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1.
Bioact Mater ; 8: 309-324, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34541403

RESUMO

Polyetheretherketone (PEEK) has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance. However, its biological inertness, poor osteoinduction, and weak antibacterial activity make the clinical applications in a dilemma. Inspired by the mussel adhesion mechanism, here we reported a biomimetic surface strategy for rational integration and optimization of anti-infectivity and osteo-inductivity onto PEEK surfaces using a mussel foot proteins (Mfps)-mimic peptide with clickable azido terminal. The peptide enables mussel-like adhesion on PEEK biomaterial surfaces, leaving azido groups for the further steps of biofunctionalizations. In this study, antimicrobial peptide (AMP) and osteogenic growth peptide (OGP) were bioorthogonally clicked on the azido-modified PEEK biomaterials to obtain a dual-effect of host defense and tissue repair. Since bioorthogonal clicking allows precise collocation between AMP and OGP through changing their feeding molar ratios, an optimal PEEK surface was finally obtained in this research, which could long-term inhibit bacterial growth, stabilize bone homeostasis and facilitate interfacial bone regeneration. In a word, this upgraded mussel surface strategy proposed in this study is promising for the surface bioengineering of inert medical implants, in particular, achieving rational integration of multiple biofunctions to match clinical requirements.

2.
Front Physiol ; 12: 758607, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34880777

RESUMO

Increased adipocyte and decreased osteoblast differentiation, combined with the ectopic proliferation of bone marrow mesenchymal stem cells (BM-MSCs), represent the primary causes of osteoporosis. The dysregulation of numerous intracellular bioactive factors is responsible for the aberrant differentiation and growth of BM-MSCs. In this study, we focused on a new stimulative factor, integrator complex subunit 7 (INTS7), and its cooperative protein ATP-binding cassette subfamily D member 3 (ABCD3)/high-density lipoprotein-binding protein (HDLBP) in mouse BM-MSCs. We aimed to uncover the effects of the INTS7-ABCD3/HDLBP interaction on BM-MSC biological behaviors and the potential mechanism underlying these effects. Functional in vitro experiments showed that the suppression of the INTS7-ABCD3 interaction rather than HDLBP could impair BM-MSC proliferation and induce cell apoptosis. Moreover, Alizarin Red S and Oil Red O staining, respectively, revealed that INTS7 and ABCD3 knockdown but not HDLBP knockdown could decrease osteoblastic differentiation and accelerate the adipogenic differentiation of BM-MSCs. Mechanistically, reactive oxygen species (ROS) and histone γ-H2AX quantities significantly increased, whereas the levels of antioxidants declined due to INTS7 and ABCD3 inhibition in BM-MSCs. These findings indicated that the suppression of oxidative stress could be involved in the INTS7/ABCD3 co-regulatory mechanisms for BM-MSC proliferation and differentiation, identifying new potential candidates for osteoporosis therapy.

3.
Bioengineered ; 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34847835

RESUMO

Osteoarthritis (OA) affects approximately 12% of the aging Western population. The sirtuin/forkhead box O (SIRT/FOXO) signaling pathway plays essential roles in various biological processes. Despite it has been demonstrated that ubiquitin-specific protease 3 (USP3) inhibits chondrocyte apoptosis induced by interleukin (IL)-1ß, the role of USP3/SIRT3/FOXO3 in the senescence of chondrocytes in OA is unclear. This study initially isolated articular chondrocytes and investigated the role of USP3 in IL-1ß-induced senescence of chondrocytes. After USP3 was overexpressed or silenced by lentivirus, expressions of genes and proteins were detected using quantitative polymerase chain reaction and immunoblotting, respectively. Cell cycle analysis was performed using flow cytometry. Reactive oxygen species (ROS) levels and senescence were analyzed. Then, SIRT3 was inhibited or overexpressed to explore the underlying mechanism. We found that overexpression of USP3 hindered IL-1ß-mediated cell cycle arrest, ROS generation, and chondrocyte senescence. The inhibition of SIRT3 blocked the protective effect of USP3 on cell senescence, whereas the overexpression of SIRT3 abolished USP3-silencing-induced cell senescence. Furthermore, SIRT3 attenuated cell senescence, probably by deacetylating FOXO3. USP3 upregulated SIRT3 to deacetylate FOXO3 and attenuated IL-1ß-induced chondrocyte senescence. This study demonstrated that USP3 probably attenuated IL-1ß-mediated chondrocyte senescence by deacetylating FOXO3 via SIRT3.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34886671

RESUMO

Implant-associated infections and inadequate osseointegration are two challenges of implant materials in orthopedics. In this study, a lithium-ion-loaded (Li+)/mussel-inspired antimicrobial peptide (AMP) designed to improve the osseointegration and inhibit bacterial infections effectively is prepared on a polyetheretherketone (PEEK) biomaterial surface through the combination of hydrothermal treatment and mussel-inspired chemistry. The results illustrate that the multifunctional PEEK material demonstrated a great inhibitory effect on Escherichia coli and Staphylococcus aureus, which was attributed to irreversible bacterial membrane damage. In addition, the multifunctional PEEK can simultaneously upregulate the expression of osteogenesis-associated genes/proteins via the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo assay of an infection model revealed that the multifunctional PEEK implants killed bacteria with an efficiency of 95.03%. More importantly, the multifunctional PEEK implants accelerated the implant-bone interface osseointegration compared with pure PEEK implants in the noninfection model. Overall, this work provides a promising strategy for improving orthopedic implant materials with ideal osseointegration and infection prevention simultaneously, which may have broad application clinical prospects.

5.
Pharmacol Res ; 174: 105967, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34740817

RESUMO

Osteoporosis (OP) is characterized by decreased trabecular bone volume and microarchitectural deterioration in the medullary cavity. Urolithin A (UA) is a biologically active metabolite generated by the gut microbiota. UA is the measurable product considered the most relevant urolithin as the final metabolic product of polyphenolic compounds. Considering that catabolic effects mediated by the intestinal microbiota are highly involved in pathological bone disorders, exploring the biological influence and molecular mechanisms by which UA alleviates OP is crucial. Our study aimed to investigate the effect of UA administration on OP progression in the context of estrogen deficiency-induced bone loss. The in vivo results indicated that UA effectively reduced ovariectomy-induced systemic bone loss. In vitro, UA suppressed Receptor Activator for Nuclear Factor-κB Ligand (RANKL)-triggered osteoclastogenesis in a concentration-dependent manner. Signal transduction studies and sequencing analysis showed that UA significantly decreased the expression of inflammatory cytokines (e.g., IL-6 and TNF-α) in osteoclasts. Additionally, attenuation of inflammatory signaling cascades inhibited the NF-κB-activated NOD-like receptor signaling pathway, which eventually led to decreased cytoplasmic secretion of IL-1ß and IL-18 and reduced expression of pyroptosis markers (NLRP3, GSDMD, and caspase-1). Consistent with this finding, an NLRP3 inflammasome inhibitor (MCC950) was employed to treat OP, and modulation of pyroptosis was found to ameliorate osteoclastogenesis and bone loss in ovariectomized (OVX) mice, suggesting that UA suppressed osteoclast formation by regulating the inflammatory signal-dependent pyroptosis pathway. Conceivably, UA administration may be a safe and promising therapeutic strategy for osteoclast-related bone diseases such as OP.

6.
Cell Death Dis ; 12(11): 1035, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34718335

RESUMO

In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3ß/ß-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.

7.
Bioengineered ; 12(1): 6821-6830, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34622712

RESUMO

Osteoporosis is a progressive bone disease in the elderly and lacks an effective classification method of patients. This study constructed a gene signature for an accurate prediction and classification of osteoporosis patients. Three gene expression datasets of osteoporosis samples were acquired from the Gene Expression Omnibus database with pre-set criteria. Differentially expressed genes (DEGs) between normal and diseased osteoporosis samples were screened using Limma package in R language. Protein-protein interaction (PPI) network was established based on interaction data of the DEGs from the Human Protein Reference Database. Classification accuracy of the classifier was assessed with sensitivity, specificity and area under curve (AUC) using the pROC package in the R. Pathway enrichment analysis was performed on feature genes with clusterProfiler. A total of 310 differentially expressed genes between two samples were associated with positive regulation of protein secretion and cytokine secretion, neutrophil-mediated immunity, and neutrophil activation. PPI network of DEGs consisted of 12 genes. A SVM classifier based on five feature genes was developed to classify osteoporosis samples, showing a higher prediction accuracy and AUC for GSE35959, GSE62402, GSE13850, GSE56814, GSE56815 and GSE7429 datasets. A SVM classifier with a high accuracy was developed for predicting osteoporosis. The genes included may be the potential feature genes in osteoporosis development.AbbreviationsDEGs: Differentially expressed genes; PPI: protein-protein interaction; WHO: World Health Organization; SVM: Support vector machine; GEO: Gene Expression Omnibus; KEGG: Kyoto Encyclopedia of Genes and Genomes; GO: Gene Ontology; BP: Biological Process; CC: Cellular Component; MF: Molecular Function; SVM: Support vector machines.

8.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 35(10): 1273-1280, 2021 Oct 15.
Artigo em Chinês | MEDLINE | ID: mdl-34651480

RESUMO

Objective: To estimate the early effectivenss of computer navigation-assisted total knee arthroplasty (TKA) by comparing with traditional TKA. Methods: The clinical data of 89 patients (100 knees) underwent primary TKA between October 2017 and July 2018 were analyzed retrospectively, including 44 patients (50 knees) who completed the TKA under the computer-assisted navigation system as the navigation group and 45 patients (50 knees) treated with traditional TKA as the control group. There was no significant difference between the two groups ( P>0.05) in gender, age, body mass index, diagnosis, side, disease duration, Kellgren-Lawrence classification of osteoarthritis, and preoperative American Hospital for Special Surgery (HSS) score, range of motion (ROM), hip-knee-ankle angle (HKA) deviation. The operation time, incision length, difference in hemoglobin before and after operation, postoperative hospital stay, and the complications were recorded and compared between the two groups. The HSS score, ROM, and joint forgetting score (FJS-12) were used to evaluate knee joint function in all patients. Unilateral patients also underwent postoperative time of up and go test and short physical performance battery (SPPB) test. At 1 day after operation, the HKA, mechanical lateral distal femoral angle (mLDFA), mechanical medial proximal tibial angle (mMPTA), sagittal femoral component angle (sFCA), and sagittal tibial component angle (sTCA) were measured and calculated the difference between the above index and the target value (deviation); and the joint line convergence angle (JLCA) was also measured. Results: The operations of the two groups were successfully completed, and the incisions healed by first intention. The operation time and incision length of the navigation group were longer than those of the control group ( P<0.05); the difference in difference of hemoglobin before and after the operation and the postoperative hospital stay between groups was not significant ( P>0.05). Patients in the two groups were followed up 27-40 months, with an average of 33.6 months. Posterior tibial vein thrombosis occurred in 1 case in each of the two groups, and 1 case in the control group experienced repeated knee joint swelling. The HSS scores of the two groups gradually increased after operation ( P<0.05); HSS scores in the navigation group at 1 and 2 years after operation, and knee ROM and FJS-12 scores at 2 years were significantly higher than those in the control group ( P<0.05). There was no significant difference in the postoperative time of up and go test and SPPB results between the two groups at 7 days after operation ( P>0.05); the postoperative time of up and go test of the navigation group was shorter than that of the control group at 2 years ( t=-2.226, P=0.029), but there was no significant difference in SPPB ( t=0.429, P=0.669). X-ray film measurement at 1 day after operation showed that the deviation of HKA after TKA in the navigation group was smaller than that of the control group ( t=-7.392, P=0.000); among them, the HKA deviations of 50 knees (100%) in the navigation group and 36 knees (72%) in the control group were less than 3°, showing significant difference between the two groups ( χ 2=16.279, P=0.000). The JLCA and the deviations of mLDFA, mMPTA, sFCA, and sTCA in the navigation group were smaller than those in the control group ( P<0.05). Conclusion: Compared with traditional TKA, computer navigation-assisted TKA can obtain more accurate prosthesis implantation position and lower limb force line and better early effectiveness. But there is a certain learning curve, and the operation time and incision length would be extended in the early stage of technology application.


Assuntos
Artroplastia do Joelho , Prótese do Joelho , Osteoartrite do Joelho , Computadores , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgia , Estudos Retrospectivos
9.
Biochem Genet ; 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34228237

RESUMO

It is known that miRNA mediates the formation of osteogenesis, but the mechanism by which miRNA let-7a-5p regulates osteogenesis in osteoporosis (OP) is not yet understood. This paper aims to probe into the regulatory mechanism of miRNA let-7a-5p in the development of OP. Fresh femoral trabecular bones of patients with osteoporotic fracture (OP group, n = 25) and non-OP osteoarthritis (Non-OP group, n = 23) who underwent hip replacement in our hospital from December 2016 to December 2019 were collected. The expression and protein levels of miRNA let-7a-5p and V-AKT murine thymoma viral oncogene homolog 3 (RNA KCNQ1OT1) were detected. C2C12 cells were purchased and osteogenic differentiation model was constructed by BMP2 induction. After miRNA let-7a-5p up-regulation or down-regulation by transfection of corresponding mimics and inhibitors, the impacts of miRNA let-7a-5p and RNA KCNQ1OT1 on osteogenic differentiation-related factors (OC, ALP, COL1A1) in C2C12 cells were analyzed. The determination of targeting correlation of miRNA let-7a-5p with RNA KCNQ1OT1 was performed by dual-luciferase reporter (DLR). In OP samples, miRNA let-7a-5p was notably declined while RNA KCNQ1OT1 were remarkably up-regulated. MiRNA let-7a-5p reduced in C2C12 cells as BMP2 treatment proceeded. MiRNA let-7a-5p up-regulation or RNA KCNQ1OT1 down-regulation increased OC, ALP, COL1A1 levels and ALP activity. RNA KCNQ1OT1 was directly targeted to miR-497-5p. RNA KCNQ1OT1 up-regulation weakened the promoting effect of miRNA let-7a-5p up-regulation on osteoblast differentiation. MiRNA let-7a-5p up-regulation can target to reduce RNA KCNQ1OT1 and promote osteoblast differentiation, thereby improving the development of osteoporosis.

10.
Front Immunol ; 12: 657687, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079546

RESUMO

Peri-prosthetic osteolysis (PPO) and following aseptic loosening are regarded as the prime reasons for implant failure after joint replacement. Increasing evidence indicated that wear-debris-irritated inflammatory response and macrophage polarization state play essential roles in this osteolytic process. Harmine, a ß-carboline alkaloid primitively extracted from the Peganum harmala seeds, has been reported to have various pharmacological effects on monoamine oxidase action, insulin intake, vasodilatation and central nervous systems. However, the impact of harmine on debris-induced osteolysis has not been demonstrated, and whether harmine participates in regulating macrophage polarization and subsequent osteogenic differentiation in particle-irritated osteolysis remains unknown. In the present study, we investigated the effect of harmine on titanium (Ti) particle-induced osteolysis in vivo and in vitro. The results suggested harmine notably alleviated Ti particle-induced bone resorption in a murine PPO model. Harmine was also found to suppress the particle-induced inflammatory response and shift the polarization of macrophages from M1 phenotypes to M2 phenotypes in vivo and in vitro, which improved anti-inflammatory and bone-related cytokines levels. In the conditioned medium from Ti particle-stimulated murine macrophage RAW264.7 cells treated with harmine, the osteoblast differentiation ability of mouse pre-osteoblastic MC3T3-E1 cells was greatly increased. And we also provided evidences that the immunomodulatory capacity of harmine might be attributed to the inhibition of the c-Jun N-terminal kinase (JNK) in wear particle-treated macrophages. All the results strongly show that harmine might be a promising therapeutic agent to treat PPO.


Assuntos
Doenças Ósseas/etiologia , Doenças Ósseas/metabolismo , Harmina/farmacologia , Macrófagos/imunologia , Macrófagos/metabolismo , Osteogênese/efeitos dos fármacos , Titânio/efeitos adversos , Animais , Biomarcadores , Doenças Ósseas/diagnóstico , Doenças Ósseas/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Imunofluorescência , Imuno-Histoquímica , Inflamação/complicações , Inflamação/etiologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/metabolismo , Osteólise/diagnóstico , Osteólise/tratamento farmacológico , Osteólise/etiologia , Osteólise/metabolismo , Células RAW 264.7 , Microtomografia por Raio-X
11.
Sci China Life Sci ; 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34125371

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease that eventually leads to disability. Inflammatory cell infiltration, severe joint breaking and systemic bone loss are the main clinical symptoms. In this study, we established a collagen-induced arthritis (CIA) model and found a large number of M1 macrophages and pyroptosis, which are important sources of proinflammatory cytokines. Punicalagin (PUN) is an active substance extracted from pomegranate peel. We found that it inhibited joint inflammation, cartilage damage and systemic bone destruction in CIA mice. PUN effectively alleviated the high expression of inflammatory cytokines in synovial tissue in vivo. PUN treatment shifted macrophages from the M1 phenotype to the M2 phenotype after stimulation with lipopolysaccharide (LPS) and interferon (IFN)-γ. The expression of inducible nitric oxide synthase (iNOS) and other proinflammatory cytokines released by M1 macrophages was decreased in the PUN treatment group. However, simultaneously, the expression of markers of anti-inflammatory M2 macrophages, such as arginase (Arg)-1 and interleukin (IL)-10, was increased. In addition, PUN treatment attenuated pyroptosis by downregulating the expression of NLRP3 and caspase-1, thereby preventing inflammatory cell death resulting from the release of IL-1ß and IL-18. Mechanistically, PUN inhibited the activation of receptor activators of the nuclear factor-κB (NF-κB) signaling pathway, which contributes to M1 polarization and pyroptosis of macrophages. We concluded that PUN ameliorated pathological inflammation by inhibiting M1 phenotype polarization and pyroptosis and has great potential as a therapeutic treatment for human RA.

12.
Clin Transl Med ; 11(6): e447, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34185425

RESUMO

Glucocorticoids (GCs) are used in treating viral infections, acute spinal cord injury, autoimmune diseases, and shock. Several patients develop GC-induced osteonecrosis of the femoral head (ONFH). However, the pathogenic mechanisms underlying GC-induced ONFH remain poorly understood. GC-directed bone marrow mesenchymal stem cells (BMSCs) fate is an important factor that determines GC-induced ONFH. At high concentrations, GCs induce BMSC apoptosis by promoting oxidative stress. In the present study, we aimed to elucidate the molecular mechanisms that relieve GC-induced oxidative stress in BMSCs, which would be vital for treating ONFH. The endocannabinoid system regulates oxidative stress in multiple organs. Here, we found that monoacylglycerol lipase (MAGL), a key molecule in the endocannabinoid system, was significantly upregulated during GC treatment in osteoblasts both in vitro and in vivo. MAGL expression was positively correlated with expression of the NADPH oxidase family and apoptosis-related proteins. Functional analysis showed that MAGL inhibition markedly reduced oxidative stress and partially rescued BMSC apoptosis. Additionally, in vivo studies indicated that MAGL inhibition effectively attenuated GC-induced ONFH. Pathway analysis showed that MAGL inhibition regulated oxidative stress in BMSCs via the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The expression of Nrf2, a major regulator of intracellular antioxidants, was upregulated by inhibiting MAGL. Nrf2 activation can mimic the effect of MAGL inhibition and significantly reduce GC-induced oxidative damage in BMSCs. The beneficial effects of MAGL inhibition were attenuated after the blockade of the Keap1/Nrf2 antioxidant signaling pathway. Notably, pharmacological blockade of MAGL conferred femoral head protection in GC-induced ONFH, even after oxidative stress responses were initiated. Therefore, MAGL may represent a novel target for the prevention and treatment of GC-induced ONFH.

13.
J Healthc Eng ; 2021: 5569872, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34035884

RESUMO

The incidence of inverted knee osteoarthritis is slowly increasing, there are technical limitations in the treatment, and the operation is difficult. In this article, we will study the benefits and costs of arthroscopic cleaning treatments based on intelligent electronic medicine. This article focuses on knee osteoarthritis patients in the EL database. There are 12 male patients, accounting for 66.67%, and 6 female patients, accounting for 33.33%. The average body mass index (BMI) of the patients was 28.08, the average time from first knee discomfort to surgery was 28.44 months, and the average time of arthroscopic debridement treatment for patients with VKOH knee osteoarthritis was 143.11 minutes. One case of perioperative complication occurred within 35 days after operation, which was a soleus muscle intermuscular venous thrombosis. After immobilization and enhanced anticoagulation for 1 week, it was stable without risk of shedding. The average postoperative study time was 20.00 months. The electronic medical arthroscopy cleaning treatment plan in this article can greatly improve the quality of life of patients and can check the pathological state in time, with low cost. In the course of treatment, comprehensive treatment costs can be saved by 45%. Arthroscopic clean-up treatment can not only reduce knee pain and other uncomfortable symptoms, restore normal knee joint function, and improve the quality of life of patients, but also correct the unequal length of the lower limbs, thereby avoiding spinal degeneration caused by knee instability. Therefore, it is the first choice for the treatment of advanced knee osteoarthritis in patients with VKOH.

14.
Bioact Mater ; 6(10): 3343-3357, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33817415

RESUMO

Periprosthetic osteolysis (PPO) remains the key factor in implant failure and subsequent revision surgery and is mainly triggered by wear particles. Previous studies have shown that inhibition of osteoblastic differentiation is the most widespread incident affecting the interface of trabecular and loosening prostheses. Additionally, the NLRP3 inflammasome is activated by prosthetic particles. Sirtuin3, an NAD+-dependent deacetylase of mitochondria, regulates the function of mitochondria in diverse activities. However, whether SIRT3 can mitigate wear debris-induced osteolysis by inhibiting the NLRP3 inflammasome and enhancing osteogenesis has not been previously reported. Therefore, we investigated the role of SIRT3 during the process of titanium (Ti) particle-induced osteolysis. We revealed that upregulated SIRT3 dramatically attenuated Ti particle-induced osteogenic inhibition through suppression of the NLRP3 inflammasome and improvement of osteogenesis in vivo and in vitro. Moreover, we found that SIRT3 interference in the process of Ti particle-induced osteolysis relied on the GSK-3ß/ß-catenin signalling pathway. Collectively, these findings indicated that SIRT3 may serve as a rational new treatment against debris-induced PPO by deacetylase-dependent inflammasome attenuation.

15.
Orthop Surg ; 13(3): 989-1000, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33821565

RESUMO

OBJECTIVE: To evaluate mid- to long-term results of revision total hip arthroplasty for massive femoral bone loss using a cementless modular, fluted, tapered stem. METHODS: This is a retrospective study performed at a single hospital. During the period of January 2007 to January 2015, 33 patients (34 hips) underwent primary revision surgery with cementless modular, fluted, tapered stems due to femoral bone loss. Sixteen men and 17 women were included in the study, with an average age of 63.9 ± 11.7 years (range, 27 to 88 years). Operative data including operative duration, length of incision, drainage volume and duration, blood loss and transfusion, cases of bone graft and extended trochanteric osteotomy were recorded. Clinical evaluation was performed using Harris hip score (HHS), visual analogue scale (VAS), and patients' satisfaction. Radiographic data including femoral stem fixation, subsidence, integrin of allograft bone, and leg length discrepancy were assessed. Complications and survivorship were evaluated using Kaplan-Meier survival rate. RESULTS: The mean follow-up was 9.1 ± 2.5 years (range, 5-13 years). The Harris hip score was 43.6 ± 11.5 preoperatively and maintained at 86.5 ± 6.6 at the time of latest follow-up (P < 0. 05). The X-ray showed bone ingrowth fixation in 30 hips (88%), fibrous stable fixation in three hips (9%), and instability in one hip (3%). The average stem subsidence was 3.9 ± 2.2 mm (range, 1 to 10 mm). The mean difference in leg length in our study was 3.3 ± 2.7 mm (range, 0 to 10 mm), and the leg length discrepancy in 28 (82%) patients was within 5 mm. No case of junction fracture was observed. Seven (21%) intraoperative fractures occurred in our study. Three (9%) cases with infection were observed after revision. Six (18%) patients had lower limb vein thrombosis. The survivorship of prostheses with re-revision for any reason was 95% (95% CI, 12.0 to 13.0) at the 10-year follow-up. Three (9%) re-revisions were needed, including one for aseptic loosening, one for dislocation, and one for infection. CONCLUSION: The mid- to long-term results of revision total hip arthroplasty with the cementless modular, fluted, tapered stems are encouraging for massive femoral bone loss.


Assuntos
Artroplastia de Quadril/métodos , Prótese de Quadril , Desenho de Prótese , Reoperação/métodos , Humanos
16.
Int J Biol Sci ; 17(5): 1382-1394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33867853

RESUMO

Implant-derived wear particles can be phagocytosed by local macrophages, triggering an inflammatory cascade that can drive the activation and recruitment of osteoclasts, thereby inducing peri-prosthetic osteolysis. Efforts to suppress pro-inflammatory cytokine release and osteoclastsogenesis thus represent primary approaches to treating and preventing such osteolysis. Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylases that control diverse metabolic processes. However, whether SIRT3 could mitigate wear debris-induced osteolysis has not been reported. Herein we explored the impact of the SIRT3 on titanium particle-induced osteolysis. Tartrate resistant acid phosphatase (TRAP) staining revealed that the inhibition of SIRT3 suppressed nuclear factor-κB ligand (RANKL)-mediated osteoclasts activation in a dose-dependent fashion. Notably, inhibition of SIRT3 also suppressed matrix metallopeptidase 9 (MMP9) and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) expression at the mRNA and protein levels, while also inhibiting the mRNA expression of dendritic cell-specific transmembrane protein (DC-STAMP), ATPase H+ Transporting V0 Subunit D2 (Atp6v0d2), TRAP and Cathepsin K (CTSK) . In addition, inhibition of SIRT3 suppressed titanium particle-induced tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) expression and prevented titanium particle-induced osteolysis and bone loss in vivo. This inhibition of osteoclasts differentiation was found to be linked to the downregulation and reduced phosphorylation of JNK and ERK. Taken together, inhibition of SIRT3 may be a potential target for titanium particle-induced bone loss.

17.
Exp Cell Res ; 401(1): 112513, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33567325

RESUMO

PURPOSE: Femoral head necrosis (FHN) is a common disease of hip. However, the pathogenesis of FHN is not well understood. This study attempted to explore the potentially important genes and proteins involved in FHN. METHODS: We integrated the transcriptomic and proteomic methods to quantitatively screen the differentially expressed genes (DEGs) and proteins (DEPs) between Control and FHN groups. Gene ontology (GO) terms and KEGG pathway enrichment analysis were used to assess the roles of DEGs and DEPs. qRT-PCR and western blot were performed to verify the key genes/proteins in FHN. CCK-8 assay was performed to measure cell viability. The protein expression of Bax and Bcl-2 were used to evaluate cell apoptosis. RESULTS: Transcriptome and proteome studies indicated 758 DEGs and 1097 DEPs between Control and FHN groups, respectively. Cell division, extracellular exosome, and serine-type endopeptidase activity were the most common terms in biological process (BP), cellular component (CC), and molecular function (MF) enrichment, respectively. DEPs were mainly enriched in cellular process, cell, and binding for BP, CC, and MF categories, respectively. DEGs were mainly involved in PI3K-Akt pathway and DEPs were mainly focused in glycolysis/gluconeogenesis pathway. Notably, 14 down-regulated and 22 up-regulated genes/proteins were detected at both the transcript and protein level. LRG1, SERPINE2, STMN1, COL14A1, SLC37A2, and MMP2 were determined as the key genes/proteins in FHN. SERPINE2/STMN1 overexpression increased viability and decreased apoptosis of dexamethasone-treated MC3T3-E1 cells. CONCLUSIONS: Our study investigated some pivotal regulatory genes/proteins in the pathogenesis of FHN, providing novel insight into the genes/proteins involved in FHN.


Assuntos
Necrose da Cabeça do Fêmur/genética , Proteoma/genética , Proteômica , Transcriptoma/genética , Células 3T3 , Animais , Sobrevivência Celular/genética , Dexametasona/farmacologia , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Ontologia Genética , Humanos , Camundongos , Fosfatidilinositol 3-Quinases/genética , Proteoma/classificação , Proteínas Proto-Oncogênicas c-bcl-2/genética , Serpina E2/genética , Estatmina/genética , Esteroides/toxicidade , Proteína X Associada a bcl-2/genética
18.
Int Immunopharmacol ; 94: 107459, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33611061

RESUMO

Wear debris-induced osteoclast accumulation around implants plays a crucial role during the progression of periprosthetic osteolysis (PPO). We have confirmed that acetyl-11-keto-ß-boswellic acid (AKBA) promotes bone formation and protects against particle-induced bone destruction in vivo. However, the effect of AKBA on titanium-induced bone resorption is unknown. In this study, we detected the inhibitory effect of AKBA on titanium-induced bone erosion in vivo and used RAW264.7 cells and bone marrow macrophages (BMMs) to investigate the effect and underlying mechanism of AKBA on the differentiation and resorptive function of osteoclasts. Our findings revealed that AKBA inhibited particle-induced bone loss and osteoclast formation in vivo. Furthermore, AKBA exerted inhibitory effects on RANKL-induced osteoclastogenesis, osteoclastic ring-dependent resorption and the expression of osteoclast marker genes via the ERK signaling pathway in vitro. Our data further established the protective effect of AKBA on titanium particle-induced bone erosion from a new perspective of bone erosion prevention, strongly confirming that AKBA is an appropriate agent for protection against PPO.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Triterpenos/uso terapêutico , Animais , Conservadores da Densidade Óssea/farmacologia , Regulação para Baixo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteogênese/efeitos dos fármacos , Osteólise/induzido quimicamente , Osteólise/tratamento farmacológico , Células RAW 264.7 , Crânio , Titânio , Triterpenos/farmacologia
19.
Int Immunopharmacol ; 90: 106846, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33168412

RESUMO

Accumulating evidence has highlighted the remarkable role of long noncoding RNAs (lncRNAs) in the pathogenesis of various diseases including osteoarthritis (OA). Since current treatment available for OA has limited efficacy, it is urgent to elucidate the pathogenesis of OA. Therefore, we aimed at elucidating the specific regulatory role of LINC00671 in OA progression. Differentially expressed lncRNAs were initially screened using the OA profile. LINC00671, ONECUT2, and Smurf2 expression in OA cartilage tissues were determined, while their interaction was verified by RNA-pull down assay, ChIP, and dual-luciferase reporter gene assay. After chondrocytes were transfected with shRNA and overexpressed plasmids, the proliferation and apoptosis were determined. Meanwhile, extracellular matrix (ECM)-related proteins were detected by Western blot analysis. Establishment of the OA model was performed by surgical destabilization of the medial meniscus (DMM) surgery in mice. Upregulation of LINC00671, ONECUT2, and Smurf2 expression were detected in OA cartilage. LINC00671 was bound to ONECUT2 and ONECUT2 was conjugated to Smurf2. Overexpression of LINC00671 resulted in inhibited chondrocytes proliferation, enhanced apoptosis, and ECM degradation, which was readily reversed by silencing ONECUT2 or Smurf2. Furthermore, LINC00671 induced GSK-3ß ubiquitination and upregulated ß-catenin expression through Smurf2. In vivo experiment revealed that silencing of LINC00671 or GSK-3ß activator resulted in alleviated ECM degradation and ameliorated OA progression. Collectively, these data demonstrated that LINC00671 exacerbates OA progression through GSK-3ß ubiquitination by upregulating ONECUT2-mediated Smurf2.


Assuntos
Condrócitos/enzimologia , Matriz Extracelular/enzimologia , Proteínas de Homeodomínio/metabolismo , Articulação do Joelho/enzimologia , Osteoartrite do Joelho/enzimologia , RNA Longo não Codificante/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adulto , Idoso , Animais , Apoptose , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Condrócitos/patologia , Bases de Dados Genéticas , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/patologia , Feminino , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Articulação do Joelho/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/patologia , RNA Longo não Codificante/genética , Transdução de Sinais , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
20.
Jt Dis Relat Surg ; 31(3): 411-418, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32962569

RESUMO

OBJECTIVES: This study aims to explore the mechanism by which osteoblast autophagy participated in glucocorticoid-induced femoral head necrosis (FHN). MATERIALS AND METHODS: Thirty male specific-pathogen-free C57 mice (age, one month; weighing 20-25 g) were randomly divided into blank control, dexamethasone and rapamycin-dexamethasone groups (n=10). After six weeks of intervention, right femoral head was obtained to observe morphology and to calculate percentage of empty lacunae. MC3T3-E1 cells were randomly divided into normal, dexamethasone, rapamycin and dexamethasone-rapamycin groups, and cultured for 24 h. Microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, mammalian target of rapamycin (mTOR) and Beclin-1 protein expressions were detected by Western blot. RESULTS: In rapamycin-dexamethasone group, some bone trabeculae in medullary cavity ruptured and atrophied, and subchondral bone underwent local necrosis. The total apoptosis rates of dexamethasone and rapamycin-dexamethasone groups surpassed that of blank control group, and the former two groups had significantly different rates (p<0.001). LC3-II/LC3-I of dexamethasone group was lower than those of rapamycin and dexamethasone-rapamycin groups (p<0.001), and the ratio of rapamycin group surpassed that of dexamethasone-rapamycin group (p<0.001). Dexamethasone group had higher mTOR protein expression than those of rapamycin and dexamethasone- rapamycin groups (p<0.001), and the expression of rapamycin group was lower than that of dexamethasone-rapamycin group (p<0.001). The Beclin-1 protein expression of dexamethasone group was lower than those of rapamycin and dexamethasone- rapamycin groups (p<0.001), and the expression of rapamycin group exceeded that of dexamethasone-rapamycin group (p<0.05). CONCLUSION: Osteoblast autophagy may play a crucial protective role in dexamethasone-induced FHN. The attenuation of autophagy may be related to the affected expressions of key autophagy regulators mTOR and Beclin-1.


Assuntos
Autofagia/efeitos dos fármacos , Necrose da Cabeça do Fêmur , Glucocorticoides/farmacologia , Osteoblastos , Sirolimo/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/metabolismo , Necrose da Cabeça do Fêmur/patologia , Necrose da Cabeça do Fêmur/prevenção & controle , Imunossupressores/farmacologia , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento
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