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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.
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Exossomos , Células-Tronco Mesenquimais , Osteólise , Humanos , Administração Intravenosa , MacrófagosRESUMO
Random skin flap grafting is the most common skin grafting technique in reconstructive surgery. Despite progress in techniques, the incidence of distal flap necrosis still exceeds 3%, which limits its use in clinical practice. Current methods for treating distal flap necrosis are still lacking. Pinocembrin (Pino) can inhibit reactive oxygen species (ROS) and cell death in a variety of diseases, such as cardiovascular diseases, but the role of Pino in random flaps has not been explored. Therefore, we explore how Pino can enhance flap survival and its specific upstream mechanisms via macroscopic examination, Doppler, immunohistochemistry, and western blot. The results suggested that Pino can enhance the viability of random flaps by inhibiting ROS, pyroptosis and apoptosis. The above effects were reversed by co-administration of Pino with adeno-associated virus-silencing information regulator 2 homolog 3 (SIRT3) shRNA, proving the beneficial effect of Pino on the flaps relied on SIRT3. In addition, we also found that Pino up-regulates SIRT3 expression by activating the AMP-activated protein kinase (AMPK) pathway. This study proved that Pino can improve random flap viability by eliminating ROS, and ROS-induced cell death through the activation of SIRT3, which are triggered by the AMPK/PGC-1α signaling pathway.
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Piroptose , Sirtuína 3 , Humanos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Sirtuína 3/metabolismo , Apoptose , NecroseRESUMO
Osteoporosis results from an imbalance between bone formation and bone resorption. Traditional drugs for treating osteoporosis are associated with serious side effects, and thus, new treatment methods are required. This study investigated the role of differentially expressed microRNAs during osteoclast differentiation and osteoclast activity during osteoarthritis as well as the associated underlying mechanisms. We used a microarray to screen microRNAs that decreased in the process of osteoclast differentiation and verified miR-21-5p to decrease significantly using RT-qPCR. In follow-up experiments, we found that miR-21-5p targets SKP2 to regulate osteoclast differentiation. In vivo, ovariectomized mice were used to simulate perimenopausal osteoporosis induced by estrogen deficiency, and miR-21-5p treatment inhibited bone resorption and maintained bone cortex and trabecular structure. These results suggest that miR-21-5p is a new therapeutic target for osteoporosis.
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Diferenciação Celular , Modelos Animais de Doenças , MicroRNAs/genética , Osteoclastos/citologia , Osteogênese , Osteoporose/patologia , Proteínas Quinases Associadas a Fase S/metabolismo , Animais , Feminino , Camundongos , Osteoclastos/metabolismo , Osteoporose/genética , Osteoporose/metabolismo , Células RAW 264.7 , Proteínas Quinases Associadas a Fase S/genéticaRESUMO
OBJECTIVES: Circular RNAs (circRNAs) have emerged as significant biological regulators. Herein, we aimed to elucidate the role of an unidentified circRNA (circPDE4B) that is reportedly downregulated in osteoarthritis (OA) tissues. METHODS: The effects of circPDE4B were explored in human and mouse chondrocytes in vitro. Specifically, RNA pull-down (RPD)-mass spectrometry analysis (MS), immunoprecipitation, glutathione-S-transferase (GST) pull-down, RNA immunoprecipitation and RPD assays were performed to verify the interactions between circPDE4B and the RIC8 guanine nucleotide exchange factor A (RIC8A)/midline 1 (MID1) complex. A mouse model of OA was also employed to confirm the role of circPDE4B in OA pathogenesis in vivo. RESULTS: circPDE4B regulates chondrocyte cell viability and extracellular matrix metabolism. Mechanistically, FUS RNA binding protein (FUS) was found to promote the splicing of circPDE4B, while downregulation of circPDE4B in OA is partially caused by upstream inhibition of FUS. Moreover, circPDE4B facilitates the association between RIC8A and MID1 by acting as a scaffold to promote RIC8A degradation through proteasomal degradation. Furthermore, ubiquitination of RIC8A at K415 abrogates RIC8A degradation. The circPDE4B-RIC8A axis was observed to play an important role in regulating downstream p38 mitogen-activated protein kinase (MAPK) signalling. Furthermore, delivery of a circPDE4B adeno-associated virus (AAV) abrogates the breakdown of cartilage matrix by medial meniscus destabilisation in mice, whereas a RIC8A AAV induces the opposite effect. CONCLUSION: This work highlights the function of the circPDE4B-RIC8A axis in OA joints, as well as its regulation of MAPK-p38, suggesting this axis as a potential therapeutic target for OA.
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Cartilagem Articular/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Osteoartrite/genética , RNA Circular , Regeneração/genética , Animais , Cartilagem Articular/citologia , Cartilagem Articular/fisiologia , Sobrevivência Celular/genética , Condrócitos/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Camundongos , Osteoartrite/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Proteína FUS de Ligação a RNA/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Following the publication of the original paper [1], one corresponding author was inadvertently missed.
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Postmenopausal osteoporosis is initiated by estrogen withdrawal and is characterized mainly by overactivated osteoclastic bone resorption. Targeting TNF receptor-associated factor 6 (TRAF6) or its downstream signaling pathways to modulate osteoclast formation and function is an appealing strategy for osteoclast-related disorders. In the present study, we determined the effect of tomatidine, a steroidal alkaloid derived from Solanaceae, on the formation and function of receptor activator of NF-κB (RANK) ligand-induced osteoclasts and the underlying mechanism. Tomatidine inhibited osteoclast formation in a dose-dependent manner and decreased the expression of osteoclast marker genes. Actin ring formation and osteoclastic bone resorption were attenuated in the presence of tomatidine in vitro. Eight weeks after ovariectomy, tomatidine prevented estrogen deficiency-induced bone loss and restored the mechanical properties of the femur. At the molecular level, tomatidine abrogated phosphorylation of c-Jun N-terminal kinase (JNK)/p38, NF-κB, and protein kinase B (Akt) pathway proteins by suppressing RANK expression, inhibiting the binding of TRAF6 to RANK, and downregulating the osteoclastogenesis marker-related protein expression. In summary, these data demonstrated that tomatidine attenuated osteoclast formation and function by modulating multiple TRAF6-mediated pathways. Therefore, tomatidine could be a novel candidate for the treatment of osteoclast-related disorders, including osteoporosis.-Hu, B., Sun, X., Yang, Y., Ying, Z., Meng, J., Zhou, C., Jiang, G., Li, S., Wu, F., Zhao, X., Zhu, H., Wu, H., Cai, X., Shi, Z., Yan, S. Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency-induced bone mass loss by modulating TRAF6-mediated signaling.
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Reabsorção Óssea/tratamento farmacológico , Estrogênios/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/metabolismo , Tomatina/análogos & derivados , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Ovariectomia/efeitos adversos , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Tomatina/farmacologiaRESUMO
BACKGROUND: CircMYO10 is a circular RNA generated by back-splicing of gene MYO10 and is upregulated in osteosarcoma cell lines, but its functional role in osteosarcoma is still unknown. This study aimed to clarify the mechanism of circMYO10 in osteosarcoma. METHODS: CircMYO10 expression in 10 paired osteosarcoma and chondroma tissues was assessed by quantitative reverse transcription polymerase chain reaction (PCR). The function of circMYO10/miR-370-3p/RUVBL1 axis was assessed regarding two key characteristics: proliferation and endothelial-mesenchymal transition (EMT). Bioinformatics analysis, western blotting, real-time PCR, fluorescence in situ hybridization, immunoprecipitation, RNA pull-down assays, luciferase reporter assays, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Stably transfected MG63 cells were injected via tail vein or subcutaneously into nude mice to assess the role of circMYO10 in vivo. RESULTS: CircMYO10 was significantly upregulated, while miR-370-3p was downregulated, in osteosarcoma cell lines and human osteosarcoma samples. Silencing circMYO10 inhibited cell proliferation and EMT in vivo and in vitro. Mechanistic investigations revealed that miR-370-3p targets RUVBL1 directly, and inhibits the interaction between RUVBL1 and ß-catenin/LEF1 complex while circMYO10 showed a contrary effect via the inhibition of miR-370-3p. RUVBL1 was found to be complexed with chromatin remodeling and histone-modifying factor TIP60, and lymphoid enhancer factor-1 (LEF1) to promote histone H4K16 acetylation (H4K16Ac) in the vicinity of the promoter region of gene C-myc. Chromatin immunoprecipitation methods showed that miR-370-3p sponge promotes H4K16Ac in the indicated region, which is partially abrogated by RUVBL1 small hairpin RNA (shRNA) while circMYO10 showed a contrary result via the inhibition of miR-370-3p. Either miR-370-3p sponge or ShRUVBL1 attenuated circMYO10-induced phenotypes in osteosarcoma cell lines. MiR-370-3p inhibition abrogated the inhibition of proliferation, EMT of osteosarcoma cells in vitro and in vivo seen upon circMYO10 suppression via Wnt/ß-catenin signaling. CONCLUSIONS: CircMYO10 promotes osteosarcoma progression by regulating miR-370-3p/RUVBL1 axis to promote chromatin remodeling and thus enhances the transcriptional activity of ß-catenin/LEF1 complex, which indicates that circMYO10 may be a potential therapeutic target for osteosarcoma treatment.
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ATPases Associadas a Diversas Atividades Celulares/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Proteínas de Transporte/genética , Montagem e Desmontagem da Cromatina , DNA Helicases/genética , MicroRNAs/genética , Miosinas/genética , Osteossarcoma/genética , Osteossarcoma/metabolismo , RNA Circular , Regiões 3' não Traduzidas , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Metilação , Camundongos , Metástase Neoplásica , Osteossarcoma/patologia , Regiões Promotoras Genéticas , Ligação Proteica , Interferência de RNA , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
OBJECTIVES: Circular RNAs (circRNA) expression aberration has been identified in various human diseases. In this study, we investigated whether circRNAs could act as competing endogenous RNAs to regulate the pathological process of osteoarthritis (OA). METHODS: CircRNA deep sequencing was performed to the expression of circRNAs between OA and control cartilage tissues. The regulatory and functional role of CircSERPINE2 upregulation was examined in OA and was validated in vitro and in vivo, downstream target of CircSERPINE2 was explored. RNA pull down, a luciferase reporter assay, biotin-coupled microRNA capture and fluorescence in situ hybridisation were used to evaluate the interaction between CircSERPINE2 and miR-1271-5 p, as well as the target mRNA, E26 transformation-specific-related gene (ERG). The role and mechanism of CircSERPINE2 in OA was also explored in rabbit models. RESULTS: The decreased expression of CircSERPINE2 in the OA cartilage tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of extracellular matrix (ECM). Mechanistically, CircSERPINE2 acted as a sponge of miR-1271-5 p and functioned in human chondrocytes (HCs) through targeting miR-1271-5 p and ERG. Intra-articular injection of adeno-associated virus-CircSERPINE2-wt alleviated OA in the rabbit model. CONCLUSIONS: Our results reveal an important role for a novel circRNA-CircSERPINE2 in OA progression. CircSERPINE2 overexpression could alleviate HCs apoptosis and promote anabolism of ECM through miR-1271-ERG pathway. It provides a potentially effective therapeutic strategy for OA progression.
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MicroRNAs/metabolismo , Osteoartrite/genética , Serpina E2/fisiologia , Animais , Apoptose/genética , Artrite Experimental/terapia , Cartilagem Articular/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Células Cultivadas , Condrócitos/metabolismo , Matriz Extracelular/metabolismo , Feminino , Marcação de Genes , Terapia Genética/métodos , Humanos , Masculino , MicroRNAs/genética , Terapia de Alvo Molecular/métodos , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/terapia , RNA Circular/metabolismo , Coelhos , Serpina E2/genéticaRESUMO
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.
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Exossomos , Osteólise , Humanos , Osteólise/induzido quimicamente , Células-Tronco , Exossomos/metabolismo , Membrana Celular , MacrófagosRESUMO
Kümmell disease (KD) causes serious vertebral body collapse in patients. However, only a few case reports have been conducted and the number of patients with KD investigated was limited. Additionally, the frequently used poly(methyl methacrylate) (PMMA) bone cement for KD is limited by excessive modulus and poor biocompatibility. Herein, we aimed to modify PMMA bone cement with mineralized collagen (MC), and compare the clinical effects, image performance and finite element analysis between the modified bone cement and PMMA bone cement for the treatment of phase I and II KD. Thirty-nine KD patients treated with PMMA bone cement and 40 KD patients treated with MC-modified PMMA bone cement from June 2015 to March 2017 were retrospectively analyzed. The surgical procedure, intraoperative blood loss, hospital stay and complications were compared between different groups. Visual analog scale, Oswestry disability index, anterior vertebral height, posterior vertebral height, computed tomography value, adjacent vertebral re-fracture, Cobb angle and wedge-shaped correction angle were evaluated. Additionally, the representative sample was selected for finite element analysis. We found that the MC-modified PMMA bone cement could achieve the same effect as that of PMMA bone cement and was associated with better vertebral height restoration in the long term.
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Osteoarthritis (OA), characterized as an end-stage syndrome caused by risk factors accumulated with age, significantly impacts quality of life in the elderly. Circular RNAs (circRNAs) are receiving increasing attention regarding their role in OA progression and development; however, their role in the regulation of age-induced and oxidative stress-related OA remains unclear. Methods: Herein, we explored oxidative stress in articular cartilage obtained from patients of different ages. The presence of circRSU1 was detected using RNA sequencing of H2O2-stimulated primary human articular chondrocytes (HCs), and validated in articular cartilage and HCs using fluorescence in situ hybridization (FISH) staining. miR-93-5p and mitogen-activated protein kinase kinase kinase 8 (MAP3K8) were identified as interactive circRSU1 partners based on annotation and target prediction databases, and their associations were identified through dual-luciferase reporter analysis. The effect of the circRSU1-miR-93-5p-MAP3K8 axis on HCs was confirmed using western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and reactive oxygen species (ROS) analyses. CircRSU1 and its mutant were ectopically expressed in mice to assess their effects in destabilization of the medial meniscus (DMM) in mice. Results: We found a marked upregulation of circRSU1 in H2O2-treated HCs and OA articular cartilage from elderly individuals. circRSU1 was induced by IL-1ß and H2O2 stimulation, and it subsequently regulated oxidative stress-triggered inflammation and extracellular matrix (ECM) maintenance in HCs, by modulating the MEK/ERK1/2 and NF-κB cascades. Ectopic expression of circRSU1 in mouse joints promoted the production of ROS and loss of ECM, which was rescued by mutation of the mir-93-5p target sequence in circRSU1. Conclusion: We identified a circRSU1-miR-93-5p-MAP3K8 axis that modulates the progression of OA via oxidative stress regulation, which could serve as a potential target for OA therapy.
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Cartilagem Articular/patologia , MAP Quinase Quinase Quinases/metabolismo , MicroRNAs/genética , Osteoartrite/patologia , Estresse Oxidativo , Proteínas Proto-Oncogênicas/metabolismo , RNA Circular/genética , Fatores de Transcrição/genética , Animais , Apoptose , Biomarcadores/metabolismo , Cartilagem Articular/metabolismo , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Humanos , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/genética , Osteoartrite/metabolismo , Proteínas Proto-Oncogênicas/genéticaRESUMO
Rationale: Osteoarthritis (OA) is the most common joint disease worldwide. Previous studies have identified the imbalance between extracellular matrix (ECM) catabolism and anabolism in cartilage tissue as the main cause. To date, there is no cure for OA despite a few symptomatic treatments. This study aimed to investigate the role of CircCDK14, a novel circRNA factor, in the progression of OA, and to elucidate its underlying molecular mechanisms. Methods: The function of CircCDK14 in OA, as well as the interaction between CircCDK14 and its downstream target (miR-125a-5p) and mRNA target (Smad2), was evaluated by western blot (WB), immunofluorescence (IF), RNA immunoprecipitation (RIP), quantitative RT-PCR, luciferase assay and fluorescence in situ hybridization (FISH). Rabbit models were introduced to examine the function and mechanism of CircCDK14 in OA in vivo. Results: In our present study, we found that CircCDK14, while being down-regulated in the joint wearing position, regulated metabolism, inhibited apoptosis and promoted proliferation in the cartilage. Mechanically, the protective effect of CircCDK14 was mediated by miR-125a-5p sponging, which downregulated the Smad2 expression and led to the dysfunction of TGF-ß signaling pathway. Intra-articular injection of adeno-associated virus-CircCDK14 also alleviated OA in the rabbit model. Conclusion: Our study revealed an important role of CircCDK14/miR-125a-5p/Smad2 axis in OA progression and provided a potential molecular therapeutic strategy for the treatment of OA.
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Quinases Ciclina-Dependentes/metabolismo , MicroRNAs/metabolismo , Osteoartrite/metabolismo , RNA Circular/metabolismo , Proteína Smad2/metabolismo , Animais , Apoptose/fisiologia , Cartilagem/metabolismo , Proliferação de Células/fisiologia , Condrócitos/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo/fisiologia , Matriz Extracelular/metabolismo , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Coelhos , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Lumbar intervertebral disc degeneration (IVDD) is the most common cause of low back pain (LBP). Among all the factors leading to IVDD, lumbar cartilage endplate (LCE) degeneration is considered a key factor. In the present study, we investigate the effect and regulation of carbonic anhydrase 12 (CA12) in LCE, which catalyzes hydration of CO2 and participates in a variety of biological processes, including acid-base balance and calcification. Our results show that CA12, downregulated in degenerated LCE, could maintain anabolism and prevent calcification in the endplate. Furthermore, CA12 is regulated by the IGF-1/IGF-1R/PI3K/CREB signaling pathway. When we overexpressed CA12 in LCE, the decreased anabolism induced by inflammatory cytokine could be rescued. In contrast, reducing CA12 expression, either with siRNA, PI3Kinhibitor, or CREB inhibitor, could downregulate anabolism and cause apoptosis and then calcification in LCE. The protective effects of IGF-1 are even diminished with low-expressed CA12. Similar results are also obtained in an ex vivo model. Consequently, our results reveal a novel pathway, IGF-1/IGF-1R/PI3K/CREB/CA12, that takes a protective role in LCE degeneration by maintaining anabolism and preventing calcification and apoptosis. This study proposes a novel molecular target, CA12, to delay LCE degeneration.
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Osteoarthritis (OA) is a degenerative joint disease. Currently, apart from symptomatic treatment or joint replacement, no other effective treatments for OA exist. The mechanisms underlying OA remain elusive and require further research. Circular RNAs (circRNAs) are known to be involved in many diseases; however, their function in OA is not yet fully understood. Here, we identified a novel circRNA, Circ0083429. The role of Circ0083429 in OA was confirmed via western blot (WB), quantitative real-time PCR (qRT-PCR), and immunofluorescence (IF) through knockdown and overexpression experiments. The binding of Circ0083429 to downstream miR-346 and its target gene SMAD3 was predicted via bioinformatics analysis and verified using a luciferase reporter assay and RNA pulldown experiments. Finally, the function of Circ0083429 was evaluated in mouse OA models. In our study, we found that Circ0083429 regulates the homeostasis of the extracellular matrix (ECM) in human chondrocytes. Mechanistically, Circ0083429 affects OA by regulating the mRNA level of SMAD3 through the sponging of microRNA (miRNA)-346. Injecting adeno-associated virus Circ0083429 into the intra-junction of the mouse knee alleviated OA. In conclusion, Circ0083429 regulates the ECM via the regulation of the downstream miRNA-346/SMAD3 in human chondrocytes, which provides a new therapeutic strategy for OA.
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Particle-induced implant loosening is a major challenge to long-term survival of joint prostheses. Administration of intermittent parathyroid hormone (PTH) has shown potential in the treatment of cases of early-stage periprosthetic osteolysis, while sequential administration of intermittent PTH (iPTH) and bisphosphonates (Bps) has achieved significant effects on treatment of postmenopausal osteoporosis. The objective of this study was to determine whether sequential treatment could preserve bone mass and implant fixation during a pathological course of peri-implant osteolysis in a rat model. Ninety male Sprague Dawley rats were randomly divided into nine groups, four of which were used for confirmation of establishment of the peri-implant osteolysis model at two time points, while the other five were used to determine the efficiency of the sequential treatment on peri-implant osteolysis. Implant fixation and peri-implant bone mass were evaluated using biomechanical testing, micro-CT analysis, and histology at 6 and 12 weeks postoperative. The biomechanical test demonstrated that the maximum loading force during a push-out test was significantly elevated in the sequential treatment group compared to the osteolysis group and iPTH withdrawal group at 12 weeks. Peri-implant bone morphology also indicated a robust increase in bone volume in the sequential treatment group. Sequential administration of iPTH and Bps was effective in preventing experimental peri-implant osteolysis, resulting in improved implant fixation and increased peri-implant bone volume. Clinical significance: The innovative application of sequential treatment in peri-implant osteolysis could be used clinically to improve the prognosis of patients with early-stage periprosthetic osteolysis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1489-1497, 2019.
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Conservadores da Densidade Óssea/administração & dosagem , Osteólise/tratamento farmacológico , Hormônio Paratireóideo/administração & dosagem , Falha de Prótese/efeitos dos fármacos , Ácido Zoledrônico/administração & dosagem , Animais , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Avaliação Pré-Clínica de Medicamentos , Masculino , Osteólise/diagnóstico por imagem , Osteólise/etiologia , Osteólise/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Microtomografia por Raio-XRESUMO
Osteolysis is an osteolytic lesion featured by enhanced osteoclast formation and potent bone erosion. Lacking of effective regimen for treatment of the pathological process highlights the importance of identifying agents that can suppress the differentiation and function of osteoclast. Artemether is a natural compound derived from Artemisia annua L. and it is popularized for the treatment of malaria. In present study, we demonstrated that artemether could suppress RANKL-induced osteoclastogenesis and expression of osteoclast marker genes such as tartrate-resistant acid phosphatase, cathepsin K, matrix metalloproteinase 9, nuclear factor of activated T-cell cytoplasmic 1, and dendritic cell-specific transmembrane protein. It inhibited the osteoclastic bone resorption in a dose-dependent manner in vitro. Furthermore, artemether attenuated RANKL-induced MAPKs (ERK, JNK, p-38) activity. In addition, we have showed that artemether was able to mitigate bone erosion in a murine model of LPS-induced inflammatory bone loss. Taken together, these findings suggest that artemether reduces inflammatory bone loss via inhibition of MAPKs activation during osteoclast differentiation, and it might be a potential candidate for the treatment of osteoclast-related disorders.
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Artemeter/farmacologia , Conservadores da Densidade Óssea/farmacologia , Remodelação Óssea/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteólise/prevenção & controle , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/enzimologia , Osteoclastos/patologia , Osteogênese/genética , Osteólise/induzido quimicamente , Osteólise/enzimologia , Osteólise/patologia , Ligante RANK/farmacologia , Células RAW 264.7RESUMO
As a chronic disease, osteoarthritis (OA) leads to the degradation of both cartilage and subchondral bone, its development being mediated by proinflammatory cytokines like interleukin-1ß. In the present study, the anti-inflammatory effect of specnuezhenide (SPN) in OA and its underlying mechanism were studied in vitro and in vivo. The results showed that SPN decreases the expression of cartilage matrix-degrading enzymes and the activation of NF-κB and wnt/ß-catenin signaling, and increases chondrocyte-specific gene expression in IL-1ß-induced inflammation in chondrocytes. Furthermore, SPN treatment prevents the degeneration of both cartilage and subchondral bone in a rat model of OA. To the best of our knowledge, this study is the first to report that SPN decreases interleukin-1ß-induced inflammation in rat chondrocytes by inhibiting the activation of the NF-κB and wnt/ß-catenin pathways, and, thus, has therapeutic potential in the treatment of OA.
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Aseptic loosening and periprosthetic osteolysis are the leading causes of total joint arthroplasty failure, which occurs as a result of chronic inflammatory response and enhanced osteoclast activity. Here we showed that stevioside, a natural compound isolated from Stevia rebaudiana, exhibited preventative effects on titanium particle-induced osteolysis in a mouse calvarial model. Further histological assessment and real-time PCR analysis indicated that stevioside prevented titanium particle-induced osteolysis by inhibiting osteoclast formation and inflammatory cytokine expression in vivo. In vitro, we found that stevioside could suppress RANKL-induced osteoclastogenesis and titanium particle-induced inflammatory response in a dose-dependent manner. Mechanistically, stevioside achieved these effects by disrupting the phosphorylation of TAK1 and subsequent activation of NF-κB/MAPKs signaling pathways. Collectively, our data suggest that stevioside effectively suppresses osteoclastogenesis and inflammatory response both in vitro and in vivo, and it might be a potential therapy for particle-induced osteolysis and other osteolytic diseases.
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Low-intensity pulsed ultrasound (LIPUS), which is a noninvasive form of mechanical energy, has been utilized as a clinical therapy for bone fracture healing. However, the mechanism how LIPUS affects osteoclast formation and osteoclast activity, has not been fully detailed. Here we found that LIPUS inhibited RANKL-induced osteoclast differentiation in vitro, characterized by decreased number and area of tartrate-resistant acid phosphatase (TRAP) positive cells. Moreover, the expression levels of osteoclast-specific gene were also suppressed by LIPUS treatment. Interestingly, F-actin staining and resorption pit assay showed that LIPUS did not affect the bone resorptive activity of mature osteoclasts. Mechanistically, LIPUS achieved these inhibitory effects by disrupting the phosphorylation of ERK and subsequent activation of the osteoclastic transcription factors, c-Fos and NFATc1. Collectively, our results demonstrated that LIPUS effectively suppresses osteoclast differentiation and osteoclast-specific gene expression through the inhibition of ERK-c-Fos-NFATC1 cascades.
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OBJECTIVE: Several studies have been performed to investigate the association between SMAD3 gene polymorphism and osteoarthritis (OA), but the results were inconclusive. This study aims to determine whether SMAD3 polymorphism is associated with risk of OA. METHOD: A comprehensive literature search in PubMed, Embase, and ISI Web of Science for relevant studies was performed. After extracting data from eligible studies, we chose the fixed or random effect model according to the heterogeneity test. Estimation of publication bias and sensitivity analysis were conducted to confirm the stability of this meta-analysis. RESULTS: In total, 10 studies from 6 articles with 5093 OA patients and 5699 controls were enrolled in this meta-analysis. The combined results revealed significant association between SMAD3 rs12901499 polymorphism and the risk of OA (allele model: OR 1.21, 95% CI 1.07-1.38). Subgroup analysis revealed that G allele increased the risk of OA in Caucasians, but not in Asians (allele model: Caucasians: OR 1.31, 95% CI 1.18-1.44; Asians: OR 1.24, 95% CI 0.95-1.61). And the pooled results revealed significant association between SMAD3 rs12901499 polymorphism and both knee and hip OA (knee OA: OR 1.18, 95% CI 1.04-1.34; hip OA: OR 1.31, 95% CI 1.18-1.44). CONCLUSION: The current meta-analysis revealed that the G variant of SMAD3 rs12901499 polymorphism increased the risk of OA in Caucasians. Further well-designed studies with larger sample size in different ethnic populations are required to confirm these results.