RESUMEN
Osteosarcoma, a highly aggressive bone cancer, often develops resistance to conventional chemotherapeutics, leading to poor prognosis and survival rates. The malignancy and chemoresistance of osteosarcoma pose significant challenges in its treatment, highlighting the critical need for novel therapeutic approaches. Bruton's tyrosine kinase (BTK) plays a pivotal role in B-cell development and has been linked to various cancers, including breast, lung, and oral cancers, where it contributes to tumor growth and chemoresistance. Despite its established importance in these malignancies, the impact of BTK on osteosarcoma remains unexplored. Our study delves into the expression levels of BTK in osteosarcoma tissues by data from the GEO and TCGA database, revealing a marked increase in BTK expression compared with primary osteoblasts and a potential correlation with primary site progression. Through our investigations, we identified a subset of osteosarcoma cells, named cis-HOS, which exhibited resistance to cisplatin. These cells displayed characteristics of cancer stem cells (CSCs), demonstrated a higher angiogenesis effect, and had an increased migration ability. Notably, an upregulation of BTK was observed in these cisplatin-resistant cells. The application of ibrutinib, a BTK inhibitor, significantly mitigated these aggressive traits. Our study demonstrates that BTK plays a crucial role in conferring chemoresistance in osteosarcoma. The upregulation of BTK in cisplatin-resistant cells was effectively countered by ibrutinib. These findings underscore the potential of targeting BTK as an effective strategy to overcome chemoresistance in osteosarcoma treatment.
RESUMEN
Chondrosarcoma is a malignant bone tumor that emerges from abnormalities in cartilaginous tissue and is related with lung metastases. Nicotinamide phosphoribosyltransferase (NAMPT) is an adipocytokine reported to enhance tumor metastasis. Our results from clinical samples and the Gene Expression Omnibus data set reveal that NAMPT levels are markedly higher in chondrosarcoma patients than in normal individuals. NAMPT stimulation significantly increased lysyl oxidase (LOX) production in chondrosarcoma cells. Additionally, NAMPT increased LOX-dependent cell migration and invasion in chondrosarcoma by suppressing miR-26b-5p generation through the c-Src and Akt signaling pathways. Overexpression of NAMPT promoted chondrosarcoma metastasis to the lung in vivo. Furthermore, knockdown of LOX counteracted NAMPT-facilitated metastasis. Thus, the NAMPT/LOX axis presents a novel target for treating the metastasis of chondrosarcoma.
RESUMEN
Low back pain stands as a significant factor in disability, largely resulting from intervertebral disc degeneration (IVDD). High glucose (HG) levels have been implicated in the pathogenesis of IVDD. However, the detailed mechanism of HG in IVDD is largely unknown. Our clinical results revealed that fibrosis markers such as CTGF, Col1a1, ATF4, and EIF2 are highly expressed in advanced-stage IVDD patients. Stimulation of human annulus fibrosus cells (HAFCs) with HG, but not mannitol, promotes fibrosis protein production. Ingenuity Pathway Analysis in the GSE database found that the mTOR, PKCδ, and NF-κB pathways were significantly changed during IVDD. The mTOR, PKCδ, and NF-κB inhibitors or siRNAs all abolished HG-induced fibrosis protein production. In addition, treatment of HAFCs with HG enhances the activation of mTOR, PKCδ, and NF-κB pathways. Thus, HG facilitates fibrosis in IVDD through mTOR, PKCδ, and NF-κB pathways. These results underscore the critical role of HG as a fibrotic factor in the progression of IVDD.
Asunto(s)
Anillo Fibroso , Fibrosis , Glucosa , FN-kappa B , Proteína Quinasa C-delta , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Proteína Quinasa C-delta/metabolismo , Fibrosis/metabolismo , FN-kappa B/metabolismo , Glucosa/metabolismo , Anillo Fibroso/metabolismo , Anillo Fibroso/patología , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Masculino , Femenino , Persona de Mediana Edad , Células Cultivadas , AdultoRESUMEN
Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Lymphangiogenesis plays an essential role in cancer metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with VEGF-D generation and lymphangiogenesis in chondrosarcoma remains undetermined. Our results from clinical samples reveal that VEGF-D levels are markedly higher in chondrosarcoma patients than in normal individuals. Visfatin stimulation promotes VEGF-D-dependent lymphatic endothelial cell lymphangiogenesis. We also found that visfatin induces VEGF-D production by activating HIF-1α and reducing miR-2277-3p generation through the Raf/MEK/ERK signaling cascade. Importantly, visfatin controls chondrosarcoma-related lymphangiogenesis in vivo. Therefore, visfatin is a promising target in the treatment of chondrosarcoma lymphangiogenesis.
Asunto(s)
Neoplasias Óseas , Condrosarcoma , Subunidad alfa del Factor 1 Inducible por Hipoxia , Linfangiogénesis , MicroARNs , Nicotinamida Fosforribosiltransferasa , Factor D de Crecimiento Endotelial Vascular , Humanos , Condrosarcoma/metabolismo , Condrosarcoma/genética , Condrosarcoma/patología , Linfangiogénesis/genética , MicroARNs/genética , MicroARNs/metabolismo , Nicotinamida Fosforribosiltransferasa/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Factor D de Crecimiento Endotelial Vascular/metabolismo , Factor D de Crecimiento Endotelial Vascular/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Animales , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Ratones , Citocinas/metabolismo , Masculino , Femenino , Sistema de Señalización de MAP QuinasasRESUMEN
Osteoporosis, a condition defined by low BMD (typically < -2.5 SD), causes a higher fracture risk and leads to significant economic, social, and clinical impacts. Genome-wide studies mainly in Caucasians have found many genetic links to osteoporosis, fractures, and BMD, with limited research in East Asians (EAS). We investigated the genetic aspects of BMD in 86 716 individuals from the Taiwan Biobank and their causal links to health conditions within EAS. A genome-wide association study (GWAS) was conducted, followed by observational studies, polygenic risk score assessments, and genetic correlation analyses to identify associated health conditions linked to BMD. GWAS and gene-based GWAS studies identified 78 significant SNPs and 75 genes related to BMD, highlighting pathways like Hedgehog, WNT-mediated, and TGF-ß. Our cross-trait linkage disequilibrium score regression analyses for BMD and osteoporosis consistently validated their genetic correlations with BMI and type 2 diabetes (T2D) in EAS. Higher BMD was linked to lower osteoporosis risk but increased BMI and T2D, whereas osteoporosis linked to lower BMI, waist circumference, hemoglobinA1c, and reduced T2D risk. Bidirectional Mendelian randomization analyses revealed that a higher BMI causally increases BMD in EAS. However, no direct causal relationships were found between BMD and T2D, or between osteoporosis and either BMI or T2D. This study identified key genetic factors for bone health in Taiwan, and revealed significant health conditions in EAS, particularly highlighting the genetic interplay between bone health and metabolic traits like T2D and BMI.
We investigated how genetics affect bone health and related conditions like diabetes and obesity in 86 716 EAS. Previously, most studies focused on Caucasian populations, but our work helps to understand these issues in EAS. Our findings show that stronger bones are linked to a lower chance of osteoporosis but a higher risk of obesity and T2D. On the other hand, those with osteoporosis tend to have lower body weight and a decreased risk of diabetes, illustrating a complex relationship between bone health and body metabolism. Future research will focus on deeper genetic interactions and developing targeted interventions for bone health and related metabolic disorders in EAS.
Asunto(s)
Pueblo Asiatico , Densidad Ósea , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Densidad Ósea/genética , Femenino , Masculino , Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/genética , Persona de Mediana Edad , Taiwán/epidemiología , Osteoporosis/genética , Índice de Masa Corporal , Anciano , Desequilibrio de Ligamiento , Herencia Multifactorial , Análisis de la Aleatorización Mendeliana , Pueblos del Este de AsiaRESUMEN
Two-stage revision with an antibiotic-loaded cement articulating spacer is a standard treatment for chronic prosthetic knee infection (PKI); however, mechanical complications can occur during the spacer period. There is limited evidence on the association between surgeon volume and mechanical complications after resection arthroplasty (RA) using an articulating spacer. This study aimed to compare the rates of mechanical complications and reoperation after RA with articulating spacers by surgeons with high volumes (HV) and low volumes (LV) of RA performed and analyzed the risk factors for mechanical failure. The retrospective study investigated 203 patients treated with PKIs who underwent RA with articulating spacers and were divided according to the number of RAs performed by the surgeons: HV (≥14 RAs/year) or LV (<14 RAs/year). Rates of mechanical complications and reoperations were compared. Risk factors for mechanical complications were analyzed. Of the 203 patients, 105 and 98 were treated by two HV and six LV surgeons, respectively. The mechanical complication rate was lower in HV surgeons (3.8%) than in LV surgeons (36.7%) (p < 0.001). The reoperation rate for mechanical complications was lower in HV surgeons (0.9%) than in LV surgeons (24.5%) (p < 0.001). Additionally, 47.2% of patients required hinge knees after mechanical spacer failure. Medial proximal tibial angle < 87°, recurvatum angle > 5°, and the use of a tibial spacer without a cement stem extension were risk factors for mechanical complications. Based on these findings, we made the following three conclusions: (1) HV surgeons had a lower rate of mechanical complications and reoperation than LV surgeons; (2) mechanical complications increased the level of constraint in final revision knee arthroplasty; and (3) all surgeons should avoid tibial spacer varus malalignment and recurvatum deformity and always use a cement stem extension with a tibial spacer.
RESUMEN
Osteoarthritis (OA) is a low-grade inflammatory joint illness in which monocytes migrate and infiltrate synovial tissue, differentiating into the pro-inflammatory M1 macrophage phenotype. IL-17 is a proinflammatory mediator principally generated by Th17 cells, which is elevated in OA patients; nevertheless, investigators have yet to elucidate the function of IL-17 in M1 polarization during OA development. Our analysis of clinical tissues and results from the open online dataset discovered that the level of M1 macrophage markers is elevated in human OA tissue samples than in normal tissue. High-throughput screening demonstrated that MCP-1 is a potential candidate factor after IL-17 treatment in OA synovial fibroblasts (OASFs). Immunohistochemistry data revealed that the level of MCP-1 is higher in humans and mice with OA than in normal tissues. IL-17 stimulation facilitates MCP-1-dependent macrophage polarization to the M1 phenotype. It also appears that IL-17 enhances MCP-1 synthesis in human OASFs, enhancing monocyte migration via the JAK and STAT3 signaling cascades. Our findings indicate the IL-17/MCP-1 axis as a novel strategy for the remedy of OA.
Asunto(s)
Movimiento Celular , Quimiocina CCL2 , Interleucina-17 , Macrófagos , Monocitos , Osteoartritis , Animales , Humanos , Masculino , Ratones , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/inmunología , Interleucina-17/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Monocitos/inmunología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Osteoartritis/inmunología , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Membrana Sinovial/inmunología , Membrana Sinovial/patologíaRESUMEN
Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Extracellular vesicles called exosomes are primarily used as mediators of intercellular signal transmission to control tumor metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with exosome generation in chondrosarcoma motility remains undetermined. Our results found that overexpressing visfatin augments the production of exosomes from chondrosarcoma cells. Visfatin-treated chondrosarcoma exosomes educate macrophage polarization towards the M2 but not M1 phenotype. Interestingly, M2 macrophages polarized by exosomes return to chondrosarcoma cells to facilitate cell motility. According to these findings, chondrosarcoma cells emit more exosomes when treated with visfatin. The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.
Asunto(s)
Movimiento Celular , Condrosarcoma , Exosomas , Macrófagos , Nicotinamida Fosforribosiltransferasa , Condrosarcoma/patología , Condrosarcoma/metabolismo , Exosomas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Humanos , Nicotinamida Fosforribosiltransferasa/metabolismo , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Óseas/patología , Neoplasias Óseas/metabolismo , Citocinas/metabolismoRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder in which monocytes adhering to synovial tissue differentiate into the pro-inflammatory M1 macrophage phenotype. Nerve growth factors (NGF) referred to as neurotrophins have been associated with inflammatory events; however, researchers have yet to elucidate the role of NGF in RA. Our examination of clinical tissue samples and analysis of data sourced from the Gene Expression Omnibus dataset unveiled elevated expression levels of M1 macrophage markers in human RA synovial tissue samples compared to normal tissue, with no such distinction observed for M2 markers. Furthermore, immunofluorescence data depicted increased expression levels of NGF and M1 macrophages in RA mice in contrast to normal mice. It appears that NGF stimulation facilitates macrophage polarization from the M0 to the M1 phenotype. It also appears that NGF promotes ICAM-1 production in human RA synovial fibroblasts, which enhances monocyte adhesion through the TrkA, MEK/ERK, and AP-1 signaling cascades. Our findings indicate NGF/TrkA axis as a novel target for the treatment of RA.
Asunto(s)
Artritis Reumatoide , Molécula 1 de Adhesión Intercelular , Monocitos , Factor de Crecimiento Nervioso , Animales , Humanos , Ratones , Artritis Reumatoide/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Factor de Crecimiento Nervioso/metabolismoRESUMEN
Rheumatoid arthritis (RA) is a well-known autoimmune disorder associated with joint pain, joint swelling, cartilage and bone degradation as well as deformity. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a crucial role in multiple cellular pathogenesis processes, including RA. TNF-α is a vital proinflammatory factor in the progression of RA. However, the role of CXCL13 in TNF-α production in RA has not been fully explored. Our analysis of both database and clinical samples revealed higher levels of CXCL13 and TNF-α in RA samples compared to healthy controls. CXCL13 concentration-dependently induces TNF-α synthesis in RA synovial fibroblasts. CXCL13 enhances TNF-α expression by interacting with the CXCR5 receptor, activating the ERK/p38 pathways, and inhibiting miR-330-3p generation. Importantly, treatment with CXCL13 shRNA counteracted the upregulation of TNF-α production induced by collagen-induced arthritis. Our findings support the notion that CXCL13 is a promising target in the treatment of RA.
Asunto(s)
Artritis Experimental , Artritis Reumatoide , Enfermedades Autoinmunes , MicroARNs , Animales , Factor de Necrosis Tumoral alfa/farmacología , Artritis Reumatoide/genética , MicroARNs/genéticaRESUMEN
Osteoarthritis (OA) is a prevalent joint disease commonly associated with aging and obesity, which can lead to pain, stiffness, joint dysfunction, and disability. Omentin-1 (also called intelectin-1) is a newly discovered adipokine, which plays a protective role in suppressing the secretion of pro-inflammatory cytokines. Based on data from the Gene Expression Omnibus (GEO) dataset and clinical samples obtained at our institution revealed, determined that omentin-1 and IL-4 (an anti-inflammatory cytokine) levels were significantly lower in OA patients than in normal controls. Omentin-1 was shown to induce IL-4-depedent anti-inflammatory responses and M2 macrophage polarization in OA synovial fibroblasts via the PI3K, ERK, and AMPK pathways. Administering omentin-1 was shown to block cartilage degradation and bone erosion resulting from anterior cruciate ligament transection by inhibiting the production of pro-inflammatory cytokines and promoting M2 macrophage polarization in vivo. Our findings indicate omentin-1 as a promising therapeutic avenue for the treatment for OA.
Asunto(s)
Citocinas , Interleucina-4 , Macrófagos , Osteoartritis , Humanos , Citocinas/metabolismo , Interleucina-4/inmunología , Macrófagos/inmunología , Osteoartritis/inmunologíaRESUMEN
Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting reactive oxygen species (ROS) accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.
Asunto(s)
Neoplasias Óseas , Condrosarcoma , Humanos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Anfirregulina/genética , Glutamina , Resistencia a Antineoplásicos/genética , Condrosarcoma/tratamiento farmacológico , Condrosarcoma/genética , Línea Celular Tumoral , Antígenos de Histocompatibilidad Menor , Sistema de Transporte de Aminoácidos ASCRESUMEN
Chondrosarcoma is a primary malignant bone tumor. Traditional therapy is not very effective, and it is prone to metastasis in the late stage. The tumor microenvironment (TME) plays a key role in the progression and metastasis of chondrosarcoma, and hypoxia is one of the key factors in the formation of TME. However, the detailed mechanism of how hypoxia affects tumor progression and metastasis in chondrosarcoma is still not fully understood. In this study, we focused on the mechanism of interaction between hypoxic chondrosarcoma cells (SW1353) and macrophages. Our results suggest that hypoxia enhances the release of exosomes from chondrosarcoma cells. These hypoxia-induced exosomes promoted macrophage polarization towards the M2 phenotype, characterized by the expression of CD163 and CD206, but not the M1 phenotype, characterized by CD86 expression. Further analysis revealed that M2 macrophages polarized by exosomes expressed arginase-1 and feedback to chondrosarcoma cells to promote migration. These results suggest that chondrosarcoma cells secrete more exosomes in a hypoxic microenvironment, and these hypoxia-derived exosomes induce the polarization of macrophages into an M2 phenotype, ultimately promoting the metastatic behavior of chondrosarcoma cells.
Asunto(s)
Exosomas , MicroARNs , Humanos , Exosomas/metabolismo , Macrófagos/metabolismo , Línea Celular Tumoral , Hipoxia/metabolismo , Fenotipo , Microambiente Tumoral/genética , MicroARNs/metabolismoRESUMEN
Osteosarcoma is a common malignant tumor in children and adolescents, known for its aggressive invasion and distant metastasis, leading to a poor prognosis. Matrix metalloproteinases (MMPs) can degrade the extracellular matrix and basement membranes through their proteolytic activity, thereby promoting osteosarcoma metastasis. Chemokine ligand 2 (CCL2) is a well-studied chemokine that plays a significant role in the cell motility of many cancers. However, its specific involvement in osteosarcoma metastasis is not fully understood. The aim of this study is to examine the role of miRNAs in CCL2-mediated MMP expression and cell motility in human osteosarcoma. The analysis of immunohistochemistry data and databases associated a positive correlation between CCL2 or MMP-3 levels with the metastasis of osteosarcoma patients. The in vivo lung metastatic osteosarcoma model also demonstrated similar effects, showing higher levels of CCL2 and MMP-3 in lung metastatic osteosarcoma tissues. The stimulation of osteosarcoma cells with CCL2 enhanced migration and invasion abilities through the upregulation of MMP-3 synthesis. Our results also indicate that CCL2 enhances MMP-3-dependent cell motility by inhibiting miR-3659 synthesis. Therefore, CCL2 represents a promising therapeutic target for treating metastasis in osteosarcoma.
RESUMEN
Bone loss is a major issue for patients with osteoporosis, arthritis, periodontitis, and bone metastasis; however, anti-resorption drugs used to treat bone loss have been linked to a variety of adverse effects. Helminthostachys zeylanica (L.) Hook, belonging to the family Ophioglossaceae, is commonly used in traditional Chinese medicine to treat inflammation and liver problems. In the current study, ugonin L extracted from H. zeylanica was shown to reduce the receptor activator of nuclear factor kappa beta ligand (RANKL)-induced osteoclastogenesis in RAW264.7 cells in a concentration-dependent manner. Ugonin L treatment also inhibited the mRNA expression of osteoclast markers. Ugonin L was also shown to promote cell apoptosis in mature osteoclasts and suppress RANKL-induced ERK, p38, JNK, and NF-κB activation. Taken together, ugonin L appears to be a promising candidate for the development of novel anti-resorption therapies.
Asunto(s)
Enfermedades Óseas Metabólicas , FN-kappa B , Humanos , Apoptosis , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteogénesis , Transducción de Señal , Medicamentos Herbarios Chinos/farmacología , Ligando RANK/efectos de los fármacos , Ligando RANK/metabolismoRESUMEN
Pelvic-acetabular fractures lead to high mortality in elders and their association between different groups is not known. Our results indicate that older age with pelvic-acetabular fracture was significantly associated with mortality. This finding may help planning and allocating healthcare resources, risk stratification, and optimizing the treatment of pelvic fractures. PURPOSE: Pelvic or acetabular fractures are among main outcomes of low-energy trauma such as falls, especially in older adults. They represent approximately 3-8% of all fractures and are associated with a high mortality rate ranging from 4 to 28%. This study is aimed at comparing the incidence and trends of hip fractures and pelvic-acetabular fractures in the Taiwanese general population, gender differences in adults aged over 65 years, and mortality risk between pelvic or acetabular fractures and hip fractures and surgery trends in patients with these fractures. METHODS: A retrospective study was conducted extracting data from the National Health Insurance Research Database of patients diagnosed with hip fracture and pelvic acetabular fracture between 2000 and 2018. RESULTS: Older age with pelvic-acetabular fracture was significantly associated with increased mortality. No significant differences were found in comorbidities between the two fracture groups. Results provide clear epidemiological evidence for trends in pelvic-acetabular fractures in Taiwan and demonstrate the need for better strategies to manage these fractures and comorbidities, particularly in older adults. CONCLUSION: Findings of this study may aid in planning and allocating healthcare resources, risk stratification, and optimizing the treatment of pelvic fractures among older adults in Taiwan.
Asunto(s)
Fracturas Óseas , Fracturas de Cadera , Huesos Pélvicos , Fracturas de la Columna Vertebral , Humanos , Anciano , Estudios Retrospectivos , Taiwán/epidemiología , Acetábulo/lesiones , Acetábulo/cirugía , Fracturas de Cadera/epidemiología , Fracturas de Cadera/cirugía , Fracturas Óseas/epidemiología , Fracturas Óseas/terapia , Fracturas Óseas/complicaciones , Huesos Pélvicos/lesiones , Fracturas de la Columna Vertebral/complicaciones , EnvejecimientoRESUMEN
Chondrosarcoma has a high propensity to metastasize and responds poorly to chemotherapy and radiation treatment. The enzymatic activity of matrix metalloproteinases (MMPs) is very important in chondrosarcoma metastasis. Melatonin exhibits anticarcinogenic activity in many types of cancers by suppressing the expression of certain MMP family members, but this has not yet been clearly determined in chondrosarcoma. Our study demonstrates that MMP7 plays an essential role in chondrosarcoma cell proliferation, migration, and anoikis resistance. We also found that MMP7 is highly expressed in chondrosarcomas. Our in vitro and in vivo investigations show that melatonin strongly inhibits chondrosarcoma cell proliferation, migration, and anoikis resistance by directly suppressing MMP7 expression. Melatonin reduced MMP7 synthesis by promoting levels of miR-520f-3p expression, which were downregulated in human chondrosarcoma tissue samples. Pharmacological inhibition of miR-520f-3p markedly reversed the effects of melatonin upon chondrosarcoma proliferation and metastasis. Thus, our study suggests that melatonin has therapeutic potential for reducing the tumorigenesis and metastatic potential of chondrosarcoma via the miR-520f-3p/MMP7 axis.
Asunto(s)
Condrosarcoma , Melatonina , MicroARNs , Humanos , MicroARNs/genética , Línea Celular Tumoral , Melatonina/farmacología , Metaloproteinasa 7 de la Matriz/metabolismo , Proliferación Celular , Condrosarcoma/tratamiento farmacológico , Condrosarcoma/genética , Condrosarcoma/metabolismo , Movimiento Celular , Regulación Neoplásica de la Expresión GénicaRESUMEN
New therapeutic approaches are needed for metastatic osteosarcoma (OS), as survival rates remain low despite surgery and chemotherapy. Epigenetic changes, such as histone H3 methylation, play key roles in many cancers including OS, although the underlying mechanisms are not clear. In this study, human OS tissue and OS cell lines displayed lower levels of histone H3 lysine trimethylation compared with normal bone tissue and osteoblast cells. Treating OS cells with the histone lysine demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX-1) dose-dependently increased histone H3 methylation and inhibited cellular migratory and invasive capabilities, suppressed matrix metalloproteinase expression, reversed epithelial-to-mesenchymal transition by increasing levels of epithelial markers E-cadherin and ZO-1 and decreasing the expression of mesenchymal markers N-cadherin, vimentin, and TWIST, and also reduced stemness properties. An analysis of cultivated MG63 cisplatin-resistant (MG63-CR) cells revealed lower histone H3 lysine trimethylation levels compared with levels in MG63 cells. Exposing MG63-CR cells to IOX-1 increased histone H3 trimethylation and ATP-binding cassette transporter expression, potentially sensitizing MG63-CR cells to cisplatin. In conclusion, our study suggests that histone H3 lysine trimethylation is associated with metastatic OS and that IOX-1 or other epigenetic modulators present promising strategies to inhibit metastatic OS progression.
Asunto(s)
Neoplasias Óseas , Osteosarcoma , Humanos , Histonas/metabolismo , Lisina/metabolismo , Cisplatino/farmacología , Osteosarcoma/tratamiento farmacológico , Neoplasias Óseas/tratamiento farmacológicoRESUMEN
Inverse restricted kinematic alignment (irKA) was modified from restricted kinematic alignment for total knee arthroplasty (TKA). This prospective single-center study aimed to evaluate the outcomes of irKA-TKA on all knee subtypes classified by Asia specific (Huang's) phenotypes. A total of 96 knees that underwent irKA-TKA at one hospital between January 2018 and June 2020 were included, with 15 knees classified in Type 1, nine in Type 2, 15 in Type 3, 47 in Type 4, and 10 in Type 5 by Huang's phenotypes. Outcomes were knee alignment measures and patient-reported satisfaction evaluated by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and traditional Chinese version of the Forgotten Joint Score-12 (FJS-12). Follow-up was one year. Type 4 knee was most significantly corrected in all angles by irKA-TKA, followed by Type 2 and 3 knees. Type 5 and 1 knee were only significantly corrected in some angles. The correlation between FJS-12 and WOMAC was good at 6 months (Pearson correlation coefficient (r) = 0.74) and moderate at 6 weeks, 3 months, and 12 months during follow-up (r = 0.37~0.47). FJS-12 and WOMAC displayed comparable hip-knee-ankle angle cut-off value (4.71° vs. 6.20°), sensitivity (70.49% vs. 67.19%), specificity (84.00% vs. 85.71%), and Youden index (54.49% vs. 52.90%) in prediction of good prognosis. In conclusion, irKA-TKA corrects knee alignment in all knee types with increasing satisfaction for one-year follow-up. Knees with presurgical varus deformity are most recommended for irKA-TKA. Both presurgical scores of the traditional Chinese version of FJS-12 and WOMAC predict the prognosis of irKA-TKA.
RESUMEN
Lung cancer is an extremely common cancer and metastatic lung cancer has a greatly low survival rate. Lymphangiogenesis is essential for the development and metastasis of lung cancer. The adipokine angiopoietin-like protein 2 (ANGPTL2) regulates tumor progression and metastasis, although the functions of ANGPTL2 in lung cancer are unknown. Analysis of data from TCGA genomics program, the GEPIA web server and the Oncomine database revealed that higher levels of ANGPTL2 expression were correlated with progressive disease and lymph node metastasis. ANGPTL2 enhanced VEGF-A-dependent lymphatic endothelial cell (LEC) tube formation and migration. Integrin α5ß1, p38 and nuclear factor (NF)-κB signaling mediated ANGPTL2-regulated lymphangiogenesis. Importantly, overexpression ANGPTL2 facilitated tumor growth and lymphangiogenesis in vivo. Thus, ANGPTL2 is a promising therapeutic object for treating lung cancer.