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J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31650157


CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.

Imunoglobulinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Neurossecreção/fisiologia , Somatotrofos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Hormônio do Crescimento/biossíntese , Humanos , Imunoglobulinas/deficiência , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Proteínas de Membrana/deficiência , Camundongos , Pessoa de Meia-Idade
Methods Mol Biol ; 1801: 123-154, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29892822


Thyroid hormone has profound effects on skeletal development and adult bone maintenance. Here, we review the current literature concerning thyroid hormone action in bone and cartilage in relation to human disease and animal models. We describe state-of-the-art imaging and biomechanical methods used to determine structural and functional parameters in the skeletal phenotyping of mouse models.

Desenvolvimento Ósseo , Osso e Ossos/fisiologia , Receptores dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo , Fatores Etários , Animais , Remodelação Óssea , Osso e Ossos/diagnóstico por imagem , Cartilagem/metabolismo , Condrócitos/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Camundongos , Mutação , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Receptores dos Hormônios Tireóideos/genética , Hormônios Tireóideos/genética , Microtomografia por Raio-X
Bone ; 114: 62-71, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29883787


BACKGROUND: Generalised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. METHODS: We performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n = 240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n = 1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n = 900), with Z-scores -1.5 to -4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. RESULTS: We observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF] = 0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF = 0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-ß regulated BMP-driven osteoblast differentiation. Rs9292469 (downstream of NPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n = 32,965). We found Spon1 was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereas Npr3 expression was more variable. CONCLUSION: We report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study.

Densidade Óssea/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Vértebras Lombares/diagnóstico por imagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Vértebras Lombares/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
Am J Physiol Endocrinol Metab ; 307(6): E527-37, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25117405


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.

Glicoproteínas/deficiência , Inflamação/patologia , Células 3T3-L1 , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Animais , Células CHO , Linhagem Celular , Carvão Vegetal/química , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Glicoproteínas/genética , Glicoproteínas/fisiologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Iodeto Peroxidase/metabolismo , Lipopolissacarídeos/farmacologia , Fígado/patologia , Camundongos , Camundongos Knockout , Músculo Esquelético/patologia , Hormônios Peptídicos/genética , Hormônios Peptídicos/fisiologia , Hormônios Tireóideos/metabolismo
Minerva Endocrinol ; 36(1): 71-85, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21460788


Thyroid hormones are critical determinants of postnatal skeletal development. Thyroid hormone deficiency or excess in children results in severe abnormalities of linear growth and bone maturation. These clinical observations have been recapitulated in mutant mice and these models have facilitated studies of the mechanisms of thyroid hormone action in the developing skeleton. In this review, we consider in detail the direct and indirect effects of thyroid hormone on bone and the molecular mechanisms involved.

Desenvolvimento Ósseo , Osso e Ossos/metabolismo , Hormônios Tireóideos/metabolismo , Tireotropina/metabolismo , Animais , Remodelação Óssea , Medicina Baseada em Evidências , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotireoidismo/metabolismo , Tri-Iodotironina/metabolismo
Arch Biochem Biophys ; 503(1): 129-36, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20599658


The hypothalamic-pituitary-thyroid axis plays a key role in skeletal development, acquisition of peak bone mass and regulation of adult bone turnover. Euthyroid status is essential for maintenance of optimal bone mineralization and strength. In population studies, hypothyroidism and hyperthyroidism have both been associated with an increased risk of fracture. Furthermore, recent studies in healthy euthyroid post-menopausal women indicate that thyroid status in the upper normal range is also associated with low bone mineral density and an increased risk of non-vertebral fracture. Studies in mutant mice have demonstrated that thyroid hormone receptor α is the major mediator of T3 action in bone and that thyroid hormones exert anabolic actions during growth but have catabolic effects on the adult skeleton. Nevertheless, TSH has also been proposed to be a direct negative regulator of bone turnover, although the relative importance of T3 and TSH actions in the skeleton has yet to be clarified.

Osso e Ossos , Glândula Tireoide , Animais , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Humanos , Doenças da Glândula Tireoide/tratamento farmacológico , Doenças da Glândula Tireoide/metabolismo , Doenças da Glândula Tireoide/fisiopatologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/fisiopatologia , Tireotropina/metabolismo , Tireotropina/farmacologia , Tri-Iodotironina Reversa/metabolismo , Tri-Iodotironina Reversa/farmacologia