Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Mais filtros

Intervalo de ano de publicação
Bone ; 123: 39-47, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30878523


Genome-wide association studies (GWAS) have repeatedly identified genetic variants associated with bone mineral density (BMD) and osteoporotic fracture in non-coding regions of C7ORF76, a poorly studied gene of unknown function. The aim of the present study was to elucidate the causality and molecular mechanisms underlying the association. We re-sequenced the genomic region in two extreme BMD groups from the BARCOS cohort of postmenopausal women to search for functionally relevant variants. Eight selected variants were tested for association in the complete cohort and 2 of them (rs4342521 and rs10085588) were found significantly associated with lumbar spine BMD and nominally associated with osteoporotic fracture. cis-eQTL analyses of these 2 SNPs, together with SNP rs4727338 (GWAS lead SNP in Estrada et al., Nat Genet. 44:491-501, 2012), performed in human primary osteoblasts, disclosed a statistically significant influence on the expression of the proximal neighbouring gene SLC25A13 and a tendency on the distal SHFM1. We then studied the functionality of a putative upstream regulatory element (UPE), containing rs10085588. Luciferase reporter assays showed transactivation capability with a strong allele-dependent effect. Finally, 4C-seq experiments in osteoblastic cell lines showed that the UPE interacted with different tissue-specific enhancers and a lncRNA (LOC100506136) in the region. In summary, this study is the first one to analyse in depth the functionality of C7ORF76 genomic region. We provide functional regulatory evidence for the rs10085588, which may be a causal SNP within the 7q21.3 GWAS signal for osteoporosis.

J Bone Miner Res ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30496603


The role of the calcium-sensing receptor (CaSR) as a regulator of parathyroid hormone secretion is well established, but its function in bone is less well defined. In an effort to elucidate the CaSR's skeletal role, bone tissue and material characteristics from patients with autosomal dominant hypocalcemia (ADH), a genetic form of primary hypoparathyroidism caused by CASR gain-of-function mutations, were compared to patients with postsurgical hypoparathyroidism (PSH). Bone structure and formation/resorption indices and mineralization density distribution (BMDD), were examined in transiliac biopsy samples from PSH (n = 13) and ADH (n = 6) patients by histomorphometry and quantitative backscatter electron imaging, respectively. Bone mineral density (BMD by DXA) and biochemical characteristics were measured at the time of the biopsy. As both study groups comprised children and adults, all measured biopsy parameters and BMD outcomes were converted to Z-scores for comparison. Histomorphometric indices were normal and not different between ADH and PSH, with the exception of mineral apposition rate Z-score, which was higher in the ADH group. Similarly, average BMD Z-scores were normal and not different between ADH and PSH. Significant differences were observed for the BMDD: average Z-scores of mean and typical degree of mineralization (CaMean, CaPeak, respectively) were lower (p = 0.02 and p = 0.03, respectively), while the heterogeneity of mineralization (CaWidth) and percentage of lower mineralized areas (CaLow) were increased in ADH vs. PSH (p = 0.01 and p = 0.002, respectively). The BMDD outcomes point toward a direct, PTH-independent role of the CaSR in the regulation of bone mineralization.

Proc Natl Acad Sci U S A ; 115(3): E428-E437, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29282319


Fibrous dysplasia (FD) is a disease caused by postzygotic activating mutations of GNAS (R201C and R201H) that encode the α-subunit of the Gs stimulatory protein. FD is characterized by the development of areas of abnormal fibroosseous tissue in the bones, resulting in skeletal deformities, fractures, and pain. Despite the well-defined genetic alterations underlying FD, whether GNAS activation is sufficient for FD initiation and the molecular and cellular consequences of GNAS mutations remains largely unresolved, and there are no currently available targeted therapeutic options for FD. Here, we have developed a conditional tetracycline (Tet)-inducible animal model expressing the GαsR201C in the skeletal stem cell (SSC) lineage (Tet-GαsR201C/Prrx1-Cre/LSL-rtTA-IRES-GFP mice), which develops typical FD bone lesions in both embryos and adult mice in less than 2 weeks following doxycycline (Dox) administration. Conditional GαsR201C expression promoted PKA activation and proliferation of SSCs along the osteogenic lineage but halted their differentiation to mature osteoblasts. Rather, as is seen clinically, areas of woven bone admixed with fibrous tissue were formed. GαsR201C caused the concomitant expression of receptor activator of nuclear factor kappa-B ligand (Rankl) that led to marked osteoclastogenesis and bone resorption. GαsR201C expression ablation by Dox withdrawal resulted in FD-like lesion regression, supporting the rationale for Gαs-targeted drugs to attempt FD cure. This model, which develops FD-like lesions that can form rapidly and revert on cessation of mutant Gαs expression, provides an opportunity to identify the molecular mechanism underlying FD initiation and progression and accelerate the development of new treatment options.

Displasia Fibrosa Óssea/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Antibacterianos/toxicidade , Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/patologia , Diferenciação Celular , Doxiciclina/toxicidade , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Camundongos , Mutação
J Bone Miner Res ; 32(8): 1667-1671, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28459498


Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which unregulated hypersecretion of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMT) causes renal phosphate wasting, hypophosphatemia, and osteomalacia. The resulting mineral homeostasis abnormalities and skeletal manifestations can be reversed with surgical resection of the tumor. Unfortunately, PMTs are often difficult to locate, and medical treatment with oral phosphate and vitamin D analogues is either insufficient to manage the disease or not tolerated. Octreotide has been proposed as a potential treatment for TIO due to the presence of somatostatin receptors (SSTR) on PMTs; however, the role of somatostatin signaling in PMTs and the efficacy of treatment of TIOs with somatostatin analogues is not clear. In an effort to evaluate the efficacy of octreotide therapy in TIO, five subjects with TIO were treated with octreotide for 3 days. Blood intact FGF23, phosphate, and 1,25(OH)2 D3 , and tubular reabsorption of phosphate (TRP) were measured at frequent time points during treatment. Octreotide's effects were assessed by comparing group means of the biochemical parameters at each time-point to mean baseline values. There were no significant changes in blood phosphate, FGF23, 1,25(OH)2 D3 , or TRP during octreotide treatment, consistent with a lack of efficacy of octreotide in treating TIO. © 2017 American Society for Bone and Mineral Research.

Calcitriol/sangue , Fatores de Crescimento de Fibroblastos/sangue , Octreotida/administração & dosagem , Osteomalacia , Síndromes Paraneoplásicas , Fosfatos/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteomalacia/sangue , Osteomalacia/tratamento farmacológico , Síndromes Paraneoplásicas/sangue , Síndromes Paraneoplásicas/tratamento farmacológico
J Am Acad Dermatol ; 75(2): 420-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27444071


BACKGROUND: We recently demonstrated multilineage somatic mosaicism in cutaneous skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor (FGF)-23, and hypophosphatemia, finding identical RAS mutations in affected skin and bone. OBJECTIVE: We sought to: (1) provide an updated overview of CSHS; (2) review its pathobiology; (3) present a new patient with CSHS; and (4) discuss treatment modalities. METHODS: We searched PubMed for "nevus AND rickets," and "nevus AND hypophosphatemia," identifying cases of nevi with hypophosphatemic rickets or elevated serum FGF-23. For our additional patient with CSHS, we performed histopathologic and radiographic surveys of skin and skeletal lesions, respectively. Sequencing was performed for HRAS, KRAS, and NRAS to determine causative mutations. RESULTS: Our new case harbored somatic activating HRAS p.G13 R mutation in affected tissue, consistent with previous findings. Although the mechanism of FGF-23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF-23 antibody KRN-23 may be useful in managing CSHS. LIMITATIONS: Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable. CONCLUSION: Patients with nevi in association with skeletal disease should be evaluated for serum phosphate and FGF-23. Further studies investigating the role of RAS in FGF-23 regulation are needed.

Genes ras/genética , Mosaicismo , Nevo Pigmentado/genética , Osteomalacia/genética , Raquitismo Hipofosfatêmico/genética , Neoplasias Cutâneas/genética , Anticorpos Monoclonais/uso terapêutico , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Nevo Pigmentado/tratamento farmacológico , Osteomalacia/tratamento farmacológico , Raquitismo Hipofosfatêmico/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Síndrome
Hum Mol Genet ; 23(2): 397-407, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24006476


Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

Fatores de Crescimento de Fibroblastos/sangue , GTP Fosfo-Hidrolases/genética , Hipofosfatemia/genética , Proteínas de Membrana/genética , Nevo Pigmentado/genética , Osteomalacia/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Cutâneas/genética , Adolescente , Criança , Exoma , Feminino , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/patologia , Masculino , Mutação , Nevo , Nevo Pigmentado/sangue , Nevo Pigmentado/patologia , Osteomalacia/sangue , Osteomalacia/patologia , Análise de Sequência de DNA , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia
Arch Esp Urol ; 66(3): 302-4, 2013 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-23648750


OBJECTIVE: To study lytic lesions in a patient with past history of renal cancer. METHODS: A 62 year-old man was admitted to hospital for investigation of the cause of polyostotic bone pain. RESULTS: Brown tumors due to hyperparathyroidism turned out to be the cause of bone pain. CONCLUSIONS: Differential diagnosis is important in daily practice in order to provide a correct treatment for each condition.

Hiperparatireoidismo , Osteíte Fibrosa Cística , Diagnóstico Diferencial , Humanos , Neoplasias Renais/diagnóstico
Arch. esp. urol. (Ed. impr.) ; 66(3): 302-304, abr. 2013. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-111818


OBJETIVO: Estudio de lesiones líticas en un paciente con antecedentes de cancer renal. MÉTODOS: Varón de 62 años que ingresa en el hospital para estudio de dolor óseo en multiples localizaciones. RESULTADOS: La causa del dolor resultó ser tumores pardos secundarios a hiperparatiroidismo por paratiroides aberrante. CONCLUSIONES: Importancia del diagnóstico diferencial en la práctica diaria para proporcionar un correcto tratamiento(AU)

OBJECTIVE: To study lytic lesions in a patient with past history of renal cancer. METHODS: A 62 year-old man was admitted to hospital for investigation of the cause of polyostotic bone pain. RESULTS: Brown tumors due to hyperparathyroidism turned out to be the cause of bone pain. CONCLUSIONS: Differential diagnosis is important in daily practice in order to provide a correct treatment for each condition(AU)

Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Renais/complicações , Neoplasias Renais/fisiopatologia , Dor/complicações , Dor/diagnóstico , Hiperparatireoidismo/complicações , Hiperparatireoidismo/diagnóstico , Diagnóstico Diferencial , Litíase/complicações , Litíase/diagnóstico , Dor/etiologia , Hiperparatireoidismo/fisiopatologia , Hiperparatireoidismo/terapia