RESUMEN
BACKGROUND: Peripheral triangular fibrocartilage complex (TFCC) tears may induce instability of the distal radioulnar joint (DRUJ). In this biomechanical study, simulated peripheral tears of the TFCC were examined on the stability of the DRUJ. Restabilization effect of the DRUJ by ulnar shortening and direct repair of those injuries were sequentially examined. METHOD: The DRUJ stiffness was measured in intact, simulated two types of peripheral tears (ulnar and extended ulnodorsal) at three forearm positions: neutral, 60° pronation and 60° supination in 8 fresh frozen cadaver specimens. After the tears were sutured with stitches or after simulated ulnar shortening of 3 mm, the DRUJ stiffness was again measured. RESULTS: The ulnar and ulnodorsal TFCC tears decreased the DRUJ stiffness significantly compared with the intact in all forearm positions. When ulnar shortening was done for the ulnar tear, the DRUJ stiffness increased significantly in the neutral and 60° pronated positions. When the ulnar TFCC tear was repaired, the DRUJ stiffness increased significantly in all forearm positions. DRUJ stiffness did not increase either with ulnar shortening or repair in ulnodorsal tear of the TFCC, however. CONCLUSION: The simulated TFCC tears indicated significant loss of DRUJ stiffness. Direct repair or ulnar shortening was effective only on treatment of the ulnar tear of the TFCC in this study.
Asunto(s)
Inestabilidad de la Articulación , Fibrocartílago Triangular , Traumatismos de la Muñeca , Fenómenos Biomecánicos , Humanos , Inestabilidad de la Articulación/cirugía , Supinación , Fibrocartílago Triangular/cirugía , Traumatismos de la Muñeca/diagnóstico por imagen , Traumatismos de la Muñeca/cirugía , Articulación de la Muñeca/cirugíaRESUMEN
Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), also called cell migration-inducing protein (CEMIP; alias KIAA1199), plays a key role in the degradation of HA in skin and arthritic synovial fibroblasts, but its functions in osteoarthritic (OA) cartilage remain elusive. Here, we investigated the expression and roles of HYBID in human OA cartilage. HYBID was highly expressed by chondrocytes in the HA-depleted area of OA cartilage, and HYBID immunoreactivity was correlated with Mankin score, the histopathologic severity of OA lesions of cartilage. Real-time quantitative PCR indicated that HYBID expression was significantly higher in OA cartilage than in control cartilage. In addition, OA chondrocytes exhibited HA-degrading activity, which was abolished by knock-down of HYBID by siRNAs. Although OA chondrocytes also expressed certain levels of hyaluronidases 1 and 2 and CD44, knock-down of these molecules exhibited negligible effects on HA degradation. Double immunostaining of HYBID and clathrin heavy chain revealed that HYBID was localized in the clathrin-coated vesicles, and HA was endocytosed within the vesicles of OA chondrocytes. Among eight factors including cytokines and growth factors examined, only tumor necrosis factor α stimulated OA chondrocytes to overexpress HYBID. These data are the first to demonstrate that HYBID is up-regulated in OA cartilage, and suggest that tumor necrosis factor α-stimulated HYBID plays a role in HA degradation in OA cartilage.
Asunto(s)
Cartílago Articular/patología , Condrocitos/patología , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/metabolismo , Osteoartritis/patología , Cartílago Articular/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Condrocitos/metabolismo , Humanos , Osteoartritis/metabolismoRESUMEN
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.
Asunto(s)
Cromosomas Humanos Par 9/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Escoliosis/genética , Adolescente , Animales , China , Proteínas de Unión al ADN/metabolismo , Embrión no Mamífero/metabolismo , Embrión no Mamífero/patología , Estudio de Asociación del Genoma Completo , Humanos , Japón , Luciferasas , Oportunidad Relativa , Escoliosis/patología , Factor de Transcripción YY1/metabolismo , Pez CebraRESUMEN
Although human induced pluripotent stem cell (hiPSC) derivatives are considered promising cellular resources for regenerative medicine, their tumorigenicity potentially limits their clinical application in hiPSC technologies. We previously demonstrated that oncogenic hiPSC-derived neural stem/progenitor cells (hiPSC-NS/PCs) produced tumor-like tissues that were distinct from teratomas. To gain insight into the mechanisms underlying the regulation of tumorigenicity in hiPSC-NS/PCs, we performed an integrated analysis using the Infinium HumanMethylation450 BeadChip array and the HumanHT-12 v4.0 Expression BeadChip array to compare the comprehensive DNA methylation and gene expression profiles of tumorigenic hiPSC-NS/PCs (253G1-NS/PCs) and non-tumorigenic cells (201B7-NS/PCs). Although the DNA methylation profiles of 253G1-hiPSCs and 201B7-hiPSCs were similar regardless of passage number, the methylation status of the global DNA methylation profiles of 253G1-NS/PCs and 201B7-NS/PCs differed; the genomic regions surrounding the transcriptional start site of the CAT and PSMD5 genes were hypermethylated in 253G1-NS/PCs but not in 201B7-NS/PCs. Interestingly, the aberrant DNA methylation profile was more pronounced in 253G1-NS/PCs that had been passaged more than 15 times. In addition, we identified aberrations in DNA methylation at the RBP1 gene locus; the DNA methylation frequency in RBP1 changed as 253G1-NS/PCs were sequentially passaged. These results indicate that different NS/PC clones have different DNA methylomes and that DNA methylation patterns are unstable as cells are passaged. Therefore, DNA methylation profiles should be included in the criteria used to evaluate the tumorigenicity of hiPSC-NS/PCs in the clinical setting. Stem Cells 2017;35:1316-1327.
Asunto(s)
Carcinogénesis/genética , Metilación de ADN/genética , Epigénesis Genética , Genoma Humano , Células Madre Pluripotentes Inducidas/patología , Células-Madre Neurales/patología , Biomarcadores de Tumor/genética , Carcinogénesis/patología , Proliferación Celular/genética , Perfilación de la Expresión Génica , Genes Supresores de Tumor , Estudios de Asociación Genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Modelos Biológicos , Células-Madre Neurales/metabolismoRESUMEN
White matter abnormalities in the CNS have been reported recently in various neurological and psychiatric disorders. Quantitation of non-Gaussianity for water diffusion by q-space diffusional MRI (QSI) renders biological diffusion barriers such as myelin sheaths; however, the time-consuming nature of this method hinders its clinical application. In the current study, we aimed to refine QSI protocols to enable their clinical application and to visualize myelin signals in a clinical setting. For this purpose, animal studies were first performed to optimize the acquisition protocol of a non-Gaussian QSI metric. The heat map of standardized kurtosis values derived from optimal QSI (myelin map) was then created. Histological validation of the myelin map was performed in myelin-deficient mice and in a nonhuman primate by monitoring its variation during demyelination and remyelination after chemical spinal cord injury. The results demonstrated that it was sensitive enough to depict dysmyelination, demyelination, and remyelination in animal models. Finally, its utility in clinical practice was assessed by a pilot clinical study in a selected group of patients with multiple sclerosis (MS). The human myelin map could be obtained within 10 min with a 3 T MR scanner. Use of the myelin map was practical for visualizing white matter and it sensitively detected reappearance of myelin signals after demyelination, possibly reflecting remyelination in MS patients. Our results together suggest that the myelin map, a kurtosis-related heat map obtainable with time-saving QSI, may be a novel and clinically useful means of visualizing myelin in the human CNS. SIGNIFICANCE STATEMENT: Myelin abnormalities in the CNS have been gaining increasing attention in various neurological and psychiatric diseases. However, appropriate methods with which to monitor CNS myelin in daily clinical practice have been lacking. In the current study, we introduced a novel MRI modality that produces the "myelin map." The myelin map accurately depicted myelin status in mice and nonhuman primates and in a pilot clinical study of multiple sclerosis patients, suggesting that it is useful in detecting possibly remyelinated lesions. A myelin map of the human brain could be obtained in <10 min using a 3 T scanner and it therefore promises to be a powerful tool for researchers and clinicians examining myelin-related diseases.
Asunto(s)
Mapeo Encefálico , Enfermedades Desmielinizantes/patología , Imagen de Difusión por Resonancia Magnética , Vaina de Mielina/patología , Sustancia Blanca/patología , Adulto , Animales , Callithrix , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Lisofosfatidilcolinas/toxicidad , Masculino , Ratones , Ratones Jimpy , Ratones Mutantes , Esclerosis Múltiple/patología , Mutación/genética , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Sustancia Blanca/ultraestructuraRESUMEN
Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes.
Asunto(s)
Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Animales , Western Blotting , Línea Celular , Glucosa/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Ratones Noqueados , Ratones Transgénicos , Desnervación Muscular , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/inervación , Músculo Esquelético/patología , Atrofia Muscular/etiología , Miostatina/genética , Miostatina/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Restricción Física/efectos adversos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteína Smad2/genética , Proteína smad3/genética , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Satellite cells (SCs) are muscle-specific stem cells that are essential for the regeneration of damaged muscles. Although SCs have a robust capacity to regenerate myofibers, the number of SCs decreases with aging, leading to insufficient recovery after muscle injury. We herein show that ADAM10 (a disintegrin and metalloprotease 10), a membrane-bound proteolytic enzyme with a critical role in Notch processing (S2 cleavage), is essential for the maintenance of SC quiescence. We generated mutant mice in which ADAM10 in SCs can be conditionally abrogated by tamoxifen injection. Tamoxifen-treated mutant mice did not show any apparent defects and grew normally under unchallenged conditions. However, these mice showed a nearly complete loss of muscle regeneration after chemically induced muscle injury. In situ hybridization and flow cytometric analyses revealed that the mutant mice had significantly less SCs compared with wild type controls. Of note, we found that inactivation of ADAM10 in SCs severely compromised Notch signaling and led to dysregulated myogenic differentiation, ultimately resulting in deprivation of the SC pool in vivo. Taken together, the present findings underscore the role of ADAM10 as an indispensable component of Notch signaling in SCs and for maintaining the SC pool.
Asunto(s)
Proteínas ADAM/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Proteínas de la Membrana/metabolismo , Células Satélite del Músculo Esquelético/metabolismo , Proteínas ADAM/genética , Proteína ADAM10 , Secretasas de la Proteína Precursora del Amiloide/genética , Animales , Diferenciación Celular , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Receptores Notch/metabolismo , Células Satélite del Músculo Esquelético/citología , Transducción de SeñalRESUMEN
Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that de-differentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitamin D3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition.
Asunto(s)
Hiperglucemia/metabolismo , Hiperglucemia/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células de Schwann/metabolismo , Células de Schwann/patología , Sorbitol/metabolismo , Aldehído Reductasa/antagonistas & inhibidores , Animales , Calcitriol/análogos & derivados , Calcitriol/farmacología , Desdiferenciación Celular/fisiología , Células Cultivadas , Enfermedades Desmielinizantes/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/patología , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Glucosa/metabolismo , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Ratas , Rodanina/análogos & derivados , Rodanina/farmacología , Células de Schwann/efectos de los fármacos , Nervio Ciático/metabolismo , Nervio Ciático/patología , Tiazolidinas/farmacología , Vitamina D/análogos & derivadosRESUMEN
Formation of foreign body giant cells (FBGCs) occurs following implantation of medical devices such as artificial joints and is implicated in implant failure associated with inflammation or microbial infection. Two major macrophage subpopulations, M1 and M2, play different roles in inflammation and wound healing, respectively. Therefore, M1/M2 polarization is crucial for the development of various inflammation-related diseases. Here, we show that FBGCs do not resorb bone but rather express M2 macrophage-like wound healing and inflammation-terminating molecules in vitro. We also found that FBGC formation was significantly inhibited by inflammatory cytokines or infection mimetics in vitro. Interleukin-1 receptor-associated kinase-4 (IRAK4) deficiency did not alter osteoclast formation in vitro, and IRAK4-deficient mice showed normal bone mineral density in vivo. However, IRAK4-deficient mice were protected from excessive osteoclastogenesis induced by IL-1ß in vitro or by LPS, an infection mimetic of Gram-negative bacteria, in vivo. Furthermore, IRAK4 deficiency restored FBGC formation and expression of M2 macrophage markers inhibited by inflammatory cytokines in vitro or by LPS in vivo. Our results demonstrate that osteoclasts and FBGCs are reciprocally regulated and identify IRAK4 as a potential therapeutic target to inhibit stimulated osteoclastogenesis and rescue inhibited FBGC formation under inflammatory and infectious conditions without altering physiological bone resorption.
Asunto(s)
Diferenciación Celular/genética , Células Gigantes de Cuerpo Extraño/metabolismo , Inflamación/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/genética , Animales , Resorción Ósea/genética , Resorción Ósea/metabolismo , Regulación del Desarrollo de la Expresión Génica , Inflamación/patología , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Macrófagos/metabolismo , Ratones , Osteoclastos/metabolismo , Osteólisis/genética , Osteólisis/patologíaRESUMEN
The number of osteoporosis patients is increasing not only in women but in men. Male osteoporosis occurs due to aging or androgen depletion therapies, leading to fractures. However, molecular mechanisms underlying male osteoporosis remain unidentified. Here, we show that hypoxia inducible factor 1 alpha (Hif1α) is required for development of testosterone deficiency-induced male osteoporosis. We found that in mice Hif1α protein accumulates in osteoclasts following orchidectomy (ORX) in vivo. In vitro, Hif1α protein accumulated in osteoclasts cultured in hypoxic conditions, but Hif1α protein rather than mRNA levels were suppressed by testosterone treatment, even in hypoxia. Administration of a Hif1α inhibitor to ORX mice abrogated testosterone deficiency-induced osteoclast activation and bone loss but did not alter osteoclast activities or bone phenotypes in sham-operated, testosterone-sufficient animals. We conclude that Hif1α protein accumulation due to testosterone-deficiency promotes development of male osteoporosis. Thus Hif1α protein could be targeted to inhibit pathologically-activated osteoclasts under testosterone-deficient conditions to treat male osteoporosis patients.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patología , Osteoporosis/metabolismo , Osteoporosis/patología , Testosterona/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The increasing number of osteoporosis patients is a pressing issue worldwide. Osteoporosis frequently causes fragility fractures, limiting activities of daily life and increasing mortality. Many osteoporosis patients take numerous medicines due to other health issues; thus, it would be preferable if a single medicine could ameliorate osteoporosis and other conditions. Here, we screened 96 randomly selected drugs targeting various diseases for their ability to inhibit differentiation of osteoclasts, which play a pivotal role in development of osteoporosis, and identified methotrexate (MTX), as a potential inhibitor. MTX is currently used to treat sarcomas or leukemic malignancies or auto-inflammatory diseases such as rheumatoid arthritis (RA) through its anti-proliferative and immunosuppressive activities; however, a direct effect on osteoclast differentiation has not been shown. Here, we report that osteoclast formation and expression of osteoclastic genes such as NFATc1 and DC-STAMP, which are induced by the cytokine RANKL, are significantly inhibited by MTX. We found that RANKL-dependent calcium (Ca) influx into osteoclast progenitors was significantly inhibited by MTX. RA patients often develop osteoporosis, and osteoclasts are reportedly required for joint destruction; thus, MTX treatment could have a beneficial effect on RA patients exhibiting high osteoclast activity by preventing both osteoporosis and joint destruction.
Asunto(s)
Calcio/metabolismo , Metotrexato/farmacología , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Células Madre/efectos de los fármacos , Animales , Células Cultivadas , Ratones Endogámicos C57BL , Osteoclastos/metabolismo , Ligando RANK/farmacología , Células Madre/metabolismoRESUMEN
Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.
Asunto(s)
Antineoplásicos/farmacología , Arsenicales/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/metabolismo , Proteínas Nucleares/metabolismo , Óxidos/farmacología , Serina-Treonina Quinasas TOR/biosíntesis , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Trióxido de Arsénico , Línea Celular Tumoral , Receptores ErbB/biosíntesis , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Masculino , Ratones , Proteínas Nucleares/genética , Proteína de la Leucemia Promielocítica , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogen-dependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1α was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1α in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1α inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1α inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.
Asunto(s)
Estradiol/análogos & derivados , Estrógenos/deficiencia , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Osteoclastos/fisiología , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteoporosis Posmenopáusica/fisiopatología , 2-Metoxiestradiol , Administración Oral , Animales , Células Cultivadas , Cruzamientos Genéticos , Ensayo de Inmunoadsorción Enzimática , Estradiol/administración & dosificación , Estradiol/farmacología , Femenino , Genotipo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Immunoblotting , Inmunohistoquímica , Inmunoprecipitación , Etiquetado Corte-Fin in Situ , Ratones , Ratones Noqueados , Osteoclastos/efectos de los fármacos , Osteoporosis Posmenopáusica/metabolismo , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Although various risk factors have been reported for adjacent segment degeneration after lumbar fusion, the exact mechanisms and risk factors related to adjacent segment degeneration have not been clear. The present study was conducted to evaluate the risk factors for radiological adjacent segment degeneration in patients surgically treated for single-level L4 spondylolisthesis focusing on a single pathology, a specific fusion level, at a set interval. METHODS: We assessed preoperative and five-year postoperative radiographs for 72 patients who underwent L4-5 anterior or posterior lumbar interbody fusion for single-level L4 degenerative spondylolisthesis. Adjacent segment degeneration was defined as imaging evidence of one or more of the following conditions at L1-2, L2-3, or L3-4: 1) a loss of more than 20% of the preoperative disc height, 2) anterolisthesis or retrolisthesis greater than 3 mm, 3) or osteophyte formation greater than 3 mm. RESULTS: We found adjacent segment degeneration in 21 patients, with 31 discs affected. Multiple logistic regression analysis identified the following significant independent risk factors for adjacent segment degeneration: female gender (odds ratio 10.80; 95% confidence interval 1.20-96.89), posterior lumbar interbody fusion (odds ratio 7.70; 95% confidence interval 1.82-32.66), and pre-existing disc degeneration (odds ratio 12.29; 95% confidence interval 1.69-89.27). CONCLUSIONS: Female gender, posterior lumbar interbody fusion, and pre-existing disc degeneration were significant independent risk factors for radiologically diagnosed adjacent segment degeneration in patients treated for L4 degenerative spondylolisthesis by interbody lumbar fusion.
Asunto(s)
Degeneración del Disco Intervertebral/diagnóstico , Vértebras Lumbares/diagnóstico por imagen , Complicaciones Posoperatorias/diagnóstico , Radiografía/métodos , Medición de Riesgo/métodos , Fusión Vertebral/efectos adversos , Espondilolistesis/cirugía , Femenino , Humanos , Incidencia , Degeneración del Disco Intervertebral/etiología , Japón/epidemiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Factores de Riesgo , Espondilolistesis/diagnósticoRESUMEN
BACKGROUND: In Japan, ossification of the posterior longitudinal ligament (OPLL) has been designated as an intractable disease by the Ministry of Health, Labour, and Welfare. Here we aimed to clarify the epidemiological characteristics of severe OPLL patients by analyzing a national registry of this disease that uses clinical investigation registration forms. METHODS: We retrospectively investigated clinical investigation registration forms for 24,502 patients with OPLL. We examined the sex distribution, age of disease onset, period from disease onset to registration, family history, site of ossification as determined by plain radiographs, Japanese Orthopaedic Association score, and number of OPLL surgeries. RESULTS: The male-to-female ratios were 2.7:1 and 1.9:1 for new and renewed registrations, respectively. The mean ages at disease onset were 61.1 and 59.7 years for new and renewed registrations, respectively. The mean periods from disease onset to registration were 2.6 and 8.4 years for new and renewed registrations, respectively. The percentages of new registrations with and without family history were 5.3% and 51.5%, respectively (unknown for 43.3%). Of the new registrations, 3511, 359, and 200 cases exhibited ossification in the cervical spine, thoracic spine, and lumbar spine, respectively; the corresponding numbers for renewed registrations were 13,710, 2484, and 1508. The Japanese Orthopaedic Association score was 9.9 ± 3.6 for new registrations, and the mean score recovery rate for renewed registrations was 6.0%. The number of OPLL surgeries was one or zero, two, three, four, or five for 21,785, 2167, 412, 99, and 39 patients, respectively, with 11.1% of all patients having undergone multiple surgeries. CONCLUSIONS: This study offers new insight into the epidemiological characteristics of severe OPLL. In particular, we found that the age of disease onset was higher than previously reported, the period from disease onset to registration (surgery) was relatively short, and about 90% of the patients required only a single surgery.
Asunto(s)
Procedimientos Ortopédicos/estadística & datos numéricos , Osificación del Ligamento Longitudinal Posterior/epidemiología , Osificación del Ligamento Longitudinal Posterior/cirugía , Sistema de Registros , Adulto , Distribución por Edad , Edad de Inicio , Anciano , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/patología , Distribución de Chi-Cuadrado , Femenino , Humanos , Incidencia , Japón/epidemiología , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Procedimientos Ortopédicos/métodos , Osificación del Ligamento Longitudinal Posterior/diagnóstico por imagen , Pronóstico , Radiografía/métodos , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por Sexo , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/patología , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
Ulnar deviation is a common complication in patients with rheumatoid arthritis (RA). We report a case of an unusual radial deviation of the middle finger caused by an occult intramuscular ganglion of the second interosseous muscle (IOM) in a patient with RA. The resection of the ganglion did not resolve the problem, and the full range of motion of the metacarpophalangeal (MP) joint was achieved through dissection of the tendon of the second dorsal IOM.
Asunto(s)
Artritis Reumatoide/complicaciones , Deformidades Adquiridas de la Mano , Articulación Metacarpofalángica , Procedimientos Ortopédicos/métodos , Tendones , Anciano , Disección/métodos , Femenino , Dedos , Deformidades Adquiridas de la Mano/diagnóstico , Deformidades Adquiridas de la Mano/etiología , Deformidades Adquiridas de la Mano/fisiopatología , Deformidades Adquiridas de la Mano/cirugía , Humanos , Articulación Metacarpofalángica/diagnóstico por imagen , Articulación Metacarpofalángica/fisiopatología , Rango del Movimiento Articular , Tendones/patología , Tendones/cirugía , Resultado del TratamientoRESUMEN
The objective of this study was to determine the role of FIH-1 in regulating HIF-1 activity in the nucleus pulposus (NP) cells and the control of this regulation by binding and sequestration of FIH-1 by Mint3. FIH-1 and Mint3 were both expressed in the NP and were shown to strongly co-localize within the cell nucleus. Although both mRNA and protein expression of FIH-1 decreased in hypoxia, only Mint3 protein levels were hypoxiasensitive. Overexpression of FIH-1 was able to reduce HIF-1 function, as seen by changes in activities of hypoxia response element-luciferase reporter and HIF-1-C-TAD and HIF-2-TAD. Moreover, co-transfection of either full-length Mint3 or the N terminus of Mint3 abrogated FIH-1-dependent reduction in HIF-1 activity under both normoxia and hypoxia. Nuclear levels of FIH-1 and Mint3 decreased in hypoxia, and the use of specific nuclear import and export inhibitors clearly showed that cellular compartmentalization of overexpressed FIH-1 was critical for its regulation of HIF-1 activity in NP cells. Interestingly, microarray results after stable silencing of FIH-1 showed no significant changes in transcripts of classical HIF-1 target genes. However, expression of several other transcripts, including those of the Notch pathway, changed in FIH-1-silenced cells. Moreover, co-transfection of Notch-ICD could restore suppression of HIF-1-TAD activity by exogenous FIH-1. Taken together, these results suggest that, possibly due to low endogenous levels and/or preferential association with substrates such as Notch, FIH-1 activity does not represent a major mechanism by which NP cells control HIF-1-dependent transcription, a testament to their adaptation to a unique hypoxic niche.
Asunto(s)
Proteínas Portadoras/metabolismo , Pulpa Dental/metabolismo , Factor 1 Inducible por Hipoxia/metabolismo , Oxigenasas de Función Mixta/metabolismo , Proteínas/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Transcripción Genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas Portadoras/genética , Hipoxia de la Célula/genética , Línea Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Pulpa Dental/citología , Humanos , Factor 1 Inducible por Hipoxia/genética , Oxigenasas de Función Mixta/genética , Proteínas/genética , Ratas , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas Represoras/genéticaRESUMEN
Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme-linked immunosorbent assay-based screening of such mouse tumor lysates identified platelet-derived growth factor-BB (PDGF-BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non-malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor ß) was highly expressed in OS cells. Platelet-derived growth factor-BB induced activation of both MEK-ERK and phosphatidylinositol 3-kinase-protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF-BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Doxorrubicina/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Animales , Becaplermina , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Humanos , Mesilato de Imatinib , Ratones Endogámicos C57BL , Osteosarcoma , Proteínas Proto-Oncogénicas c-sis/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in significant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-deficient mice in vivo. Altered osteoblastogenesis in Bcl6-deficient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Osteoblastos/metabolismo , Osteogénesis/fisiología , Factor de Transcripción STAT1/antagonistas & inhibidores , Células 3T3 , Animales , Sitios de Unión/genética , Remodelación Ósea/genética , Remodelación Ósea/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , ADN/genética , ADN/metabolismo , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoblastos/citología , Osteoclastos/citología , Osteoclastos/metabolismo , Osteogénesis/genética , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-bcl-6 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT1/deficiencia , Factor de Transcripción STAT1/genéticaRESUMEN
Previous studies have demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) into the lesioned spinal cord can promote functional recovery following incomplete spinal cord injury (SCI) in animal models. However, this strategy is insufficient following complete SCI because of the gap at the lesion epicenter. To obtain functional recovery in a mouse model of complete SCI, this study uses a novel collagen-based microfiber as a scaffold for engrafted NS/PCs. We hypothesized that the NS/PC-microfiber combination would facilitate lesion closure as well as transplant survival in the transected spinal cord. NS/PCs were seeded inside the novel microfibers, where they maintained their capacity to differentiate and proliferate. After transplantation, the stumps of the transected spinal cord were successfully bridged by the NS/PC-laden microfibers. Moreover, the transplanted cells migrated into the host spinal cord and differentiated into three neural lineages (astrocytes, neurons, and oligodendrocytes). However, the NS/PC-laden scaffold could not achieve a neural connection between the rostral end of the injury and the intact caudal area of the spinal cord, nor could it achieve recovery of motor function. To obtain optimal functional recovery, a microfiber design with a modified composition may be useful. Furthermore, combinatorial therapy with rehabilitation and/or medications should also be considered for practical success of biomaterial/cell transplantation-based approaches to regenerative medicine.