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Cell-to-cell mitochondrial transfer has recently been shown to play a role in maintaining physiological functions of cell. We previously illustrated that mitochondrial transfer within osteocyte dendritic network regulates bone tissue homeostasis. However, the mechanism of triggering this process has not been explored. Here, we showed that stressed osteocytes in mice release adenosine diphosphate (ADP), resulting in triggering mitochondrial transfer from healthy osteocytes to restore the oxygen consumption rate (OCR) and to alleviate reactive oxygen species accumulation. Furthermore, we identified that P2Y2 and P2Y6 transduced the ADP signal to regulate osteocyte mitochondrial transfer. We showed that mitochondrial metabolism is impaired in aged osteocytes, and there were more extracellular nucleotides release into the matrix in aged cortical bone due to compromised membrane integrity. Conditioned medium from aged osteocytes triggered mitochondrial transfer between osteocytes to enhance the energy metabolism. Together, using osteocyte as an example, this study showed new insights into how extracellular ADP triggers healthy cells to rescue energy metabolism crisis in stressed cells via mitochondrial transfer in tissue homeostasis.
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Adenosina Difosfato , Homeostasis , Mitocondrias , Osteocitos , Animales , Osteocitos/metabolismo , Mitocondrias/metabolismo , Ratones , Adenosina Difosfato/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Consumo de Oxígeno , Metabolismo Energético , Ratones Endogámicos C57BL , Estrés FisiológicoRESUMEN
BACKGROUND: Osteoarthritis is a prevalent musculoskeletal condition, but the role of specific serum biomarkers, such as calcium, vitamin D, and C-reactive protein (CRP), in predicting mortality among individuals with osteoarthritis remains unclear. METHODS: This observational study analyzed longitudinal data from over 500,000 participants in the UK Biobank, identifying those with osteoarthritis using ICD-9/10 codes or self-reported history. We performed multivariable cox-regression and flexible parametric survival model (FPSM) for survival analysis, with adjustments made through the inverse probability of treatment weight (IPTW) for baseline covariates identified by directed acyclic graphs (DAGs). RESULTS: Of the 49,082 osteoarthritis population, the average age was 60.69 years, with 58.7% being female. During the follow-up period exceeding 15 years, a total of 5,522 people with osteoarthritis died. High serum calcium levels, compared to normal serum calcium levels, were significantly associated with all-cause mortality (hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.11, 1.59), cardiovascular diseases (CVD)-related deaths (HR 1.55, 95% CI 1.05, 2.29), and other deaths (HR 1.59, 95% CI 1.20, 2.11). Low serum calcium levels, compared to normal serum calcium levels, was linked with CVD-related deaths (HR 2.06, 95% CI 1.02, 4.14). Vitamin D insufficiency, compared to sufficient vitamin D levels, was correlated with all-cause mortality (HR 1.22, 95% CI 1.13, 1.33), CVD-related deaths (HR 1.43, 95% CI 1.20, 1.72), and other deaths (HR 1.26, 95% CI 1.09, 1.45) but not with cancer-related deaths. High serum CRP levels, compared to normal CRP levels, were associated with all outcomes (all-cause mortality: HR 1.22, 95% CI 1.12, 1.33; CVD-related death: HR 1.24, 95%CI 1.03, 1.49; cancer-related death: HR 1.23, 95% CI 1.09, 1.40; other deaths: HR 1.19, 95%CI 1.03, 1.38). CONCLUSIONS: Both high and low serum calcium levels, elevated CRP, and vitamin D insufficiency are potential predictors of increased mortality risk in the osteoarthritis population. These findings emphasize the importance of monitoring and possibly addressing these serum biomarkers in osteoarthritis populations to improve long-term outcomes. Further studies are needed to understand the underlying mechanisms and to propose therapeutic interventions.
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Biomarcadores , Proteína C-Reactiva , Calcio , Causas de Muerte , Osteoartritis , Vitamina D , Humanos , Femenino , Osteoartritis/sangre , Osteoartritis/mortalidad , Masculino , Reino Unido/epidemiología , Vitamina D/sangre , Persona de Mediana Edad , Proteína C-Reactiva/análisis , Estudios Prospectivos , Calcio/sangre , Anciano , Biomarcadores/sangre , Estudios LongitudinalesRESUMEN
Bone is one of the most sophisticated and dynamic tissues in the human body, and is characterized by its remarkable potential for regeneration. In most cases, bone has the capacity to be restored to its original form with homeostatic functionality after injury without any remaining scarring. Throughout the fascinating processes of bone regeneration, a plethora of cell lineages and signaling molecules, together with the extracellular matrix, are precisely regulated at multiple length and time scales. However, conditions, such as delayed unions (or nonunion) and critical-sized bone defects, represent thorny challenges for orthopedic surgeons. During recent decades, a variety of novel biomaterials have been designed to mimic the organic and inorganic structure of the bone microenvironment, which have tremendously promoted and accelerated bone healing throughout different stages of bone regeneration. Advances in tissue engineering endowed bone scaffolds with phenomenal osteoconductivity, osteoinductivity, vascularization and neurotization effects as well as alluring properties, such as antibacterial effects. According to the dimensional structure and functional mechanism, these biomaterials are categorized as zero-dimensional, one-dimensional, two-dimensional, three-dimensional, and four-dimensional biomaterials. In this review, we comprehensively summarized the astounding advances in emerging biomaterials for bone regeneration by categorizing them as zero-dimensional to four-dimensional biomaterials, which were further elucidated by typical examples. Hopefully, this review will provide some inspiration for the future design of biomaterials for bone tissue engineering.
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Materiales Biocompatibles , Regeneración Ósea , Nanoestructuras , Ingeniería de Tejidos/métodos , Animales , Humanos , Ratones , Andamios del TejidoRESUMEN
Alcohol consumption is regarded as one of the leading risk factors for secondary osteopenia. Coupled angiogenesis and osteogenesis via distinct type-H vessels orchestrates subtle biological processes of bone homeostasis. The dysfunction of angiogenesis and osteogenesis contributes to decreased bone mass during the development of osteopenia. Herein, we identified microRNA-136-3p was remarkedly downregulated in the mouse model of alcohol-induced osteopenia. Following the alcohol administration, downregulated microRNA-136-3p significantly suppressed vascularization and osteogenic differentiation in human umbilical vein endothelial cells (HUVECs) and bone mesenchymal stem cells (BMSCs), respectively. Furthermore, microRNA-136-3p could target phosphatase and tensin homolog deleted on chromosome ten (PTEN) in both HUVECs and BMSCs, thus substantially modulating the capacity of vessel formation and osteogenic differentiation. In the mouse model, microRNA-136-3p Agomir ameliorated alcohol-induced osteopenia, with the concomitant restoration of bone mass and type-H vessel formation. For the first time, this study demonstrated the pivotal role of microRNA-136-3p/PTEN axis in regulations of vascularization and bone formation, which might become the potential therapeutic target of alcohol-induced bone loss.
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Enfermedades Óseas Metabólicas/prevención & control , Etanol/toxicidad , Regulación de la Expresión Génica , MicroARNs/genética , Neovascularización Patológica/prevención & control , Osteogénesis , Fosfohidrolasa PTEN/metabolismo , Animales , Enfermedades Óseas Metabólicas/inducido químicamente , Enfermedades Óseas Metabólicas/genética , Enfermedades Óseas Metabólicas/metabolismo , Diferenciación Celular , Depresores del Sistema Nervioso Central/toxicidad , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Fosfohidrolasa PTEN/genéticaRESUMEN
Glucocorticoid (GC) administration is one of the main causes of osteonecrosis of the femoral head (ONFH). Inflammation, especially the TLR4/NF-κB pathway, has been demonstrated to play a pivotal role in the pathogenesis of GC-induced ONFH. Calycosin, the main bioactive extract of Astragali Radix, could substantially regulate the TLR4/NF-κB pathway. Therefore, in this study, we hypothesized that calycosin could exert beneficial effects in GC-induced ONFH. In vitro, effects of calycosin on the osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs) were determined using Alizarin red staining, alkaline phosphatase activity examination, and osteogenic-related gene assay. Meanwhile, inflammatory cytokines were detected by enzyme-linked immunosorbent assay. In vivo, 60 male Sprague-Dawley rats were randomly separated into three groups: the control group, the methylprednisolone (MPS) group, and the MPS + calycosin group. The results showed that calycosin could significantly promote dynamic bone formation and retard TLR4/NF-κB pathway. in vivo investigations indicated that calycosin could decrease the morbidity of ONFH and alleviate pathological manifestations within the femoral head. Meanwhile, calycosin could protect osseous blood supply and facilitate dynamic bone formation. The findings collectively demonstrated that calycosin could ameliorate GC-induced ONFH in rat and might become a potential candidate for pharmaceutical prevention of this intractable disease.
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BACKGROUND: This study aimed at developing a risk score predicting the probability of developing an osteonecrosis of the femoral head (ONFH) in patients with femoral neck fracture within 3 years after closed reduction internal fixation and evaluating its performance, clinical utility, and internal validity. METHODS: A retrospective follow-up study of 378 newly injured femoral neck fracture patients treated with 3 partially threaded parallel cannulated screws in 3 hospitals in Shanghai from March 2013 to January 2017 was performed. The patients were divided into development (n = 284) and validation (n = 94) cohorts. The risk score was constructed by Cox regression analysis in a form of nomogram. The performance and clinical utility were illustrated by box plots, calibration plots, and decision curve analysis. RESULTS: Eighty-three of 378 patients had developed ONFH within 3 years. Garden alignment index, time to surgery, preoperative displace, impaction, and postoperative malposition were used as predictors to construct the risk score in a form of nomogram. In the development and validation cohort, the concordance index was 0.96 and 0.94, respectively; the discrimination slope was 0.51 and 0.47, respectively. In both cohorts, the calibration slopes and intercepts were 1 and 0, respectively. The risk score was clinically useful between the risk threshold of 0% and 88%. The performance and utility in the validation data illustrated good repeatability. CONCLUSION: The risk score had satisfactory discrimination and calibration performance and demonstrated clinical utility with good internal validity. It managed to distinguish high-risk groups for post-traumatic ONFH.
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Fracturas del Cuello Femoral , Osteonecrosis , China , Cabeza Femoral , Estudios de Seguimiento , Fijación Interna de Fracturas , Humanos , Osteonecrosis/epidemiología , Osteonecrosis/etiología , Osteonecrosis/cirugía , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Characteristic pathological changes in osteonecrosis of the femoral head (ONFH) include reduced osteogenic differentiation of bone mesenchymal stem cells (BMSCs), impaired osseous circulation and increased intramedullary adipocytes deposition. Osthole is a bioactive derivative from coumarin with a wide range of pharmacotherapeutic effects. The aim of this study was to unveil the potential protective role of osthole in alcohol-induced ONFH. In vitro, ethanol (50 mmol/L) remarkably decreased the proliferation and osteogenic differentiation of BMSCs and impaired the proliferation and tube formation capacity of human umbilical vein endothelial cell (HUVECs), whereas it substantially promoted the adipogenic differentiation of BMSCs. However, osthole could reverse the effects of ethanol on osteogenesis via modulating Wnt/ß-catenin pathway, stimulate vasculogenesis and counteract adipogenesis. In vivo, the protective role of osthole was confirmed in the well-constructed rat model of ethanol-induced ONFH, demonstrated by a cascade of radiographical and pathological investigations including micro-CT scanning, haematoxylin-eosin staining, TdT-mediated dUTP nick end labelling, immunohistochemical staining and fluorochrome labelling. Taken together, for the first time, osthole was demonstrated to rescue the ethanol-induced ONFH via promoting bone formation, driving vascularization and retarding adipogenesis.
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Adipogénesis/efectos de los fármacos , Cumarinas/farmacología , Necrosis de la Cabeza Femoral/tratamiento farmacológico , Osteonecrosis/tratamiento farmacológico , Animales , Diferenciación Celular/efectos de los fármacos , Etanol/toxicidad , Cabeza Femoral/crecimiento & desarrollo , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/genética , Necrosis de la Cabeza Femoral/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Osteocalcina/genética , Osteogénesis/efectos de los fármacos , Osteonecrosis/inducido químicamente , Osteonecrosis/genética , Osteonecrosis/patología , Ratas , Ratas Sprague-Dawley , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/genéticaRESUMEN
The rising concerns of the recurrence and bone deficiency in surgical treatment of malignant bone tumors have raised an urgent need of the advance of multifunctional therapeutic platforms for efficient tumor therapy and bone regeneration. Herein, the construction of a multifunctional biomaterial system is reported by the integration of 2D Nb2 C MXene wrapped with S-nitrosothiol (RSNO)-grafted mesoporous silica with 3D-printing bioactive glass (BG) scaffolds (MBS). The near infrared (NIR)-triggered photonic hyperthermia of MXene in the NIR-II biowindow and precisely controlled nitric oxide (NO) release are coordinated for multitarget ablation of bone tumors to enhance localized osteosarcoma treatment. The in situ formed phosphorus and calcium components degraded from BG scaffold promote bone-regeneration bioactivity, augmented by sufficient blood supply triggered by on-demand NO release. The tunable NO generation plays a crucial role in sequential adjuvant tumor ablation, combinatory promotion of coupled vascularization, and bone regeneration. This study demonstrates a combinatory osteosarcoma ablation and a full osseous regeneration as enabled by the implantation of MBS. The design of multifunctional scaffolds with the specific features of controllable NO release, highly efficient photothermal conversion, and stimulatory bone regeneration provides an intriguing biomaterial platform for the diversified treatment of bone tumors.
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Regeneración Ósea , Óxido Nítrico , Osteosarcoma , Impresión Tridimensional , Dióxido de Silicio , Andamios del Tejido , Humanos , Recurrencia Local de Neoplasia , Osteosarcoma/terapia , Impresión Tridimensional/instrumentación , Dióxido de Silicio/química , Ingeniería de Tejidos , Andamios del Tejido/química , Andamios del Tejido/normasRESUMEN
Inflammation plays an important role in osteonecrosis. Obesity, a risk factor for osteonecrosis, leads to a chronic inflammatory status. We hypothesized that inflammation mediated the effects of obesity on osteonecrosis and tested our hypothesis in a mouse model of osteonecrosis. We fed mice with a high-fat diet (HFD) for 12 weeks before osteonecrosis induction by methylprednisolone and examined bone structure and IL-6 expression. Then we investigated the effects of IL-6 deletion in mice with osteonecrosis on the HFD. Next, we isolated bone marrow cells and determined the cell types responsible for HFD-induced IL-6 secretion. Finally, we investigated the roles of macrophages and macrophage-driven IL-6 in HFD-mediated effects on osteonecrosis and osteogenesis of bone marrow stromal cells (BMSCs). The HFD lead to exacerbated destruction of the femoral head in mice with osteonecrosis and increased IL-6 expression in macrophages. Il-6 knockout or macrophage depletion suppressed the effects of the HFD on bone damage. When co-cultured with macrophages isolated from HFD-fed mice with osteonecrosis, BMSCs showed reduced viability and suppressed osteogenic differentiation. Our results suggest that macrophage-driven IL-6 bridges obesity and osteonecrosis and inhibition of IL-6 or depletion of macrophage may represent a therapeutic strategy for obesity-associated osteonecrosis.
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Dieta Alta en Grasa/efectos adversos , Inflamación/metabolismo , Interleucina-6/metabolismo , Macrófagos/inmunología , Obesidad/metabolismo , Osteonecrosis/metabolismo , Animales , Diferenciación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Inflamación/inmunología , Interleucina-6/genética , Masculino , Metilprednisolona , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/inmunología , Osteogénesis , Osteonecrosis/inmunología , Transducción de SeñalRESUMEN
BACKGROUND: Whether IL-15 is involved in the development of steroid-induced osteonecrosis of the femoral head (ONFH) is investigated. METHODS: C57BL/6 J and l15-/-mice were injected with methylprednisolone to induce wide type osteonecrosis (WT ON) and IL-15 deficiency osteonecrosis (IL-15-/- ON). Hematoxylin-Eosin (H&E) staining and micro-computed tomography (micro-CT) scanning was used to detect the microstructure. The differentiation and formation of osteoclasts were determined with colony-forming unit-granulocyte macrophages (CFU-GM), colony-forming unit-macrophage/mononuclear (CFU-M) per tibia, and tartrate-resistant acid phosphatase (TRACP or TRAP) positive cells. Serum interleukin (IL)-15, osteocalcin, bone alkaline phosphatase (BAP), bone Gla protein (BGP), and TRACP were assayed with enzyme-linked immunosorbent assay (ELISA). The receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in the femoral heads were detected by Western blot. CD34 staining was performed to detect microvascular density. RESULTS: IL-15 secretion was increased in the femoral heads and the serum of steroid-induced ONFH mice. IL-15 deficiency may lead to up-regulated vessel remodeling, improved microstructure, and up-regulated serum osteocalcin, BAP, and BGP secretion. Both the expression of RANKL/RANK/OPG and osteoclast differentiation and formation can be down-regulated by IL-15 deficiency. CONCLUSION: IL-15 deficiency alleviates steroid-induced ONFH by impact osteoclasts via RANKL-RANK-OPG system.
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Failed treatment of intertrochanteric (IT) femoral fractures leads to remarkable disability and pain, and revision surgery is frequently accompanied by higher complication and reoperation rates than primary internal fixation or primary hip arthroplasty. There is an urgent need to establish a profound strategy for the effective surgical management of these fragile patients. Salvage options are determined according to patient physiological age, functional level, life expectancy, nonunion anatomical site, fracture pattern, remaining bone quality, bone stock, and hip joint competency. In physiologically young patients, care should be taken to preserve the vitality of the femoral head with salvage internal fixation; however, for the elderly population, conversion arthroplasty can result in early weight bearing and ambulation and eliminates the risks of delayed fracture healing. Technical challenges include a difficult surgical exposure, removal of broken implants, deformity correction, critical bone defects, poor bone quality, high perioperative fracture risk, and prolonged immobilization. Overall, the salvage of failed internal fixations of IT fractures with properly selected implants and profound techniques can lead to the formulation of valuable surgical strategies and provide patients with satisfactory clinical outcomes.
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Artroplastia de Reemplazo de Cadera , Fracturas de Cadera , Anciano , Artroplastia de Reemplazo de Cadera/efectos adversos , Fijación Interna de Fracturas/efectos adversos , Fracturas de Cadera/diagnóstico por imagen , Fracturas de Cadera/cirugía , Humanos , Reoperación , Estudios Retrospectivos , Terapia Recuperativa , Resultado del TratamientoRESUMEN
PURPOSE: Timing of surgery is the most critical prognostic factor for hip osteonecrosis treated with free vascularized fibular grafting (FVFG). Bone marrow lesion (BML) on MRI usually occurs immediately before femoral head collapse. We conducted a retrospective cohort study to evaluate whether the noncollapsed hips with BML can benefit from FVFG. METHODS: Consecutive patients undergoing modified FVFG were identified from our clinical repository between January 2014 and December 2014. Based on whether BML was pre-operatively detected, the four year radiographic and clinical outcomes were compared. RESULTS: In the BML cohort, 22 of 53 hips (42%) showed radiographic signs of osteonecrosis progression, which was significantly higher than that in the control cohort (8 of 49, 16%; P = 0.005). The BML hips showed a significantly lower pre-operative Harris Hip Score (HHS) than those without BML (77.8 vs. 85.5, P = 0.046), whereas no such difference was observed in the final HHS or its post-operative improvement (HHS 90 vs. 94, P = 0.397; HHS improvement 12 vs. 8, P = 0.067). In the subgroup of patients with a pre-operative HHS lower than 80, BML hips were associated with a slightly lower final HHS than hips without BML. Four of 5 (80%) failed hips with BML had a poor pre-operative hip function. CONCLUSION: BML indicates the last chance for a reproducible improvement in the treatment of hip osteonecrosis with FVFG before collapse. However, the concomitant lower pre-operative HHS (< 80) is a poor prognostic factor for BML-positive hips.
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Médula Ósea , Necrosis de la Cabeza Femoral , Médula Ósea/diagnóstico por imagen , Trasplante Óseo , Necrosis de la Cabeza Femoral/diagnóstico por imagen , Necrosis de la Cabeza Femoral/cirugía , Peroné/diagnóstico por imagen , Peroné/cirugía , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Charcot neuroarthropathy is a systemic disease that generates pathological changes in the musculoskeletal system, causing instability, dislocations, and deformities. Charcot neuroarthropathy of the knee, due to either diabetes mellitus or syringomyelia, is anecdotally reported with the epidemic of the diseases. However, idiopathic sensory peripheral neuropathy can inflict osteoarticular structures directly, inducing a dysfunctional Charcot neuroarthropathy. An early diagnosis and effective relief of the symptomatic deformity is essential for the treatment. CASE PRESENTATION: We report the case of a patient with idiopathic sensory peripheral neuropathy who presented with a swelling right knee, as well as distorted and painless gait disorder, diagnosed as Charcot neuroarthropathy of the knee. Partial weight bearing with a hinged knee brace was used to correct the abnormal alignment and gait posture, and bisphosphonates were prescribed to decrease pathological bone resorption. Although the alignment and Knee Society Score got a gradual deterioration, the combination of orthosis and pharmacy could alleviate the symptom to a certain extent. CONCLUSION: The diagnosis of Charcot neuroarthropathy of the knee is rare that requiring early diagnosis. The presence of features, including painlessness, numbness, and deformed arthropathy following chronic-onset algesthesia loss should be taken carefully.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico por imagen , Enfermedad de Charcot-Marie-Tooth/etiología , Articulación de la Rodilla/diagnóstico por imagen , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/diagnóstico por imagen , Adulto , Humanos , MasculinoRESUMEN
BACKGROUND: Intertrochanteric femoral fractures (IFFs) in young adults, generally due to severe trauma, are increasingly presented. Different from IFFs in the geriatric population, these fractures in young adults are always comminuted and substantially displaced. Natural traction induced by musculature following IFFs determines closed reduction on a fracture table is extremely difficult. METHODS: To achieve anatomical reduction before intramedullary nail (IMN) fixation, we made an extended or a mini petrotrochantetic incision to facilitate temporary reduction using a pointed clamp. Subsequently, a curved and cannulated wire-passer was employed to pass through a multistrand cable to surround displaced fragments and strengthen intertrochanteric fixation. Afterward, a standard procedure was conducted to nail the fracture. RESULTS: We used the surgical technique in 9 young patients with an age range of 28~ 48 years old. The fractures were categorized as AO/OTA 31-A2.2 (3 cases) and 31-A2.3 (6 cases). The injury-to-surgery interval was 2.5 days on average. Mean operation time was 55 min. All fractures achieved anatomical reduction and healed within 14 weeks postoperatively without cable breakage, implant irritation or deep infection. CONCLUSIONS: In conclusion, the surrounding technique with cerclage wire in IFFs in young adults is an effective surgical technique with easily achieved anatomical reduction to facilitate operative maneuvers and fracture healing.
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Clavos Ortopédicos , Hilos Ortopédicos , Fémur/cirugía , Fijación Intramedular de Fracturas/instrumentación , Fracturas de Cadera/cirugía , Adulto , Factores de Edad , Femenino , Fémur/diagnóstico por imagen , Fémur/fisiopatología , Fijación Intramedular de Fracturas/efectos adversos , Fijación Intramedular de Fracturas/métodos , Curación de Fractura , Fracturas de Cadera/diagnóstico por imagen , Fracturas de Cadera/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Diseño de Prótesis , Factores de Tiempo , Resultado del TratamientoRESUMEN
Excessive inflammation including IL-1ß-initiated signaling is among the earlies reactions that can cause neuronal damage following spinal cord injury (SCI). It has been suggested that microRNAs may participate in stem cell repair to facilitate functional recovery following SCI. In this study we have shown that in cultured human neural stem cells (hNSC), IL-1ß reduced the expression of both KIF3B (kinesin family member 3B) and NOSIP (nitric oxide synthase-interacting protein), two key modulators for restricting inflammation and promoting neuronal regeneration. The induction of microRNA-372 (miR-372) by IL-1ß is specifically responsible for the inhibition of KIF3B and NOSIP. The 3'-untranslated regions (UTRs) of both KIF3B and NOSIP contain targeting sequences to miR-372 that directly inhibit their expression. Moreover, we found that the expression of miR-372 was stimulated in hNSC by IL-1ß through an NF-κB binding site at its promoter region. Finally, stable overexpression of miR-372 inhibitor in hNSC rescued the IL-1ß-induced impairment as shown by significant improvements in tissue water content, myeloperoxidase activity, and behavioral assessments in SCI rats. These findings suggest a critical role of miR-372 in inflammatory signaling and pinpoint a novel target for the treatment of acute SCI.NEW & NOTEWORTHY Our data demonstrate that IL-1ß can impair the functional recovery of neural stem cell transplant therapy for spinal cord injury (SCI) treatment in rats. This effect is dependent on microRNA-372 (miR-372)-dependent gene repression of KIF3B and NOSIP. Therefore, specific knockdown of miR-372 may provide benefits for SCI treatments.
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Interleucina-1beta/farmacología , MicroARNs/genética , FN-kappa B/metabolismo , Células-Madre Neurales/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Células Cultivadas , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Masculino , MicroARNs/metabolismo , Células-Madre Neurales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ubiquitina-Proteína Ligasas , Regulación hacia ArribaRESUMEN
BACKGROUND: Alcohol abuse is known to be a leading risk factor for atraumatic osteonecrosis of the femoral head (ONFH), in which the suppression of osteogenesis plays a critical role. Cordycepin benefits bone metabolism; however, there has been no study to determine its effect on osteonecrosis. METHODS: Human bone mesenchymal stem cells (hBMSCs) were identified by multi-lineage differentiation. Alkaline phosphatase (ALP) activity, RT-PCR, western blots, immunofluorescent assay and Alizarin red staining of BMSCs were evaluated. A rat model of alcohol-induced ONFH was established to investigate the protective role of cordycepin against ethanol. Hematoxylin & eosin (H&E) staining and micro-computerized tomography (micro-CT) were performed to observe ONFH. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL). Immunohistochemical staining was carried out to detect OCN and COL1. RESULTS: Ethanol significantly suppressed ALP activity, decreased gene expression of OCN and BMP2, lowered levels of RUNX2 protein, and reduced immunofluorescence staining of OCN and COL1 and calcium formation of hBMSCs. However, these inhibitory effects were attenuated by cordycepin co-treatment at concentrations of 1 and 10 µg/mL Moreover, it was revealed that the osteo-protective effect of cordycepin was associated with modulation of the Wnt/ß-catenin pathway. In vivo, by micro-CT, TUNEL and immunohistochemical staining of OCN and COL1, we found that cordycepin administration prevented alcohol-induced ONFH. CONCLUSION: Cordycepin treatment to enhance osteogenesis may be considered a potential therapeutic approach to prevent the development of alcohol-induced ONFH.
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Diferenciación Celular/efectos de los fármacos , Desoxiadenosinas/farmacología , Etanol/toxicidad , Osteogénesis/efectos de los fármacos , Sustancias Protectoras/farmacología , Animales , Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 2/metabolismo , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Cabeza Femoral/diagnóstico por imagen , Cabeza Femoral/patología , Cuello Femoral/citología , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Modelos Animales , Osteocalcina/genética , Osteocalcina/metabolismo , Ratas , Ratas Sprague-Dawley , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismoRESUMEN
The detrimental effects of oxidative stress on the skeletal system have been documented, and understanding the mechanisms is important to design a therapeutic strategy. As an antioxidant and anti-inflammatory agent, the active ingredient of turmeric curcumin has been used as medication for numerous complications including bone loss. However, it is unclear if curcumin could influence the osteogenic potential of mesenchymal stem cells (MSCs), particularly in oxidative injuries. Here we demonstrate that curcumin treatment protects cell death caused by hydrogen peroxide (H2O2) exposure in human adipose-derived MSCs in vitro. Importantly, curcumin is able to enhance the osteoblast differentiation of human adipose-derived MSCs that is inhibited by H2O2. Notably, both oxidative stress and the inhibition of Wnt/ß-catenin signaling are attenuated by curcumin treatment. These results suggest that curcumin can promote osteoblast differentiation of MSCs and protect the inhibitory effect elicited by oxidative injury. The findings support potential use of curcumin or related antioxidants in MSC-based bone regeneration for disease related with oxidative stress-induced bone loss.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Curcumina/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Peróxido de Hidrógeno/farmacología , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteogénesis/fisiología , Estrés Oxidativo/fisiologíaRESUMEN
Hymecromone is an important coumarin drug, and carprofen is one of the most important nonsteroidal antiinflammatory drugs (NSAIDs). The present study aims to determine the influence of bovine serum albumin (BSA) on the carprofen-hymecromone interaction. The inhibition of carprofen enantiomers on the UDP-glucuronosyltransferase (UGT) 2B7-catalyzed glucuronidation of hymecromone was investigated in the UGTs incubation system with and without BSA. The inhibition capability of increased by 20% (P < 0.001) of (R)-carprofen after the addition of 0.5% BSA in the incubation mixture. In contrast, no significant difference was observed for the inhibition of (S)-carprofen on UGT2B7 activity in the absence or presence of 0.5% BSA in the incubation system. The Lineweaver-Burk plot showed that the intersection point was located in the vertical axis, indicating the competitive inhibition of (R)-carprofen on UGT2B7 in the incubation system with BSA, which is consistent with the inhibition kinetic type of (R)-carprofen on UGT2B7 in the incubation system without BSA. Furthermore, the second plot using the slopes from the Lineweaver-Burk versus the concentrations of (R)-carprofen showed that the fitting equation was y=39.997x+50. Using this equation, the inhibition kinetic parameter was calculated to be 1.3 µM. For (S)-carprofen, the intersection point was located in the horizontal axis in the Lineweaver-Burk plot for the incubation system with BSA, indicating the noncompetitive inhibition of (S)-carprofen on the activity of UGT2B7. The fitting plot of the second plot was y=24.6x+180, and the inhibition kinetic parameter was 7.3 µM. In conclusion, the present study gives a short summary of BSA's influence on the carprofen enantiomers-hymecromone interaction, which will guide the clinical application of carprofen and hymecromone.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Carbazoles/química , Cumarinas/química , Glucuronosiltransferasa/química , Himecromona/química , Albúmina Sérica Bovina/química , Animales , Antiinflamatorios no Esteroideos/farmacología , Biocatálisis , Carbazoles/farmacología , Cumarinas/farmacología , Glucuronosiltransferasa/metabolismo , Himecromona/farmacología , Cinética , EstereoisomerismoRESUMEN
Defects of the lateral malleolus and distal fibula occur occasionally, mainly because of severe trauma or wide resection of fibular neoplasms. These bony defects should be reconstructed to avoid persistent pain and to prevent an abnormal gait induced by ankle instability. Various methods of repair have been developed, including allografting, autologous iliac crest transplantation, scapular apophysis transplantation, and arthrodesis and prosthetic reconstruction. A reverse transfer of the proximal vascularized fibula is also effective. Its morphologic advantage is apparent, and the surgery is simple and direct, with no need for vascular anastomosis. We treated recurrent fibrous dysplasia in the distal fibula of a young male with wide resection and reconstruction using reverse transfer of the proximal, vascularized fibula. At the 6-year follow-up examination, the patient had an American Orthopaedic Foot and Ankle Society ankle-hindfoot score of 100, without any apparent complications. Additionally, we critically reviewed other methods for reconstructing the lateral malleolus and distal fibula and have concluded that reverse transfer of the proximal vascularized fibula compares favorably and could be the treatment of choice.
Asunto(s)
Traumatismos del Tobillo/cirugía , Articulación del Tobillo/cirugía , Displasia Fibrosa Monostótica/cirugía , Peroné/trasplante , Inestabilidad de la Articulación/cirugía , Adolescente , Articulación del Tobillo/diagnóstico por imagen , Trasplante Óseo , Niño , Displasia Fibrosa Monostótica/diagnóstico por imagen , Peroné/irrigación sanguínea , Peroné/diagnóstico por imagen , Humanos , MasculinoRESUMEN
BACKGROUND: Hook plate (HP) is popularly used for acute and severely displaced acromioclavicular (AC) dislocations. However, subacromial impingement and acromion osteolysis induced by transarticular fixation are notorious. The current case-control study was to compare transarticular fixation by HP to coracoclavicular (CC) stabilization by single multistrand titanium cable (MSTC). METHODS: Between January 2006 and August 2009, 24 patients with acute AC dislocations were surgically treated by open reduction and transarticular fixation with HP. These patients were matched to a series of 24 patients, who were managed by CC stabilization with MSTC in the same period. All AC dislocations were graded as Rockwood type V. Implant was removed 8-12 months after the primary operation in all patients, and 12 months at least were needed to assess the maintenance of AC joint. Functional results were evaluated before implant removal as well as in the last follow-up based on Constant-Murley criteria. RESULTS: There were no differences of demographic data including age, dominant gender and side, injury-to-surgery interval, operation time and follow-up period. In terms of functionality, Constant score was 95.8 ± 4.1 in MSTC group, while 76.7 ± 8.0 in HP group before implant removal (P < 0.001). In detail, MSTC was superior to HP in pain, ROM and activities. Constant score was significantly improved to 86.1 ± 5.7 after hardware removal for patients in HP (P < 0.001). Degenerative change of acromioclavicular joint presented in 16 patients (66.7%) in patients treated by HP, while it was found in only 3 patients (12.5%) treated by MSTC (P < 0.001). CONCLUSIONS: MSTC is superior to HP for the treatment of Rockwood type-V acromioclavicular dislocation both before and after removal of the implant. Hardware removal is of great benefits for functional improvement in patients treated by HP.