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1.
Nat Commun ; 13(1): 160, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013289

RESUMO

Immune response and new tissue formation are important aspects of tissue repair. However, only a single aspect is generally considered in previous biomedical interventions, and the synergistic effect is unclear. Here, a dual-effect coating with immobilized immunomodulatory metal ions (e.g., Zn2+) and osteoinductive growth factors (e.g., BMP-2 peptide) is designed via mussel adhesion-mediated ion coordination and molecular clicking strategy. Compared to the bare TiO2 group, Zn2+ can increase M2 macrophage recruitment by up to 92.5% in vivo and upregulate the expression of M2 cytokine IL-10 by 84.5%; while the dual-effect of Zn2+ and BMP-2 peptide can increase M2 macrophages recruitment by up to 124.7% in vivo and upregulate the expression of M2 cytokine IL-10 by 171%. These benefits eventually significantly enhance bone-implant mechanical fixation (203.3 N) and new bone ingrowth (82.1%) compared to the bare TiO2 (98.6 N and 45.1%, respectively). Taken together, the dual-effect coating can be utilized to synergistically modulate the osteoimmune microenvironment at the bone-implant interface, enhancing bone regeneration for successful implantation.

2.
J Mater Chem B ; 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34984428

RESUMO

Urinary tract infection (UTI) represents one of the most common nosocomial infections, which is mainly related to indwelling catheters or stents. In addition to the formation of biofilms to reduce antibiotic sensitivity, the urease-producing bacteria can also increase urine pH, causing Ca2+ and Mg2+ deposition and finally catheter obstruction. The prevention of UTIs and its complication (i.e., encrustation) thus is a great challenge in design of catheters and ureteral stents. In this work, a metal-catechol-assisted mussel chemistry (i.e., dopamine self-polymerization) was employed for surface functionalization of commercially available catheters with antimicrobial peptides (AMP), for the purpose of long-term anti-infection and encrustation prevention. To improve the stability of the polydopamine coating on polymeric stents, we used Cu2+-coordinated dopamine self-polymerization. Then, a cysteine-terminated AMP was introduced on the polydopamine coating through Michael addition. We found that the Cu2+-coordinated polydopamine coating showed improved stability and antibacterial effect. The cytotoxicity test confirmed that the bioinspired antibacterial coating showed good biocompatibility and no obvious toxicity. The results confirmed that the stents with AMP could in situ inhibit bacterial growth and biofilm formation, and finally reduce the deposition of struvite and hydroxyapatite crystals both in vitro and in vivo. We anticipate that this bioinspired strategy would develop a safe, stable and effective antibacterial coating on urinary tract medical devices for long-term bacterial inhibition and encrustation prevention.

3.
J Colloid Interface Sci ; 605: 410-424, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34332414

RESUMO

In the inflammatory peri-implant microenvironment, excessive polarization of macrophages to the proinflammatory M1 phenotype can trigger the secretion of inflammatory cytokines, which promote bone resorption and impede osteogenesis around implants. The direct consequence of this process is the failure of prosthetic implants due to aseptic loosening. To reverse the inflammatory microenvironment and prevent prosthesis loosening, a mussel adhesion-inspired surface strategy was used for bioengineering of titanium implants with integrin-binding ability. In our design, a mussel-inspired catecholic peptide with tetravalent 3,4-dihydroxy-l-phenylalanine (DOPA) and Arg-Gly-Asp (RGD) sequences was synthesized. The peptide can easily anchor to the surface of medical titanium materials through a mussel adhesive mechanism. We found that peptide-decorated titanium implants could effectively inhibit peri-implant inflammation in a wear particle model and could promote the polarization of macrophages to a pro-healing M2 phenotype by interfering with integrin-α2ß1 and integrin-αvß3. Moreover, the peptide coating increased the adherence of osteoblasts and promoted osteogenesis on titanium implants even under inflammatory conditions. This work suggested that this biomimetic catecholic integrin-binding peptide can provide facile tactics for surface bioengineering of medical prostheses with improved interfacial osteogenesis under inflammatory conditions, which might contribute greatly to the prevention of prosthesis loosening and the improvement of clinical outcomes.


Assuntos
Osteogênese , Titânio , Humanos , Inflamação/etiologia , Peptídeos , Próteses e Implantes
4.
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.

5.
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.

6.
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.

7.
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.

8.
Mol Med ; 27(1): 92, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412587

RESUMO

BACKGROUND: Nucleus pulposus cell (NPC) degeneration is widely accepted as one of the major causes of intervertebral disc (IVD) degeneration (IVDD). The pathogenesis of IVDD is complex and consists of inflammation, oxidative stress, and the loss of extracellular matrix (ECM). Cannabinoid type 2 receptor (CB2) has been shown to be involved in the pathological mechanism of a variety of diseases due to its anti-inflammatory effects and antioxidative stress capacity. METHOD: In Vitro, H2O2 was used to induce degeneration of nucleus pulposus cells, mRNA and protein expression level was determined by RT-PCR and Western Blot, and Immunocytochemical staining were used to detect expression of collagen II, aggrecan, MMP3/13, superoxide dismutase 2 (SOD2) and inducible nitric oxide synthase (iNOS). In vivo, the potential therapeutic effect of CB2 was detected in the rat acupuncture model. RESULT: In vitro, we found that the CB2 agonist (JWH133) treatment reduced the oxidative stress level in NPCs induced by hydrogen peroxide (H2O2) treatment. Furthermore, the expression of inflammatory cytokines was also decreased by JWH133 treatment. We found that collagen II and aggrecan expression was preserved, whereas matrix metalloproteinase levels were reduced. In vivo, we established a rat model by needle puncture. Imaging assessment revealed that the disc height index (DHI) and morphology of IVD were significantly improved, and the disc degeneration process was delayed by treatment of JWH133. Furthermore, immunohistochemical (IHC) staining revealed that JWH133 could inhibit the degradation of collagen II and decrease the expression of MMP3. CONCLUSIONS: The experiment indicates the oxidative stress and inflammatory response of rat NPCs induced by H2O2 could be inhibited by activating CB2. This study reveals that CB2 activation can effectively delay the development of IVDD, providing an effective therapeutic target for IVDD.

9.
Front Physiol ; 12: 672572, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220535

RESUMO

Objective: The aim of this study is to verify whether melatonin (Mel) could mitigate intervertebral disk degeneration (IVDD) in rats and to investigate the potential mechanism of it. Method: A rat acupuncture model of IVDD was established with intraperitoneal injection of Mel. The effect of Mel on IVDD was analyzed via radiologic and histological evaluations. The specific Mel receptors were investigated in both the nucleus pulposus (NP) and cartilaginous endplates (EPs). In vitro, EP cartilaginous cells (EPCs) were treated by different concentrations of Mel under lipopolysaccharide (LPS) and Luzindole conditions. In addition, LPS-induced inflammatory response and matrix degradation following nuclear factor kappa-B (NF-κB) pathway activation were investigated to confirm the potential mechanism of Mel on EPCs. Results: The percent disk height index (%DHI) and MRI signal decreased after initial puncture in the degeneration group compared with the control group, while Mel treatment protected disk height from decline and prevented the loss of water during the degeneration process. In the meantime, the histological staining of the Mel groups showed more integrity and well-ordered construction of the NP and EPs in both low and high concentration than that of the degeneration group. In addition, more deep-brown staining of type II collagen (Coll-II) was shown in the Mel groups compared with the degeneration group. Furthermore, in rat samples, immunohistochemical staining showed more positive cells of Mel receptors 1a and 1b in the EPs, instead of in the NP. Moreover, evident osteochondral lacuna formation was observed in rat EPs in the degeneration group; after Mel treatment, the osteochondral destruction alleviated accompanying fewer receptor activator for nuclear factor-κB ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP)-stained positive cells expressed in the EPs. In vitro, Mel could promote the proliferation of EPCs, which protected EPCs from degeneration under LPS treatment. What is more, Mel downregulated the inflammatory response and matrix degradation of EPCs activated by NF-κB pathway through binding to its specific receptors. Conclusion: These results indicate that Mel protects the integrity of the EPs and attenuates IVDD by binding to the Mel receptors in the EPs. It may alleviate the inflammatory response and matrix degradation of EPCs activated by NF-κB pathway.

10.
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.

11.
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
12.
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.

13.
Bioorg Chem ; 113: 104978, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34052737

RESUMO

Osteoarthritis (OA) is a chronic disease featured by joint hyperplasia, deterioration of articular cartilage, and progressive degeneration. Abnormal expression of microRNAs (miRNAs) has been found to be implicated in the pathological process of OA. In this study, the role of miR-361-5p transferred by exosomes derived from human bone mesenchymal stem cells (hBMSCs) in OA was investigated. The expression of Asp-Glu-Ala-Asp-box polypeptide 20 (DDX20) and miR-361-5p in interleukin-1ß (IL-1ß)-treated chondrocytes was determined by reverse transcription quantitative polymerase chain reaction. DDX20 was knocked down by transfection of short hairpin RNA targeting DDX20, and the effects of DDX20 downregulation on IL-1ß-induced damage of chondrocytes were detected. The interaction between DDX20 and miR-361-5p was tested by luciferase report assay. hBMSCs-derived exosomes loaded with miR-361-5p were co-incubated with chondrocytes followed by detection of cell viability, proliferation and inflammatory response. An OA rat model was established to further explore the role of miR-361-5p in vivo. Western blot, luciferase reporter and immunofluorescence staining assays were used to evaluate the activation of the nuclear factor kappa-B (NF-κB) signaling pathway. We found that DDX20 was upregulated, while miR-361-5p was underexpressed in IL-1ß-treated chondrocytes. Downregulation of DDX20 inhibits levels of matrix metalloproteinases (MMPs) and suppresses inflammation induced by IL-1ß. Mechanistically, miR-361-5p was verified to directly target DDX20. In addition, hBMSC-derived exosomes-transferred miR-361-5p alleviates chondrocyte damage and inhibits the NF-κB signaling pathway via targeting DDX20. Inhibition of NF-κB signaling reverses the effect of overexpressed DDX20 on IL-1ß-induced chondrocyte damage. Moreover, exosomal miR-361-5p alleviates OA damage in vivo. Overall, hBMSC-derived exosomal miR-361-5p alleviates OA damage by targeting DDX20 and inactivating the NF-κB signaling pathway.


Assuntos
Proteína DEAD-box 20/metabolismo , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Animais , Modelos Animais de Doenças , Humanos , MicroRNAs/genética , Ratos , Ratos Wistar , Transdução de Sinais
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.
Front Pharmacol ; 12: 648969, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833684

RESUMO

Postmenopausal osteoporosis is a disease of bone mass reduction and structural changes due to estrogen deficiency, which can eventually lead to increased pain and fracture risk. Chronic inflammatory microenvironment leading to the decreased activation of osteoblasts and inhibition of bone formation is an important pathological factor that leads to osteoporosis. Theaflavin-3,3'-digallate (TFDG) is an extract of black tea, which has potential anti-inflammatory and antiviral effects. In our study, we found that TFDG significantly increased the bone mass of ovariectomized (OVX) mice by micro-CT analysis. Compared with OVX mice, TFDG reduced the release of proinflammatory cytokines and increased the expression of osteogenic markers in vivo. In vitro experiments demonstrated that TFDG could promote the formation of osteoblasts in inflammatory environment and enhance their mineralization ability. In this process, TFDG activated MAPK, Wnt/ß-Catenin and BMP/Smad signaling pathways inhibited by TNF-α, and then promoted the transcription of osteogenic related factors including Runx2 and Osterix, promoting the differentiation and maturation of osteoblasts eventually. In general, our study confirmed that TFDG was able to promote osteoblast differentiation under inflammatory environment, enhance its mineralization ability, and ultimately increase bone mass in ovariectomized mice. These results suggested that TFDG might have the potential to be a more effective treatment of postmenopausal osteoporosis.

17.
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.

18.
Biomed Res Int ; 2021: 8851421, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33778083

RESUMO

Background: Osteoporosis is characterized by low bone mass, deterioration of bone tissue structure, and susceptibility to fracture. New and more suitable therapeutic targets need to be discovered. Methods: We collected osteoporosis-related datasets (GSE56815, GSE99624, and GSE63446). The methylation markers were obtained by differential analysis. Degree, DMNC, MCC, and MNC plug-ins were used to screen the important methylation markers in PPI network, then enrichment analysis was performed. ROC curve was used to evaluate the diagnostic effect of osteoporosis. In addition, we evaluated the difference in immune cell infiltration between osteoporotic patients and control by ssGSEA. Finally, differential miRNAs in osteoporosis were used to predict the regulators of key methylation markers. Results: A total of 2351 differentially expressed genes and 5246 differentially methylated positions were obtained between osteoporotic patients and controls. We identified 19 methylation markers by PPI network. They were mainly involved in biological functions and signaling pathways such as apoptosis and immune inflammation. HIST1H3G, MAP3K5, NOP2, OXA1L, and ZFPM2 with higher AUC values were considered key methylation markers. There were significant differences in immune cell infiltration between osteoporotic patients and controls, especially dendritic cells and natural killer cells. The correlation between MAP3K5 and immune cells was high, and its differential expression was also validated by other two datasets. In addition, NOP2 was predicted to be regulated by differentially expressed hsa-miR-3130-5p. Conclusion: Our efforts aim to provide new methylation markers as therapeutic targets for osteoporosis to better treat osteoporosis in the future.


Assuntos
Apoptose , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Regulação da Expressão Gênica , Osteoporose , Transdução de Sinais , Biomarcadores/metabolismo , Humanos , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/terapia
19.
J Cell Physiol ; 236(9): 6441-6456, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33565085

RESUMO

Senescence of nucleus pulposus (NP) cells (NPC) is a major cause of intervertebral disc degeneration (IVDD), so delay NPC senescence may be beneficial for mitigating IVDD. We studied the effect and mechanism of silent information regulator 2 homolog 3 (SIRT3) on NPC senescence in vivo and in vitro. First, we observed SIRT3 expression in normal and degenerated NPC with immunohistochemical and immunofluorescence staining. Second, using SIRT3 lentivirus transfection, reactive oxygen species probe, senescence-associated ß-galactosidase staining, polymerase chain reaction, and western blot to observe the oxidative stress, senescence, and degeneration degree among groups. Subsequently, pretreatment with adenosine monophosphate-activated protein kinase (AMPK) agonists and inhibitors, observing oxidative stress, senescence, and degeneration degree among groups. Finally, the IVDD model was constructed and divided into Ctrl, Vehicle, LV-shSIRT3, and LV-SIRT3 groups. X-ray and magnetic resonance imaging scans were performed on rat's tails after 1 week; hematoxylin and eosin and safranin-O staining were used to evaluate the degree of IVDD; immunofluorescence staining was used to observe SIRT3 expression; immunohistochemical staining was used to observe oxidative stress, senescence, and degeneration degree of NP. We found that SIRT3 expression is reduced in degenerated NP tissues but increased in H2 O2 -induced NPC. Moreover, SIRT3 upregulation decreased oxidative stress, delayed senescence, and degeneration of NPC. In addition, activation of the AMPK/PGC-1α pathway can partially mitigate the NPC oxidative stress, senescence, and degeneration caused by SIRT3 knockdown. The study in vivo revealed that local SIRT3 overexpression can significantly reduce oxidative stress and ECM degradation of NPC, delay NPC senescence, thereby mitigating IVDD. In summary, SIRT3 mediated by the AMPK/PGC-1α pathway mitigates IVDD by delaying oxidative stress-induced NPC senescence.


Assuntos
Senescência Celular , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Núcleo Pulposo/patologia , Estresse Oxidativo , Sirtuína 3/metabolismo , Adenilato Quinase/metabolismo , Adulto , Animais , Modelos Animais de Doenças , Feminino , Humanos , Peróxido de Hidrogênio/toxicidade , Degeneração do Disco Intervertebral/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Núcleo Pulposo/diagnóstico por imagem , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Punções , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
20.
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
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