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1.
Cell ; 184(5): 1330-1347.e13, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33636130

RESUMEN

Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.


Asunto(s)
Resorción Ósea/patología , Osteoclastos/patología , Ligando RANK/metabolismo , Animales , Apoptosis , Resorción Ósea/metabolismo , Fusión Celular , Células Cultivadas , Humanos , Macrófagos/citología , Ratones , Osteocondrodisplasias/tratamiento farmacológico , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patología , Osteoclastos/metabolismo , Transducción de Señal
3.
Clin Endocrinol (Oxf) ; 97(5): 664-675, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35274331

RESUMEN

OBJECTIVE: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies. DESIGN: Retrospective, multicentre and observational study. PATIENTS: Adult patients with Graves' disease treated with RI with 12 months' follow-up. MEASUREMENTS: Euthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. RESULTS: Of 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%-28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. CONCLUSIONS: Dysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.


Asunto(s)
Enfermedad de Graves , Oftalmopatía de Graves , Hipertiroidismo , Hipotiroidismo , Adulto , Antitiroideos/uso terapéutico , Enfermedad de Graves/radioterapia , Humanos , Hipertiroidismo/radioterapia , Hipotiroidismo/tratamiento farmacológico , Radioisótopos de Yodo/uso terapéutico , Estudios Retrospectivos , Tirotropina , Tiroxina/uso terapéutico
4.
J Cell Sci ; 131(11)2018 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-29871956

RESUMEN

Macrophage cell fusion and multinucleation are fundamental processes in the formation of multinucleated giant cells (MGCs) in chronic inflammatory disease and osteoclasts in the regulation of bone mass. However, this basic cell phenomenon is poorly understood despite its pathophysiological relevance. Granulomas containing multinucleated giant cells are seen in a wide variety of complex inflammatory disorders, as well as in infectious diseases. Dysregulation of osteoclastic bone resorption underlies the pathogenesis of osteoporosis and malignant osteolytic bone disease. Recent reports have shown that the formation of multinucleated giant cells and osteoclast fusion display a common molecular signature, suggesting shared genetic determinants. In this Review, we describe the background of cell-cell fusion and the similar origin of macrophages and osteoclasts. We specifically focus on the common pathways involved in osteoclast and MGC fusion. We also highlight potential approaches that could help to unravel the core mechanisms underlying bone and granulomatous disorders in humans.


Asunto(s)
Células Gigantes/metabolismo , Macrófagos/metabolismo , Osteoclastos/metabolismo , Transducción de Señal , Animales , Fusión Celular , Granuloma , Humanos
5.
Proc Natl Acad Sci U S A ; 114(52): E11323-E11332, 2017 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-29229863

RESUMEN

Thyroid hormone (TH) and TH receptors (TRs) α and ß act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRß, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding-defective TRß leads to disruption of the hypothalamic-pituitary-thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.


Asunto(s)
Sistema Hipotálamo-Hipofisario/metabolismo , Miocardio/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Transducción de Señal , Hormonas Tiroideas/metabolismo , Animales , Técnicas de Sustitución del Gen , Ratones , Ratones Noqueados , Receptores de Hormona Tiroidea/genética , Hormonas Tiroideas/genética
6.
Blood ; 129(26): 3452-3464, 2017 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-28515094

RESUMEN

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM.


Asunto(s)
Densidad Ósea/efectos de los fármacos , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Fracturas Óseas/prevención & control , Osteocitos/química , Osteogénesis/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Animales , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Proteínas Morfogenéticas Óseas/inmunología , Línea Celular Tumoral , Difosfonatos/uso terapéutico , Marcadores Genéticos/inmunología , Humanos , Imidazoles/uso terapéutico , Ratones , Mieloma Múltiple/complicaciones , Células Tumorales Cultivadas , Ácido Zoledrónico
7.
PLoS Genet ; 8(8): e1002858, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22876197

RESUMEN

Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength. These nine new genes include five whose deletion results in low bone mass and four whose deletion results in high bone mass. None of the nine genes have been implicated previously in skeletal disorders and detailed analysis of the biomechanical consequences of their deletion revealed a novel functional classification of bone structure and strength. The organ-specific and disease-focused strategy described in this study can be applied to any biological system or tractable polygenic disease, thus providing a general basis to define gene function in a system-specific manner. Application of the approach to diseases affecting other physiological systems will help to realize the full potential of the International Mouse Phenotyping Consortium.


Asunto(s)
Densidad Ósea/genética , Huesos/anatomía & histología , Ensayos Analíticos de Alto Rendimiento/métodos , Osteoporosis/genética , Animales , Fenómenos Biomecánicos , Huesos/diagnóstico por imagen , Huesos/metabolismo , Huesos/fisiología , Mapeo Cromosómico , Eliminación de Gen , Ratones , Ratones Noqueados , Microrradiografía , Imagen Multimodal , Especificidad de Órganos , Osteoporosis/diagnóstico por imagen , Osteoporosis/patología , Fenotipo , Tomografía de Emisión de Positrones , Resistencia a la Tracción , Tomografía Computarizada por Rayos X
8.
JAMA ; 313(20): 2055-65, 2015 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-26010634

RESUMEN

IMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION: Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS: Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE: Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.


Asunto(s)
Fracturas Óseas/etiología , Fracturas de Cadera/etiología , Hipertiroidismo/complicaciones , Hipotiroidismo/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fracturas de la Columna Vertebral/etiología , Tirotropina/sangre , Adulto Joven
9.
Biochim Biophys Acta ; 1830(7): 3979-86, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22634735

RESUMEN

BACKGROUND: Thyroid hormones regulate skeletal development, acquisition of peak bone mass and adult bone maintenance. Abnormal thyroid status during childhood disrupts bone maturation and linear growth, while in adulthood it results in altered bone remodeling and an increased risk of fracture SCOPE OF REVIEW: This review considers the cellular effects and molecular mechanisms of thyroid hormone action in the skeleton. Human clinical and population data are discussed in relation to the skeletal phenotypes of a series of genetically modified mouse models of disrupted thyroid hormone signaling. MAJOR CONCLUSIONS: Euthyroid status is essential for normal bone development and maintenance. Major thyroid hormone actions in skeletal cells are mediated by thyroid hormone receptor α (TRα) and result in anabolic responses during growth and development but catabolic effects in adulthood. These homeostatic responses to thyroid hormone are locally regulated in individual skeletal cell types by the relative activities of the type 2 and 3 iodothyronine deiodinases, which control the supply of the active thyroid hormone 3,5,3'-L-triiodothyronine (T3) to its receptor. GENERAL SIGNIFICANCE: Population studies indicate that both thyroid hormone deficiency and excess are associated with an increased risk of fracture. Understanding the cellular and molecular basis of T3 action in skeletal cells will lead to the identification of new targets to regulate bone turnover and mineralization in the prevention and treatment of osteoporosis. This article is part of a Special Issue entitled Thyroid hormone signaling.


Asunto(s)
Desarrollo Óseo/fisiología , Huesos/fisiología , Hormonas Tiroideas/fisiología , Animales , Desarrollo Óseo/genética , Huesos/metabolismo , Humanos , Transducción de Señal , Receptores alfa de Hormona Tiroidea/genética , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores alfa de Hormona Tiroidea/fisiología , Hormonas Tiroideas/genética , Hormonas Tiroideas/metabolismo
10.
Am J Physiol Endocrinol Metab ; 307(6): E527-37, 2014 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-25117405

RESUMEN

Thyrostimulin, a putative glycoprotein hormone, comprises the subunits GPA2 and GPB5 and activates the TSH receptor (TSHR). The observation that proinflammatory cytokines stimulate GPB5 transcription suggested a role for thyrostimulin in the pathogenesis of nonthyroidal illness syndrome (NTIS). In the present study, we induced acute inflammation by LPS administration to GPB5(-/-) and WT mice to evaluate the role of thyrostimulin in peripheral thyroid hormone metabolism during NTIS. In addition to serum thyroid hormone concentrations, we studied mRNA expression and activity of deiodinase types I, II, and III (D1, D2, and D3) in peripheral T3 target tissues, including liver, muscle, and white and brown adipose tissue (WAT and BAT), of which the latter three express the TSHR. LPS decreased serum free (f)T4 and fT3 indexes to a similar extent in GPB5(-/-) and WT mice. Serum reverse (r)T3 did not change following LPS administration. LPS also induced significant alterations in tissue D1, D2, and D3 mRNA and activity levels, but only the LPS-induced increase in WAT D2 mRNA expression differed between GPB5(-/-) and WT mice. In conclusion, lacking GPB5 during acute illness does not affect the LPS-induced decrease of serum thyroid hormones while resulting in subtle changes in tissue D2 expression that are unlikely to be mediated via the TSHR.


Asunto(s)
Glicoproteínas/deficiencia , Inflamación/patología , Células 3T3-L1 , Tejido Adiposo Pardo/patología , Tejido Adiposo Blanco/patología , Animales , Células CHO , Línea Celular , Carbón Orgánico/química , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Glicoproteínas/genética , Glicoproteínas/fisiología , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Yoduro Peroxidasa/metabolismo , Lipopolisacáridos/farmacología , Hígado/patología , Ratones , Ratones Noqueados , Músculo Esquelético/patología , Hormonas Peptídicas/genética , Hormonas Peptídicas/fisiología , Hormonas Tiroideas/metabolismo
11.
J Biol Chem ; 287(21): 17812-17822, 2012 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-22442145

RESUMEN

Thyroid hormone (T(3)) acts in chondrocytes and bone-forming osteoblasts to control bone development and maintenance, but the signaling pathways mediating these effects are poorly understood. Thrb(PV/PV) mice have a severely impaired pituitary-thyroid axis and elevated thyroid hormone levels due to a dominant-negative mutant T(3) receptor (TRß(PV)) that cannot bind T(3) and interferes with the actions of wild-type TR. Thrb(PV/PV) mice have accelerated skeletal development due to unknown mechanisms. We performed microarray studies in primary osteoblasts from wild-type mice and Thrb(PV/PV) mice. Activation of the canonical Wnt signaling in Thrb(PV/PV) mice was confirmed by in situ hybridization analysis of Wnt target gene expression in bone during postnatal growth. By contrast, T(3) treatment inhibited Wnt signaling in osteoblastic cells, suggesting that T(3) inhibits the Wnt pathway by facilitating proteasomal degradation of ß-catenin and preventing its accumulation in the nucleus. Activation of the Wnt pathway in Thrb(PV/PV) mice, however, results from a gain of function for TRß(PV) that stabilizes ß-catenin despite the presence of increased thyroid hormone levels. These studies demonstrate novel interactions between T(3) and Wnt signaling pathways in the regulation of skeletal development and bone formation.


Asunto(s)
Mutación , Osteoblastos/metabolismo , Osteogénesis/fisiología , Hipófisis/metabolismo , Receptores beta de Hormona Tiroidea/metabolismo , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismo , Animales , Ratones , Ratones Mutantes , Osteoblastos/citología , Estabilidad Proteica , Receptores beta de Hormona Tiroidea/genética , Triyodotironina/metabolismo , Triyodotironina/farmacología , beta Catenina/genética
12.
Blood ; 117(3): 1053-60, 2011 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-21088133

RESUMEN

Osteogenesis imperfecta (OI or brittle bone disease) is a disorder of connective tissues caused by mutations in the collagen genes. We previously showed that intrauterine transplantation of human blood fetal stem/stromal cells in OI mice (oim) resulted in a significant reduction of bone fracture. This work examines the cellular mechanisms and mechanical bone modifications underlying these therapeutic effects, particularly examining the direct effects of donor collagen expression on bone material properties. In this study, we found an 84% reduction in femoral fractures in transplanted oim mice. Fetal blood stem/stromal cells engrafted in bones, differentiated into mature osteoblasts, expressed osteocalcin, and produced COL1a2 protein, which is absent in oim mice. The presence of normal collagen decreased hydroxyproline content in bones, altered the apatite crystal structure, increased the bone matrix stiffness, and reduced bone brittleness. In conclusion, expression of normal collagen from mature osteoblast of donor origin significantly decreased bone brittleness by improving the mechanical integrity of the bone at the molecular, tissue, and whole bone levels.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Células Madre Fetales/trasplante , Fracturas Óseas/prevención & control , Osteogénesis Imperfecta/cirugía , Animales , Fenómenos Biomecánicos , Western Blotting , Diferenciación Celular , Colágeno/metabolismo , Colágeno Tipo I , Modelos Animales de Enfermedad , Femenino , Fracturas del Fémur/prevención & control , Fémur/metabolismo , Fémur/fisiopatología , Células Madre Fetales/citología , Células Madre Fetales/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Osteoblastos/citología , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogénesis Imperfecta/genética , Embarazo , Análisis de Componente Principal , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espectrometría Raman , Trasplante Heterólogo
13.
J Immunol ; 186(5): 2910-7, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21278350

RESUMEN

Invariant NKT (iNKT) cells modulate innate and adaptive immune responses through activation of myeloid dendritic cells and macrophages and via enhanced clonogenicity, differentiation, and egress of their shared myeloid progenitors. Because these same progenitors give rise to osteoclasts (OCs), which also mediate the egress of hematopoietic progenitors and orchestrate bone remodeling, we hypothesized that iNKT cells would extend their myeloid cell regulatory role to the development and function of OCs. In this study, we report that selective activation of iNKT cells by α-galactosylceramide causes myeloid cell egress, enhances OC progenitor and precursor development, modifies the intramedullary kinetics of mature OCs, and enhances their resorptive activity. OC progenitor activity is positively regulated by TNF-α and negatively regulated by IFN-γ, but is IL-4 and IL-17 independent. These data demonstrate a novel role of iNKT cells that couples osteoclastogenesis with myeloid cell egress in conditions of immune activation.


Asunto(s)
Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Células T Asesinas Naturales/citología , Células T Asesinas Naturales/inmunología , Osteoclastos/inmunología , Osteoclastos/metabolismo , Animales , Movimiento Celular/inmunología , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Regulación hacia Abajo/inmunología , Interferón gamma/fisiología , Factor Estimulante de Colonias de Macrófagos/fisiología , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/citología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Células T Asesinas Naturales/metabolismo , Osteoclastos/citología , Ligando RANK/fisiología , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Factor de Necrosis Tumoral alfa/fisiología , Regulación hacia Arriba/inmunología
14.
Proc Natl Acad Sci U S A ; 107(16): 7604-9, 2010 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-20368437

RESUMEN

Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3'-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.


Asunto(s)
Huesos/metabolismo , Yoduro Peroxidasa/fisiología , Osteoblastos/metabolismo , Animales , Densidad Ósea , Resorción Ósea , Hipotiroidismo/patología , Yoduro Peroxidasa/metabolismo , Ratones , Ratones Noqueados , Microscopía Confocal/métodos , Microscopía Electrónica de Rastreo/métodos , Modelos Biológicos , Fenotipo , Estrés Mecánico , Microtomografía por Rayos X/métodos , Yodotironina Deyodinasa Tipo II
15.
JCI Insight ; 8(12)2023 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-37345656

RESUMEN

Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.


Asunto(s)
Enanismo , Osteoporosis , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Animales , Ratones , Calcificación Fisiológica , Enanismo/genética , Mutación con Ganancia de Función , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética
16.
JBMR Plus ; 7(6): e10739, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37283649

RESUMEN

The nuclear factor I/X (NFIX) gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall-Smith syndrome (MSS). NFIX mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense-mediated decay (NMD) leading to NFIX haploinsufficiency, whereas NFIX mutations associated with MSS are clustered in exons 6-10 and escape NMD and result in the production of dominant-negative mutant NFIX proteins. Thus, different NFIX mutations have distinct consequences on NFIX expression. To elucidate the in vivo effects of MSS-associated NFIX exon 7 mutations, we used CRISPR-Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (Nfix Del2); in-frame deletion of 24 nucleotides (Nfix Del24); and deletion of 140 nucleotides (Nfix Del140). Nfix +/Del2, Nfix +/Del24, Nfix +/Del140, Nfix Del24/Del24, and Nfix Del140/Del140 mice were viable, normal, and fertile, with no skeletal abnormalities, but Nfix Del2/Del2 mice had significantly reduced viability (p < 0.002) and died at 2-3 weeks of age. Nfix Del2 was not cleared by NMD, and NfixDel2/Del2 mice, when compared to Nfix +/+ and Nfix +/Del2 mice, had: growth retardation; short stature with kyphosis; reduced skull length; marked porosity of the vertebrae with decreased vertebral and femoral bone mineral content; and reduced caudal vertebrae height and femur length. Plasma biochemistry analysis revealed Nfix Del2/Del2 mice to have increased total alkaline phosphatase activity but decreased C-terminal telopeptide and procollagen-type-1-N-terminal propeptide concentrations compared to Nfix +/+ and Nfix +/Del2 mice. Nfix Del2/Del2 mice were also found to have enlarged cerebral cortices and ventricular areas but smaller dentate gyrus compared to Nfix +/+ mice. Thus, Nfix Del2/Del2 mice provide a model for studying the in vivo effects of NFIX mutants that escape NMD and result in developmental abnormalities of the skeletal and neural tissues that are associated with MSS. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

17.
Endocrinology ; 163(1)2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-34669927

RESUMEN

Thyroid hormones (TH) are essential for skeletal development and adult bone homeostasis. Their bioavailability is determined by specific transporter proteins at the cell surface. The TH-specific transporter monocarboxylate transporter 8 (MCT8) was recently reported as a regulator of bone mass in mice. Given that high systemic triiodothyronine (T3) levels in Mct8 knockout (KO) mice are still able to cause trabecular bone loss, alternative TH transporters must substitute for MCT8 function in bone. In this study, we analyzed the skeletal phenotypes of male Oatp1c1 KO and Mct10 KO mice, which are euthyroid, and male Mct8/Oatp1c1 and Mct8/Mct10 double KO mice, which have elevated circulating T3 levels, to unravel the role of TH transport in bone. MicroCT analysis showed no significant trabecular bone changes in Oatp1c1 KO mice at 4 weeks and 16 weeks of age compared with wild-type littermate controls, whereas 16-week-old Mct8/Oatp1c1 double KO animals displayed trabecular bone loss. At 12 weeks, Mct10 KO mice, but not Mct8/Mct10 double KO mice, had decreased trabecular femoral bone volume with reduced osteoblast numbers. By contrast, lack of Mct10 in 24-week-old mice led to trabecular bone gain at the femur with increased osteoblast numbers and decreased osteoclast numbers whereas Mct8/Mct10 double KO did not alter bone mass. Neither Mct10 nor Mct8/Mct10 deletion affected vertebral bone structures at both ages. In vitro, osteoblast differentiation and activity were impaired by Mct10 and Mct8/Mct10-deficiency. These data demonstrate that MCT10, but not OATP1C1, is a site- and age-dependent regulator of bone mass and turnover in male mice.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Huesos/metabolismo , Animales , Transporte Biológico , Fenómenos Biomecánicos , Hueso Esponjoso/metabolismo , Diferenciación Celular , Fémur/fisiología , Homeostasis , Masculino , Ratones , Ratones Noqueados , Proteínas de Transporte de Catión Orgánico/metabolismo , Osteoblastos/citología , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteocitos/citología , Fenotipo , Simportadores/metabolismo , Glándula Tiroides/metabolismo , Hormonas Tiroideas/metabolismo , Triyodotironina/metabolismo , Microtomografía por Rayos X
18.
Biochim Biophys Acta ; 1802(11): 995-1005, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20691260

RESUMEN

Thyroid hormone receptor ß1 (TRß1) is a hormone-dependent transcription factor activated by 3,5,3'-l-triiodothyronine (T3). TRß1 functions as a tumor suppressor and disturbances of the THRB gene are frequent findings in cancer. Translational control mediated by untranslated regions (UTRs) regulates cell proliferation, metabolism and responses to cellular stress, processes that are involved in carcinogenesis. We hypothesized that reduced TRß1 expression in clear cell renal cell cancer (ccRCC) results from regulatory effects of TRß1 5' and 3'UTRs on protein translation. We determined TRß1 expression and alternative splicing of TRß1 5' and 3'UTRs in ccRCC and control tissue together with expression of the type 1 deiodinase enzyme (coded by DIO1, a TRß1 target gene). Tissue concentrations of T3 (which are generated in part by D1) and expression of miRNA-204 (an mRNA inhibitor for which a putative interaction site was identified in the TRß1 3'UTR) were also determined. TRß1 mRNA and protein levels were reduced by 70% and 91% in ccRCC and accompanied by absent D1 protein, a 58% reduction in tissue T3 concentration and 2-fold increase in miRNA-204. Structural analysis of TRß1 UTR variants indicated that reduced TRß1 expression may be maintained in ccRCC by posttranscriptional mechanisms involving 5'UTRs and miRNA-204. The tumor suppressor activity of TRß1 indicates that reduced TRß1 expression and tissue hypothyroidism in ccRCC tumors is likely to be involved in the process of carcinogenesis or in maintaining a proliferative advantage to malignant cells.


Asunto(s)
Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Receptores beta de Hormona Tiroidea/genética , Regiones no Traducidas/genética , Regiones no Traducidas 5'/genética , Empalme Alternativo , Secuencia de Bases , Western Blotting , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Riñón/metabolismo , Riñón/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , MicroARNs/genética , MicroARNs/metabolismo , Modelos Genéticos , Datos de Secuencia Molecular , Biosíntesis de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Triyodotironina/metabolismo
19.
Lancet Healthy Longev ; 2(4): e212-e221, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33842907

RESUMEN

BACKGROUND: Observational and preclinical studies show associations between selenium status, bone health, and physical function. Most adults in Europe have serum selenium below the optimum range. We hypothesised that selenium supplementation could reduce pro-resorptive actions of reactive oxygen species on osteoclasts and improve physical function. METHODS: We completed a 6-month randomised, double-blind, placebo-controlled trial. We recruited postmenopausal women older than 55 years with osteopenia or osteoporosis at the Northern General Hospital, Sheffield, UK. Participants were randomly assigned 1:1:1 to receive selenite 200 µg, 50 µg, or placebo orally once per day. Medication was supplied to the site blinded and numbered by a block randomisation sequence with a block size of 18, and participants were allocated medication in numerical order. All participants and study team were masked to treatment allocation. The primary endpoint was urine N-terminal cross-linking telopeptide of type I collagen (NTx, expressed as ratio to creatinine) at 26 weeks. Analysis included all randomly assigned participants who completed follow-up. Groups were compared with analysis of covariance with Hochberg testing. Secondary endpoints were other biochemical markers of bone turnover, bone mineral density, short physical performance battery, and grip strength. Mechanistic endpoints were glutathione peroxidase, highly sensitive C-reactive protein, and interleukin-6. This trial is registered with EU clinical trials, EudraCT 2016-002964-15, and ClinicalTrials.gov, NCT02832648, and is complete. FINDINGS: 120 participants were recruited between Jan 23, 2017, and April 11, 2018, and randomly assigned to selenite 200 µg, 50 µg, or placebo (n=40 per group). 115 (96%) of 120 participants completed follow-up and were included in the primary analysis (200 µg [n=39], 50 µg [n=39], placebo [n=37]). Median follow-up was 25·0 weeks (IQR 24·7-26·0). In the 200 µg group, mean serum selenium increased from 78·8 (95% CI 73·5-84·2) to 105·7 µg/L (99·5-111·9). Urine NTx to creatinine ratio (nmol bone collagen equivalent:mmol creatinine) did not differ significantly between treatment groups at 26 weeks: 40·5 (95% CI 34·9-47·0) for placebo, 43·4 (37·4-50·5) for 50 µg, and 42·2 (37·5-47·6) for 200 µg. None of the secondary or mechanistic endpoint measurements differed between treatment groups at 26 weeks. Seven (6%) of 120 participants were withdrawn from treatment at week 13 due to abnormal thyroid-stimulating hormone concentrations (one in the 200 µg group, three in the 50 µg group, and three in the placebo group) and abnormal blood glucose (one in the 50 µg group). There were three serious adverse events: a non-ST elevation myocardial infarction at week 18 (in the 50 µg group), a diagnosis of bowel cancer after routine population screening at week 2 (in the placebo group), and a pulmonary embolus due to metastatic bowel cancer at week 4 (in the 200 µg group). All severe adverse events were judged by the principal investigator as unrelated to trial medication. INTERPRETATION: Selenium supplementation at these doses does not affect musculoskeletal health in postmenopausal women. FUNDING: UK National Institute for Health Research Efficacy and Mechanism Evaluation programme.


Asunto(s)
Neoplasias Colorrectales , Selenio , Adulto , Anciano , Creatinina , Suplementos Dietéticos , Femenino , Humanos , Ácido Selenioso
20.
Nat Commun ; 12(1): 1309, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33637762

RESUMEN

Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Osteoartritis/genética , Sitios de Carácter Cuantitativo/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Fenotipo , Factores de Transcripción/genética , Transcriptoma
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