects osteoblasts against high-glucose induced changes by decreasing ER-stress induced apoptosis by impacting the PERK-eIF2α-ATF4-CHOP signaling pathway. The protective of melatonin against high glucose-induced ER stress and apoptosis was attenuated when the cells were pre-treated with a melatonin receptor antagonist, indicating that the effect of melatonin was mediated via the melatonin receptors in this context. These findings lay the provide mechanistic insights of melatonin’s protective action on osteoblasts and will be potentially be useful in ongoing pre-clinical and clinical studies to evaluate melatonin as a therapeutic option for diabetic osteoporosis.
Osteoporosis has become a worldwide disease characterized by a reduction in bone mineral density and the alteration of bone architecture leading to an increased risk of fragility fractures. And an increasing number of studies have indicated that osteoblasts undergo a large number of programmed death events by many different causes in osteoporosis and release NLRP3 and interleukin (e.g., inflammatory factors), which play pivotal roles in contributing to excessive differentiation of osteoclasts and result in exaggerated bone resorption. NLRP3 is activated during pyroptosis and processes the precursors of IL-1β and IL-18 into mature forms, which are released into the extracellular milieu accompanied by cell rupture. All of these compounds are the classical factors of pyroptosis. The cellular effects of pyroptosis are commonly observed in osteoporosis. Although many previous studies have focused on the pathogenesis of these inflammatory factors in osteoporosis, pyroptosis has not been previously evaluated. In this review, pyroptosis is proposed as a novel hypothesis of osteoporosis pathogenesis for the first time, thus providing a new direction for the treatment of osteoporosis in the future.
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