RESUMEN
Despite numerous attempts to correct forward head posture (FHP), definitive evidence-based screening and diagnostic methods remain elusive. This study proposes a preliminary diagnostic methodology for FHP, utilizing a noninvasive body angle measurement system as a screening test for FHP and incorporating radiological parameters for sagittal alignment. We enrolled 145 adolescents for FHP screening. The forward neck tilt angle (FNTA), defined as the angle between the vertical line and the line connecting the participant's acromion and tragus, was measured using the POM-Checker (a noninvasive depth sensor-based body angle measurement system). A whole-spine standing lateral radiograph was obtained, and eight sagittal alignment parameters were measured. Statistical analyses of the association between the FNTA and eight sagittal alignment parameters were conducted. We used 70% of the participant data to establish a preliminary diagnostic model for FHP based on FNTA and each sagittal alignment parameter. The accuracy of the model was evaluated using the remaining 30% of the participant data. All radiological parameters of sagittal alignment showed weak statistical significance with respect to FNTA (best case: r = 0.16, p = 0.0500; cranial tilt). The proposed preliminary diagnostic model for FHP demonstrated 95.35% agreement. Notably, the model using FNTA without radiological parameters accurately identified (100%) participants who required radiographic scanning for FHP diagnosis. Owing to the weak statistical significance of the association between radiological parameters and external body angle, both factors must be considered for accurate FHP diagnosis. When a clear and severe angle variation is observed in an external body angle check, medical professionals should perform radiographic scanning for an accurate FHP diagnosis. In conclusion, FNTA assessment of FNTA through the proposed preliminary diagnostic model is a significant screening factor for selecting participants who must undergo radiographic scanning so that a diagnosis of FHP can be obtained.
RESUMEN
Posttraumatic osteoarthritis is primarily characterized by articular cartilage destruction secondary to trauma or fracture events. Even while intra-articular scar tissue can be observed following ankle fractures, little is known about its nature and molecular events linking its biological activity and cartilage deterioration. Here, we investigated scar tissue's histological and molecular characteristics, and its relationship with localized articular cartilage alterations consistent with early osteoarthritic degeneration. Intra-articular scar tissues from sixty-two patients who underwent open reduction internal fixation for ankle fracture were obtained at hardware removal time (6-44 months after fracture). Histological analysis demonstrated that scar tissue has the nature of fibrosis with fibrous tissue hyperplasia, fibroblast proliferation, and chondrometaplasia. These fibrous scar tissues showed overexpressed pro-inflammatory cytokines and high mRNA expression levels of osteoarthritis-related markers (cytokines, chemokines, and enzymes) compared to the normal synovium. Furthermore, those transcriptional levels were significantly correlated with the grade of talar chondral degeneration. Our findings suggest that following an ankle fracture, the intra-articular fibrous scar tissue exhibits high catabolic and inflammatory activity, which has a long-lasting negative impact correlated to cartilage deterioration in the development of posttraumatic osteoarthritis.
Asunto(s)
Fracturas de Tobillo , Cartílago Articular , Osteoartritis , Humanos , Fracturas de Tobillo/cirugía , Cicatriz , Tobillo , Osteoartritis/etiología , Osteoartritis/metabolismo , Citocinas/metabolismo , Cartílago Articular/metabolismoRESUMEN
Aging is an independent risk factor for recurrent tearing after surgical repair of rotator cuff ruptures around the tendon-to-bone area. However, aging signature factors and related mechanisms involved in the healing of the rotator cuff are still unknown. We hypothesized that differences in proteins involved in the rotator cuff according to age may affect tendon-to-bone healing. The proteome analysis performed to identify the signature aging proteins of the rotator cuff confirmed the sirtuin signal as an age-specific protein. In particular, the expression of SIRT6 was markedly down-regulated with age. Ingenuity pathway analysis of omics data from age-dependent rat rotator cuffs and linear regression from human rotator cuffs showed SIRT6 to be closely related to the Wnt/ß-catenin signal. We confirmed that overexpression of SIRT6 in the rotator cuff and primary tenocyte regulated canonical Wnt signaling by inhibiting the transcriptional expression of sclerostin, a Wnt antagonist. Finally, SIRT6 overexpression promoted tendon-to-bone healing after tenotomy with reconstruction in elderly rats. This approach is considered an effective treatment method for recovery from recurrent rotator cuff tears, which frequently occur in the elderly.
Asunto(s)
Manguito de los Rotadores , Sirtuinas , Humanos , Anciano , Animales , Ratas , Tendones , Glicosiltransferasas , Envejecimiento , Sirtuinas/genéticaRESUMEN
Background: Supracondylar humerus (SCH) fractures in children have been traditionally categorized according to the Wilkins-modified Gartland classification scheme, which is solely based on the degree of displacement. As this classification does not consider fracture patterns in the coronal or sagittal plane, the relationship between the fracture pattern and prognosis in SCH fractures remains unclear. Therefore, the purpose of this study was to evaluate the relationship between the fracture level and prognosis of pediatric SCH fractures. Methods: Medical records and radiographs of 786 patients with SCH fractures who underwent surgical treatment between March 2004 and December 2017 were reviewed. A total of 192 patients were included in this study. Anteroposterior elbow radiographs taken at the time of injury were evaluated to obtain the level of fracture. Functional outcomes were evaluated based on modified Flynn grading at the last follow-up. Results: Of 192 patients included in this study, 24 (12.1%), 148 (74.8%), and 20 (10.1%) had fractures in zone 1 (metaphyseal-diaphyseal area), zone 2 (between zones 1 and 3), and zone 3 (metaphyseal-epiphyseal area), respectively. There were significant differences in age at the time of injury (p = 0.011), direction of fracture displacement (p = 0.014), and loss of carrying angle (p < 0.001) between fractures in zone 3 and those in zone 1 or zone 2. Zone 3 fractures and classic zone 2 fractures also showed significant difference in outcomes, with zone 3 fractures having more unsatisfactory outcome than classic zone 2 fractures (p = 0.049). Conclusions: For SCH fractures, varus deformity of the elbow was more common in zone 3 (metaphyseal-epiphyseal area) than in the other zones. Thus, pediatric orthopedic surgeons should be mindful of the possibility of cubitus varus deformity when treating SCH fractures in zone 3. A thorough postoperative follow-up is required.
Asunto(s)
Articulación del Codo , Fracturas del Húmero , Niño , Humanos , Resultado del Tratamiento , Estudios Retrospectivos , Fracturas del Húmero/diagnóstico por imagen , Fracturas del Húmero/cirugía , Húmero/cirugía , Articulación del Codo/diagnóstico por imagen , Articulación del Codo/cirugíaRESUMEN
Periodontitis is an inflammatory disease caused by microorganisms that induce the destruction of periodontal tissue. Inflamed and damaged tissue produces various inflammatory cytokines, which activate osteoclasts and induce alveolar bone loss and, eventually, tooth loss. Sirt6 expression suppresses inflammation and bone resorption; however, its role in periodontitis remains unclear. We hypothesized that Sirt6 has a protective role in periodontitis. To understand the role of Sirt6 in periodontitis, we compared periodontitis with ligature placement around the maxillary left second molar in 8-week-old control (C57BL/6J) male mice to Sirt6-overexpressing Tg (Sirt6Tg) mice, and we observed the resulting phenotypes using micro-CT. MDL801, a Sirt6 activator, was used as a therapy for periodontitis through oral gavage. Pro-inflammatory cytokines and increased osteoclast numbers were observed in alveolar bone tissue under periodontitis surgery. In the same condition, interestingly, protein levels from Sirt6 were the most downregulated among sirtuins in alveolar bone tissue. Based on micro-CT and CEJ-ABC distance, Sirt6Tg was observed to resist bone loss against ligature-induced periodontitis. Furthermore, the number of osteoclasts was significantly reduced in Sirt6Tg-ligated mice compared with control-ligated mice, although systemic inflammatory cytokines did not change. Consistent with this observation, we confirmed that bone loss was significantly reduced when MDL801, a Sirt6 activator, was included in the ligation mouse model. Our findings demonstrate that Sirt6 activation prevents bone loss against ligature-induced periodontitis. Thus, a Sirt6 activator may provide a new therapeutic approach for periodontitis.
Asunto(s)
Pérdida de Hueso Alveolar , Periodontitis , Sirtuinas , Ratones , Masculino , Animales , Ratones Endogámicos C57BL , Periodontitis/metabolismo , Inflamación/complicaciones , Pérdida de Hueso Alveolar/etiología , Pérdida de Hueso Alveolar/prevención & control , Osteoclastos/metabolismo , Modelos Animales de Enfermedad , Citocinas/metabolismo , Sirtuinas/genéticaRESUMEN
Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with an enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports the excessive accumulation of fibroadipogenic progenitors (FAPs), leading to increased fibrosis. Unexpectedly, the extent of damage and degeneration in juvenile D2-mdx muscle is significantly reduced in adults, and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance regenerative myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder B10-mdx model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with juvenile D2-mdx FAPs reduces their fusion efficacy. Wild-type juvenile D2 mice also manifest regenerative myogenic deficit and glucocorticoid treatment improves their muscle regeneration. Our findings indicate that aberrant stromal cell responses contribute to poor regenerative myogenesis and greater muscle degeneration in juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx muscle, identifying these responses as a potential therapeutic target for the treatment of DMD.
RESUMEN
Lack of dystrophin is the genetic basis for the Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2- mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2- mdx muscles is associated with enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports excessive accumulation of fibroadipogenic progenitors (FAPs). Unexpectedly, the extent of damage and degeneration of juvenile D2- mdx muscle is reduced in adults and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance myogenesis in the adult D2- mdx muscle, reaching levels comparable to the milder (B10- mdx ) mouse model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with the juvenile D2- mdx FAPs reduced their fusion efficacy and in vivo glucocorticoid treatment of juvenile D2 mouse improved muscle regeneration. Our findings indicate that aberrant stromal cell response contributes to poor myogenesis and greater muscle degeneration in dystrophic juvenile D2- mdx muscles and reversal of this reduces pathology in adult D2- mdx mouse muscle, identifying these as therapeutic targets to treat dystrophic DMD muscles.
RESUMEN
The use of long-term and high-dose bisphosphate is associated with severely suppressed bone turnover and the delayed union of fractures. However, therapeutic methods to overcome the negative effects of bisphosphonate use are lacking. Bone morphogenetic proteins (BMPs) are powerful osteoinductive proteins. The development of the delivery system using BMP has been verified to have an excellent effect on fracture healing and the enhancement of osteointegration. We hypothesized that BMPs had similar effects as autografts in patients with decreased bone healing potential due to long-term bisphosphonate treatment. Forty rats were divided into the following four groups depending upon the materials implanted into the femoral defect after ten weeks of bisphosphonate (zoledronic acid) injections: Group I: absorbable collagen sponge (control); group II: demineralized freeze-dried bone graft; group III: autogenous bone graft; and group IV: rhBMP-2 with an absorbable collagen sponge. Radiographic union, micro-computed tomography (CT) analysis, manual palpation, and histologic analysis were evaluated. The radiographic union rate, manual union rate, and micro-CT bone volume in groups III and IV were significantly higher than those in groups I and II. Groups III and IV showed similar results to each other. Although the amount of immature bone in the BMP-treated group was large, the effect was similar to that of autografts in the bone defect model in which bone turnover was severely reduced by bisphosphonate treatment. BMP might be a good substitute for autografts in patients with decreased bone healing potential due to long-term bisphosphonate treatment.
RESUMEN
Dysferlinopathy covers a spectrum of muscle disorder categorized by two major phenotypes, namely Miyoshi muscular dystrophy type 1 (MMD1, OMIM #254130) and limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2, OMIM #253601), and two minor symptoms, including asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT, OMIM #606768). We report the first Korean MMD1 misdiagnosed as Becker muscular dystrophy (BMD), which was caused by a combination of compound heterozygous c.663 + 1G > C and p.Trp992Arg of the DYSF gene. A 70-year-old male previously diagnosed with BMD was admitted for genetic counseling. Since he was clinically suspected to have dysferlinopathy but not BMD, targeted panel sequencing was performed to discover the potential hereditary cause of the suspected muscular dystrophy in the proband. Consequently, two pathogenic single nucleotide variants of the DYSF gene, c.663 + 1G > C (rs398123800) and p.Trp992Arg (rs750028300), associated with dysferlinopathy were identified. These variants were previously reported with variant allele frequencies of 0.000455 (c.663 + 1G > C) and 0.000455 (c.2974T > C; p.Trp992Arg) in the Korean population. This report emphasizes the need for common variant screening in the diagnostic algorithms of certain muscle disorders or gene panels with potential pathogenic effects and high rates of recurrent variants.
Asunto(s)
Miopatías Distales , Distrofia Muscular de Duchenne , Masculino , Humanos , Miopatías Distales/patología , Disferlina , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Proteínas de la Membrana/genética , Proteínas Musculares/genética , Errores DiagnósticosRESUMEN
Malignant hyperthermia (MH), a rare autosomal dominant pharmacogenetic disorder of skeletal muscle calcium regulation, is triggered by sevoflurane in susceptible individuals. We report a Korean having MH with multi-minicore myopathy functionally supported by RYR1-mediated intracellular Ca2+ release testing in B lymphocytes. A 14-year-old boy was admitted for the evaluation of progressive torticollis accompanied by cervicothoracic scoliosis. During the preoperative drape of the patient for the release of the sternocleidomastoid muscle under general anesthesia, his wrist and ankle were observed to have severe flexion contracture. The body temperature was 37.1 °C. To treat MH, the patient was administered a bolus of dantrolene intravenously (1.5 mg/kg) and sodium bicarbonate. After a few minutes, muscle rigidity, tachycardia, and EtCO2 all resolved. Next-generation panel sequencing for hereditary myopathy identified a novel RYR1 heterozygous missense variant (NM_000540.2: c.6898T > C; p.Ser2300Pro), which mapped to the MH2 domain of the protein, a hot spot for MH mutations. Ex vivo RYR1-mediated intracellular Ca2+ release testing in B lymphocytes showed hypersensitive Ca2+ responses to isoflurane and caffeine, resulting in an abnormal Ca2+ release only in the proband, not in his family members. Our findings expand the clinical and pathological spectra of information associated with MH with multi-minicore myopathy.
Asunto(s)
Isoflurano , Hipertermia Maligna , Masculino , Humanos , Adolescente , Hipertermia Maligna/genética , Hipertermia Maligna/metabolismo , Hipertermia Maligna/patología , Canal Liberador de Calcio Receptor de Rianodina/genética , Dantroleno , Cafeína , Calcio/metabolismo , Sevoflurano , Bicarbonato de Sodio/metabolismoRESUMEN
Expanding the exercise capacity of skeletal muscle is an emerging strategy to combat obesity-related metabolic diseases and this can be achieved by shifting skeletal muscle fibers toward slow-twitch oxidative type. Here, we report that Sirt6, an anti-aging histone deacetylase, is critical in regulating myofiber configuration toward oxidative type and that Sirt6 activator can be an exercise mimetic. Genetic inactivation of Sirt6 in skeletal muscle reduced while its transgenic overexpression increased mitochondrial oxidative capacity and exercise performance in mice. Mechanistically, we show that Sirt6 downregulated Sox6, a key repressor of slow fiber specific gene, by increasing the transcription of CREB. Sirt6 expression is elevated in chronically exercised humans, and mice treated with an activator of Sirt6 showed an increase in exercise endurance as compared to exercise-trained controls. Thus, the current study identifies Sirt6 as a molecular target for reprogramming myofiber composition toward the oxidative type and for improving muscle performance.
Asunto(s)
Músculo Esquelético , Sirtuinas , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Ratones , Mitocondrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Factores de Transcripción SOXD , Sirtuinas/genética , Sirtuinas/metabolismoRESUMEN
BACKGROUND: Malrotation after nailing of femoral shaft fractures occurs in about 25% of cases. It can cause substantial functional problems. The lesser trochanter (LT) profile has been used to assess rotational alignment. However, the extent to which the LT profile is symmetrical between limbs, whether the LT profile varies as a function of age or sex, and the efficacy of the LT profile technique remain unknown. The purpose of this study was to determine if there was a significant side-to-side length difference in the LT profile (LTD) according to age and sex. METHODS: We attempted to determine the amount of medial prominence of the lesser trochanter relative to the medial cortex of the femoral shaft (the LT profile) using 3-dimensional computed tomography (3D-CT) images of normal femora obtained bilaterally (366 subjects) in anatomic positions. We also compared the left and right sides to determine the amount of natural asymmetry by age and sex. In addition, we compared the side-to-side difference in the LT version with the LTD to determine whether the LTD represented the difference in femoral rotation. RESULTS: The LTD was <4 mm (meaning an LT version difference of <10°) in 83% of the subjects, but was ≥4 mm (an LT version difference of ≥10°) in 17%. Subset analysis demonstrated that the differences were greatest in women >70 years of age. The largest LTD (both sexes) was observed in individuals over 70 years of age (2.62 ± 1.37 mm, compared with <55 years: 1.55 ± 1.36 mm and 55 to 70 years: 2.27 ± 1.70 mm). There was no significant difference between sexes in the under-70 age groups. However, the LTD was significantly greater in women over 70 years than in men over 70 years (3.10 ± 1.42 versus 2.41 ± 1.30 mm). CONCLUSIONS: Since the LTD demonstrated side-to-side symmetry within 4 mm, or 10° of rotation, in 83% of all subjects, we consider the LT profile to be useful as a guide to assess rotational reduction clinically. However, surgeons should recognize that, in 17% of cases, using this technique could result in malrotation of ≥10°. The rate of malrotation may be even higher in women over 70, for whom supplemental techniques to ensure correct rotation may be appropriate.
Asunto(s)
Desviación Ósea/cirugía , Clavos Ortopédicos , Fracturas del Fémur/cirugía , Fémur/diagnóstico por imagen , Fijación Intramedular de Fracturas/métodos , Adulto , Anciano , Anciano de 80 o más Años , Puntos Anatómicos de Referencia , Desviación Ósea/diagnóstico , Estudios de Factibilidad , Femenino , Fracturas del Fémur/diagnóstico , Fémur/anatomía & histología , Fijación Intramedular de Fracturas/instrumentación , Humanos , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and the phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to conventional anti-cancer therapies. We evaluated the expression of CSNK2A1 and phosphorylated SIRT6 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and the phosphorylation of SIRT6 on Ser338 on resistance to the anti-cancer effects of doxorubicin. Higher expression of CSNK2A1 and phosphorylated SIRT6 was associated with shorter survival in osteosarcoma patients. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to the cytotoxic effects of doxorubicin, and the knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and the induction of the DNA damage repair pathway molecules. CSNK2A1- and SIRT6-mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells. This study suggests that blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for osteosarcomas.
Asunto(s)
Daño del ADN , Reparación del ADN , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Sirtuinas/metabolismo , Adulto , Apoptosis/efectos de los fármacos , Quinasa de la Caseína II/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Emodina/farmacología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Análisis Multivariante , Fosforilación/efectos de los fármacos , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de RegresiónRESUMEN
Accelerating wound healing with minimized bacterial infection has become a topic of interest in the development of the new generation of tissue bio-adhesives. In this study, we fabricated a hydrogel system (MGC-g-CD-ic-TCS) consisting of triclosan (TCS)-complexed beta-cyclodextrin (ß-CD)-conjugated methacrylated glycol chitosan (MGC) as an antibacterial tissue adhesive. Proton nuclear magnetic resonance (1H NMR) and differential scanning calorimetry (DSC) results showed the inclusion complex formation between MGC-g-CD and TCS. The increase of storage modulus (G') of MGC-g-CD-ic-TCS after visible light irradiation for 200 s indicated its hydrogelation. The swollen hydrogel in aqueous solution resulted in two release behaviors of an initial burst and sustained release. Importantly, in vitro and in vivo results indicated that MGC-g-CD-ic-TCS inhibited bacterial infection and improved wound healing, suggesting its high potential application as an antibacterial tissue bio-adhesive.
Asunto(s)
Adhesivos/química , Quitosano/química , Glicoles/química , Hidrogeles/química , Triclosán/química , beta-Ciclodextrinas/química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Luz , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Cicatrización de Heridas/efectos de los fármacosRESUMEN
BACKGROUND: IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited. METHODS: This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test. RESULTS: In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001). CONCLUSIONS: This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.
Asunto(s)
Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Neoplasias Retroperitoneales/diagnóstico , Sarcoma/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Extremidades/patología , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Retroperitoneales/metabolismo , Neoplasias Retroperitoneales/patología , Espacio Retroperitoneal/patología , Sarcoma/metabolismo , Sarcoma/patología , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Análisis de Supervivencia , Adulto JovenRESUMEN
Ischemic osteonecrosis (ION) can produce permanent deformity and osteoarthritis in the femoral head and other joints. No biologic treatment has been established, and the molecular mechanisms involved in the pathogenesis of ION have not been elucidated. In this work, we found that treatment with sirtuin6 (Sirt6) suppressed inflammatory cytokines, bone resorption, progression of osteoarthritis, and reduced bone deformity in an ION mouse model. We used a deacetylase mutant adenovirus to confirm that those effects were caused by the deacetylase function of Sirt6. Among the osteoclastogenic factors of osteoblasts, only the receptor activator of NF-κb ligand (RANKL) level changed in response to Sirt6 knockout in primary osteoblasts. In particular, the vitamin D receptor physically interacted with Sirt6 and induced recruitment of Sirt6 around RANKL promoters. Finally, Tg mice overexpressing Sirt6 resisted osteocyte death, bone resorption, and progression of osteoarthritis after ischemic surgery, whereas osteoblast/osteocyte-specific Sirt6 knockout mice showed aggravated bone loss and severe deformity. Our findings demonstrate that administration of Sirt6 prevents bone loss and osteoarthritis in ischemic conditions. Activation of Sirt6 in osteoblasts/osteocytes could be a new therapeutic approach to treating ION of the femoral head and other bone regions. © 2020 American Society for Bone and Mineral Research (ASBMR).
Asunto(s)
Resorción Ósea , Osteoblastos , Osteocitos , Osteonecrosis , Sirtuinas , Animales , Cabeza Femoral , Ratones , Osteoclastos , Ligando RANK , Receptores de Calcitriol , Transducción de Señal , Sirtuinas/genéticaRESUMEN
BACKGROUND: SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. METHODS: We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. RESULTS: Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. CONCLUSIONS: This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.
Asunto(s)
Daño del ADN/inmunología , Doxorrubicina/uso terapéutico , Osteosarcoma/genética , Sirtuinas/metabolismo , Adulto , Animales , Apoptosis , Doxorrubicina/farmacología , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Análisis de Supervivencia , TransfecciónRESUMEN
Osteoporosis is a degenerative disease characterized by reduced bone mass, in which deregulated bone remodeling by osteoclasts and osteoblasts is a main pathogenesis. Although recently tussilagone, a major active component of flower buds of Tussilago farfara, has been shown to inhibit osteoclastogenesis, its effect on estrogen deficiency-induced osteoporosis remains unknown. This study examined the effect of tussilagone on bone loss in ovariectomized mice and further explored its impact on osteoclast apoptosis and osteoblast formation in addition to osteoclastogenesis. Tussilagone suppression of osteoclastogenesis was confirmed in bone marrow derived macrophages, which was observed with the 1/10 concentration of that of the previous study. As demonstrated by ApoPercentage dye staining and Western blotting, tussilagone enhanced apoptosis in differentiated osteoclasts by increasing estrogen receptor α and Fas ligand expression. On the contrary, either osteoblast differentiation or mineralization was not affected by tussilagone. Lastly, administering tussilagone to mice for 6 weeks prevented trabecular microarchitecture impairment in ovariectomized mice compared to vehicle control groups. These findings suggest that tussilagone or Tussilago farfara prevents osteoporotic bone loss by suppressing osteoclast differentiation and inducing osteoclast apoptosis, and that it may therefore offer a possible remedy against resorptive bone diseases.
Asunto(s)
Osteoclastos/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Sesquiterpenos/farmacología , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Estrógenos/deficiencia , Femenino , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Osteoclastos/patología , Osteogénesis/efectos de los fármacos , Osteoporosis/metabolismo , Osteoporosis/patología , Ovariectomía , Sesquiterpenos/aislamiento & purificación , Tussilago/químicaRESUMEN
In syndesmosis injury, whether the syndesmosis screw should be removed prior to weight-bearing remains controversial. The aim of this study was to compare the functional outcome between removed screw and retained groups and between recurrence of diastasis and no diastasis groups.Fifty-six patients who had undergone open reduction and internal fixation due to syndesmosis injury were retrospectively evaluated and divided into four groups: (A) removed syndesmotic screw before weight-bearing (postoperative 3 months, nâ=â28), (B)retained (nâ=â28), (C) recurrence of diastasis (nâ=â9), and (D) no diastasis (nâ=â47). Radiological diastasis, American Orthopedic Foot Ankle Society Score (AOFAS), Short Form Health Survey-12 (SF-12), and complications (screw loosening and breakage) were evaluated between groups.AOFAS ankle-hindfoot score was 75.10â±â10.40 in group A, 77.07â±â10.60 in group B. SF-12 was 45.78â±â5.68 in group A and 47.33â±â5.83 in group B, showing no significant difference in AOFAS ankle-hindfoot score or SF-12 (Pâ=â.487, Pâ=â.319, respectively) between groups A and B. Radiological diastasis developed significantly (Pâ=â.025) more in group A (8/28) compared to that in group B (1/28). However, screw loosening or breakage developed significantly (Pâ=â.001) more in group B (4/28) compared to that in group A (0/28). AOFAS ankle-hindfoot score was 70.33â±â6.22 in group C and 76.50â±â10.26 in group D. SF-12 was 49.85â±â3.83 in group C and 47.40â±â8.01 in group D, showing no significant difference between groups C and D in AOFAS ankle-hindfoot score or SF-12 (Pâ=â.808, Pâ=â.948, respectively).Removal of syndesmotic screw before weight-bearing does not influence clinical outcomes. Although unrelated to clinical progress, recurrence of diastasis significantly increased in screw removed group. Therefore, removal of syndesmotic screw is unnecessary before weight-bearing.
Asunto(s)
Traumatismos del Tobillo/cirugía , Tornillos Óseos , Remoción de Dispositivos , Caminata , Soporte de Peso , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios RetrospectivosRESUMEN
In this study, we aimed to identify a candidate drug that can activate endogenous Angiopoietin 1 (Ang1) expression via drug repositioning as a pharmacological treatment for avascular osteonecrosis. After incubation with 821 drugs from the Food and Drug Administration (FDA)-approved drug library, Ang1 expression in U2OS cell culture media was examined by ELISA. Metformin, the first-line medication for treatment of type 2 diabetes, was selected as a candidate for in vitro and in vivo experimental evaluation. Ang1 was induced, and alkaline phosphatase activity was increased by metformin treatment in U2OS and MG63 cells. Wound healing and migration assay showed increased osteoblastic cell mobility by metformin treatment in U2OS and MG63 cells. Metformin upregulated expression of protein markers for osteoblastic differentiation in U2OS and MG63 cells but inhibited osteoclastic differentiation in Raw264.7 cells. Metformin (25 mg/kg) protected against ischemic necrosis in the epiphysis of the rat femoral head by maintaining osteoblast/osteocyte function and vascular density but inhibiting osteoclast activity in the necrotic femoral head. These findings provide novel insight into the specific biomarkers that are targeted and regulated by metformin in osteoblast differentiation and contribute to understanding the effects of these FDA-approved small-molecule drugs as novel therapeutics for ischemic osteonecrosis.