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2.
Sci Rep ; 8(1): 15710, 2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30356088

RESUMO

Mutations in the progressive ankylosis protein (NP_473368, human ANKH) cause craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and widened metaphyses in long bones. The pathogenesis of CMD remains largely unknown, and treatment for CMD is limited to surgical intervention. We have reported that knock-in mice (AnkKI/KI) carrying a F377del mutation in ANK (NM_020332, mouse ANK) replicate many features of CMD. Interestingly, ablation of the Ank gene in AnkKO/KO mice also leads to several CMD-like phenotypes. Mutations causing CMD led to decreased steady-state levels of ANK/ANKH protein due to rapid degradation. While wild type (wt) ANK was mostly associated with plasma membranes, endoplasmic reticulum (ER), Golgi apparatus and lysosomes, CMD-linked mutant ANK was aberrantly localized in cytoplasm. Inhibitors of proteasomal degradation significantly restored levels of overexpressed mutant ANK, whereas endogenous CMD-mutant ANK/ANKH levels were more strongly increased by inhibitors of lysosomal degradation. However, these inhibitors do not correct the mislocalization of mutant ANK. Co-expressing wt and CMD-mutant ANK in cells showed that CMD-mutant ANK does not negatively affect wt ANK expression and localization, and vice versa. In conclusion, our finding that CMD mutant ANK/ANKH protein is short-lived and mislocalized in cells may be part of the CMD pathogenesis.


Assuntos
Doenças do Desenvolvimento Ósseo/etiologia , Anormalidades Craniofaciais/etiologia , Hiperostose/etiologia , Hipertelorismo/etiologia , Proteínas de Transporte de Fosfato/metabolismo , Animais , Doenças do Desenvolvimento Ósseo/genética , Células Cultivadas , Anormalidades Craniofaciais/genética , Humanos , Hiperostose/genética , Hipertelorismo/genética , Camundongos , Mutação , Proteínas de Transporte de Fosfato/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , Ratos , Saccharomyces cerevisiae , Ubiquitinação
3.
Bone ; 116: 321-332, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077757

RESUMO

Sclerosteosis (SOST) refers to two extremely rare yet similar skeletal dysplasias featuring a diffusely radiodense skeleton together with congenital syndactyly. SOST1 is transmitted as an autosomal recessive (AR) trait and to date caused by ten homozygous loss-of-function mutations within the gene SOST that encodes the inhibitor of Wnt-mediated bone formation, sclerostin. SOST2 is transmitted as an autosomal dominant (AD) or AR trait and to date caused by one heterozygous or two homozygous loss-of-function mutation(s), respectively, within the gene LRP4 that encodes the sclerostin interaction protein, low-density lipoprotein receptor-related protein 4 (LRP4). Herein, we investigated two teenagers and one middle-aged man with SOST in three families living in the state of Tamil Nadu in southern India. Next generation sequencing of their genomic DNA using our high bone density gene panel revealed SOST1 in the teenagers caused by a unique homozygous nonsense SOST mutation (c.129C > G, p.Tyr43X) and SOST2 in the man caused by homozygosity for one of the two known homozygous missense LRP4 mutations (c.3508C > T, p.Arg1170Trp). He becomes the fourth individual and the first non-European recognized with SOST2. His clinical course was milder than the life-threatening SOST1 demonstrated by the teenagers who suffered blindness, deafness, and raised intracranial pressure, yet his congenital syndactyly was more striking by featuring bony fusion of digits. All three patients were from consanguineous families and heterozygosity for the SOST mutation was documented in the mothers of both teenagers. Thus, on the endogamous genetic background of Indian Tamils, SOST1 from sclerostin deficiency compared to SOST2 from LRP4 deactivation is a more severe and life-threatening disorder featuring complications due to osteosclerosis of especially the skull. In contrast, the syndactyly of SOST2 is particularly striking by involving bony fusion of some digits. Both the SOST and LRP4 mutations in this ethnic population likely reflect genetic founders.


Assuntos
Hiperostose/patologia , Sindactilia/patologia , Adolescente , Sequência de Bases , Proteínas Morfogenéticas Ósseas/genética , Osso e Ossos/metabolismo , Análise Mutacional de DNA , Família , Feminino , Marcadores Genéticos/genética , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Índia , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Pessoa de Meia-Idade , Minerais/metabolismo , Linhagem , Sindactilia/diagnóstico por imagem , Sindactilia/genética
4.
JCI Insight ; 3(11)2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29875318

RESUMO

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, µCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.


Assuntos
Anabolizantes/administração & dosagem , Glicoproteínas/antagonistas & inibidores , Hiperostose/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Sindactilia/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/administração & dosagem , Proteínas Morfogenéticas Ósseas/genética , Modelos Animais de Doenças , Feminino , Fêmur/citologia , Fêmur/diagnóstico por imagem , Fêmur/patologia , Marcadores Genéticos/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Hiperostose/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação com Perda de Função , Masculino , Camundongos , Osteócitos , Coluna Vertebral/citologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia , Sindactilia/diagnóstico por imagem , Sindactilia/genética , Sindactilia/patologia , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Microtomografia por Raio-X
5.
World Neurosurg ; 115: e774-e781, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29729471

RESUMO

BACKGROUND: Several hypotheses have been proposed regarding the mechanisms underlying meningioma-related hyperostosis. In this study, we investigated the role of osteoprotegerin (OPG), insulin-like growth factor 1 (IGF-1), endothelin 1 (ET-1), and bone morphogenetic protein (BMP) 2 and 4. METHODS: A total of 149 patients (39 males and 110 females; mean age, 62 years) who underwent surgery were included. Depending on the relationship with the bone, meningiomas were classified as hyperostotic, osteolytic, infiltrative, or unrelated. Expression of OPG, and IGF-1, ET-1, BMP-2, and BMP-4 was evaluated by tissue microarray analysis of surgical samples. RESULTS: Our series comprised 132 cases of grade I, 14 cases of grade II, and 3 cases of grade III meningiomas, according to the World Health Organization classification. Based on preoperative computed tomography scan, the cases were classified as follows: hyperostotic, n = 11; osteolytic, n = 11; infiltrative, n = 15; unrelated to the bone, n = 108. Four cases were excluded from the statistical analysis. Using receiver operating characteristic curve analysis, we identified a 2% cutoff for the mean value of IGF-1 that discriminated between osteolytic and osteoblastic lesions; cases with a mean IGF-1 expression of <2% were classified as osteolytic (P = 0.0046), whereas those with a mean OPG expression of <10% were classified as osteolytic (P = 0.048). No other significant relationships were found. CONCLUSIONS: Expression of OPG and expression of IGF-1 were found to be associated with the development of hyperostosis. Preliminary findings suggest that hyperostosis can be caused by an overexpression of osteogenic molecules that influence osteoblast/osteoclast activity. Based on our results, further studies on hyperostotic bony tissue in meningiomas are needed to better understand how meningiomas influence bone overproduction.


Assuntos
Proteínas Morfogenéticas Ósseas/biossíntese , Hiperostose/metabolismo , Fator de Crescimento Insulin-Like I/biossíntese , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Osteoprotegerina/biossíntese , Biomarcadores/metabolismo , Proteína Morfogenética Óssea 2/biossíntese , Proteína Morfogenética Óssea 2/genética , Proteínas Morfogenéticas Ósseas/genética , Endotelina-1/biossíntese , Endotelina-1/genética , Feminino , Expressão Gênica , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Fator de Crescimento Insulin-Like I/genética , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/genética , Meningioma/diagnóstico por imagem , Meningioma/genética , Pessoa de Meia-Idade , Osteoprotegerina/genética
6.
PLoS Genet ; 14(4): e1007321, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29621230

RESUMO

Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.


Assuntos
Proteínas de Transporte de Cátions/genética , Homeostase/genética , Hiperostose/genética , Mutação , Osteosclerose/genética , Base do Crânio/anormalidades , Animais , Linhagem Celular , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Hiperostose/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteosclerose/metabolismo , Transdução de Sinais/genética , Base do Crânio/metabolismo , Zinco/metabolismo
7.
Curr Osteoporos Rep ; 16(3): 256-268, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29656376

RESUMO

PURPOSE OF REVIEW: The group of sclerosing bone disorders encompasses a variety of disorders all marked by increased bone mass. In this review, we give an overview of the genetic causes of this heterogeneous group of disorders and briefly touch upon the value of these findings for the development of novel therapeutic agents. RECENT FINDINGS: Advances in the next-generation sequencing technologies are accelerating the molecular dissection of the pathogenic mechanisms underlying skeletal dysplasias. Throughout the years, the genetic cause of these disorders has been extensively studied which resulted in the identification of a variety of disease-causing genes and pathways that are involved in bone formation by osteoblasts, bone resorption by osteoclasts, or both processes. Due to this rapidly increasing knowledge, the insights into the regulatory mechanisms of bone metabolism are continuously improving resulting in the identification of novel therapeutic targets for disorders with reduced bone mass and increased bone fragility.


Assuntos
Hiperostose/genética , Osteíte Deformante/genética , Osteosclerose/genética , Picnodisostose/genética , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Remodelação Óssea/genética , Reabsorção Óssea/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/genética , Melorreostose/genética , Osteoblastos , Osteoclastos , Osteogênese/genética , Osteopetrose/genética , Osteopecilose/genética
8.
Am J Med Genet A ; 176(3): 668-675, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29341480

RESUMO

The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability. This disorder called Lenz-Majewski syndrome (LMS) is associated with gain of function mutations in PTDSS1, encoding an enzyme involved in phospholipid biosynthesis. This report illustrates that LMS is an unequivocal cutis laxa syndrome and expands the clinical and molecular spectrum of this group of disorders. In the neonatal period, brachydactyly and facial dysmorphism are two early distinctive signs, later followed by intellectual disability and hyperostotic skeletal dysplasia with severe dwarfism allowing differentiation of this condition from other cutis laxa phenotypes. Further studies are needed to understand the link between PTDSS1 and extra cellular matrix assembly.


Assuntos
Cútis Laxa/diagnóstico , Cútis Laxa/genética , Hiperostose/diagnóstico , Hiperostose/genética , Mutação , Transferases de Grupos Nitrogenados/genética , Fenótipo , Adulto , Alelos , Criança , Pré-Escolar , Éxons , Facies , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Radiografia
9.
Metabolism ; 80: 38-47, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29080811

RESUMO

Sclerosteosis and van Buchem disease (VBD) are two rare autosomal recessive disorders that results from osteoblast hyperactivity, in which progressive bone overgrowth leads to very dense bones, distortion of the face, and entrapment of cranial nerves. Sclerosteosis is caused by loss-of-function mutations in the SOST gene which encodes a secreted glycoprotein, sclerostin. VBD is caused by a noncoding deletion that removes a SOST-specific regulatory element in bone. In bone, SOST is expressed predominantly by osteocytes and sclerostin suppresses bone formation by inhibiting the canonical Wnt signaling pathway. Here we describe how human genetics studies in sclerosteosis and VBD patients, in combination with the generation of transgenic and knockout mice, has led to a better understanding of the role of sclerostin in bone metabolism.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Marcadores Genéticos/genética , Hiperostose/genética , Osteocondrodisplasias/genética , Sindactilia/genética , Animais , Modelos Animais de Doenças , Humanos , Hiperostose/patologia , Osteocondrodisplasias/patologia , Sindactilia/patologia
10.
Hum Mol Genet ; 26(23): 4572-4587, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973168

RESUMO

Bone remodeling is a balanced process between bone synthesis and degradation, maintaining homeostasis and a constant bone mass in adult life. Imbalance will lead to conditions such as osteoporosis or hyperostosis. Osteoblasts build bone, becoming embedded in bone matrix as mature osteocytes. Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling. Excessive mechanical load can lead to activation of cellular stress responses altering cell behavior and differentiation. The unfolded protein response (UPR) is a shared pathway utilized by cells to cope with stress stimuli. We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis. A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA). As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion. Thus, therapeutic agents ameliorating protein folding or the UPR can be considered as a potential therapeutic treatment.


Assuntos
Anormalidades Craniofaciais/metabolismo , Hiperostose/metabolismo , Osteocondrodisplasias/metabolismo , Osteócitos/metabolismo , Resposta a Proteínas não Dobradas , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Remodelação Óssea/fisiologia , Osso e Ossos/metabolismo , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Marcadores Genéticos/genética , Humanos , Hiperostose/genética , Hiperostose/patologia , Camundongos , Camundongos Transgênicos , Osteoblastos/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Osteócitos/patologia , Osteogênese/fisiologia , Fenilbutiratos/farmacologia , Estresse Mecânico , Via de Sinalização Wnt
11.
Stem Cell Reports ; 9(5): 1369-1376, 2017 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-29056330

RESUMO

We identified osteoclast defects in craniometaphyseal dysplasia (CMD) using an easy-to-use protocol for differentiating osteoclasts from human induced pluripotent stem cells (hiPSCs). CMD is a rare genetic bone disorder, characterized by life-long progressive thickening of craniofacial bones and abnormal shape of long bones. hiPSCs from CMD patients with an in-frame deletion of Phe377 or Ser375 in ANKH are more refractory to in vitro osteoclast differentiation than control hiPSCs. To exclude differentiation effects due to genetic variability, we generated isogenic hiPSCs, which have identical genetic background except for the ANKH mutation. Isogenic hiPSCs with ANKH mutations formed fewer osteoclasts, resorbed less bone, expressed lower levels of osteoclast marker genes, and showed decreased protein levels of ANKH and vacuolar proton pump v-ATP6v0d2. This proof-of-concept study demonstrates that efficient and reproducible differentiation of isogenic hiPSCs into osteoclasts is possible and a promising tool for investigating mechanisms of CMD or other osteoclast-related disorders.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Diferenciação Celular , Anormalidades Craniofaciais/genética , Hiperostose/genética , Hipertelorismo/genética , Células-Tronco Pluripotentes Induzidas/citologia , Osteoclastos/citologia , Proteínas de Transporte de Fosfato/genética , Adulto , Células Cultivadas , Criança , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Mutação , Osteoclastos/metabolismo
12.
J Bone Miner Res ; 32(8): 1739-1749, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28477420

RESUMO

Sclerosteosis is a rare autosomal recessive bone disorder marked by hyperostosis of the skull and tubular bones. Initially, we and others reported that sclerosteosis was caused by loss-of-function mutations in SOST, encoding sclerostin. More recently, we identified disease-causing mutations in LRP4, a binding partner of sclerostin, in three sclerosteosis patients. Upon binding to sclerostin, LRP4 can inhibit the canonical WNT signaling that is known to be an important pathway in the regulation of bone formation. To further investigate the role of LRP4 in the bone formation process, we generated an Lrp4 mutated sclerosteosis mouse model by introducing the p.Arg1170Gln mutation in the mouse genome. Extensive analysis of the bone phenotype of the Lrp4R1170Q/R1170Q knock-in (KI) mouse showed the presence of increased trabecular and cortical bone mass as a consequence of increased bone formation by the osteoblasts. In addition, three-point bending analysis also showed that the increased bone mass results in increased bone strength. In contrast to the human sclerosteosis phenotype, we could not observe syndactyly in the forelimbs or hindlimbs of the Lrp4 KI animals. Finally, we could not detect any significant changes in the bone formation and resorption markers in the serum of the mutant mice. However, the serum sclerostin levels were strongly increased and the level of sclerostin in the tibia was decreased in Lrp4R1170Q/R1170Q mice, confirming the role of LRP4 as an anchor for sclerostin in bone. In conclusion, the Lrp4R1170Q/R1170Q mouse is a good model for the human sclerosteosis phenotype caused by mutations in LRP4 and can be used in the future for further investigation of the mechanism whereby LRP4 regulates bone formation. © 2017 American Society for Bone and Mineral Research.


Assuntos
Glicoproteínas/metabolismo , Homozigoto , Hiperostose , Mutação de Sentido Incorreto , Receptores de LDL , Sindactilia , Tíbia/metabolismo , Via de Sinalização Wnt , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Glicoproteínas/genética , Humanos , Hiperostose/genética , Hiperostose/metabolismo , Hiperostose/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Knockout , Receptores de LDL/genética , Receptores de LDL/metabolismo , Sindactilia/genética , Sindactilia/metabolismo , Sindactilia/patologia , Tíbia/patologia
14.
J Negat Results Biomed ; 15(1): 18, 2016 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-27784318

RESUMO

BACKGROUND: Mutations in the human progressive ankylosis gene (ANKH; Mus musculus ortholog Ank) have been identified as cause for craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. We previously reported a knock-in (KI) mouse model (Ank KI/KI) for CMD and showed transiently lower serum phosphate (Pi) as well as significantly higher mRNA levels of fibroblast growth factor 23 (Fgf23) in Ank KI/KI mice. FGF23 is secreted by bone and acts in kidney to promote Pi wasting which leads to lower serum Pi levels. Here, we examined whether increasing the Pi level can partially rescue the CMD-like skeletal phenotype by feeding Ank +/+ and Ank KI/KI mice with high Pi (1.7 %) diet from birth for 6 weeks. We studied the Pi metabolism in Ank KI/KI mice and CMD patients by examining the Pi regulators FGF23 and parathyroid hormone (PTH). RESULTS: High Pi diet did not correct CMD-like features, including massive jawbone, increased endosteal and periosteal perimeters and extensive trabeculation of femurs in Ank KI/KI mice shown by computed microtomography (µCT). This unexpected negative result is, however, consistent with normal serum/plasma levels of the intact/active form of FGF23 and PTH in Ank KI/KI mice and in CMD patients. In addition, FGF23 protein expression was unexpectedly normal in Ank KI/KI femoral cortical bone as shown by immunohistochemistry despite increased mRNA levels for Fgf23. Renal expression of genes involved in the FGF23 bone-kidney axis, including mFgfr1, mKlotho, mNpt2a, mCyp24a1 and m1αOHase, were comparable between Ank +/+ and Ank KI/KI mice as shown by quantitative real-time PCR. Different from normal FGF23 and PTH, serum 25-hydroxyvitamin D was significantly lower in Ank KI/KI mice and vitamin D insufficiency was found in four out of seven CMD patients. CONCLUSIONS: Our data suggests that FGF23 signaling and Pi metabolism are not significantly affected in CMD and transiently low Pi level is not a major contributor to CMD.


Assuntos
Doenças do Desenvolvimento Ósseo/tratamento farmacológico , Osso e Ossos/patologia , Anormalidades Craniofaciais/tratamento farmacológico , Dieta , Suplementos Nutricionais , Hiperostose/tratamento farmacológico , Hipertelorismo/tratamento farmacológico , Fosfatos/uso terapêutico , Adolescente , Animais , Peso Corporal/efeitos dos fármacos , Doenças do Desenvolvimento Ósseo/sangue , Doenças do Desenvolvimento Ósseo/genética , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Criança , Anormalidades Craniofaciais/sangue , Anormalidades Craniofaciais/genética , Modelos Animais de Doenças , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperostose/sangue , Hiperostose/genética , Hipertelorismo/sangue , Hipertelorismo/genética , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Hormônio Paratireóideo/sangue , Fenótipo , Fosfatos/farmacologia , Vitamina D/análogos & derivados , Vitamina D/sangue , Microtomografia por Raio-X
15.
J Bone Miner Res ; 31(10): 1845-1854, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27164190

RESUMO

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.


Assuntos
Calcinose , Fatores de Crescimento de Fibroblastos/genética , Glucuronidase/genética , Hiperostose Cortical Congênita , Hiperostose , Hiperfosfatemia , N-Acetilgalactosaminiltransferases/genética , Adolescente , Adulto , Calcinose/sangue , Calcinose/genética , Calcinose/patologia , Calcinose/terapia , Criança , Estudos de Coortes , Feminino , Humanos , Hiperostose/sangue , Hiperostose/genética , Hiperostose/patologia , Hiperostose/terapia , Hiperostose Cortical Congênita/sangue , Hiperostose Cortical Congênita/genética , Hiperostose Cortical Congênita/patologia , Hiperostose Cortical Congênita/terapia , Hiperfosfatemia/sangue , Hiperfosfatemia/genética , Hiperfosfatemia/patologia , Hiperfosfatemia/terapia , Masculino
16.
Nat Rev Rheumatol ; 12(6): 323-34, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27052486

RESUMO

Osteoporosis is characterized by low bone mass and an increased risk of fracture. Genetic factors, environmental factors and gene-environment interactions all contribute to a person's lifetime risk of developing an osteoporotic fracture. This Review summarizes key advances in understanding of the genetics of bone traits and their role in osteoporosis. Candidate-gene approaches dominated this field 20 years ago, but clinical and preclinical genetic studies published in the past 5 years generally utilize more-sophisticated and better-powered genome-wide association studies (GWAS). High-throughput DNA sequencing, large genomic databases and improved methods of data analysis have greatly accelerated the gene-discovery process. Linkage analyses of single-gene traits that segregate in families with extreme phenotypes have led to the elucidation of critical pathways controlling bone mass. For example, components of the Wnt-ß-catenin signalling pathway have been validated (in both GWAS and functional studies) as contributing to various bone phenotypes. These notable advances in gene discovery suggest that the next decade will witness cataloguing of the hundreds of genes that influence bone mass and osteoporosis, which in turn will provide a roadmap for the development of new drugs that target diseases of low bone mass, including osteoporosis.


Assuntos
Densidade Óssea/genética , Osteoporose/genética , Animais , Doenças Ósseas/genética , Modelos Animais de Doenças , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperostose/genética , Osteocondrodisplasias/genética , Osteogênese Imperfeita/genética , Fenótipo , Análise de Sequência de DNA , Sindactilia/genética , Via de Sinalização Wnt/genética
17.
Clin Chim Acta ; 456: 122-127, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26820766

RESUMO

BACKGROUND: Craniometaphyseal dysplasia (CMD) is a rare genetic disorder that is characterized by progressive sclerosis of the craniofacial bones and metaphyseal widening of long bones, and biochemical indexes were mostly normal. To further the understanding of the disease from a biochemical perspective, we reported a CMD case with obviously abnormal biochemical indexes. CASE REPORT: A 1-year-old boy was referred to our clinic. Biochemical test showed obviously increased alkaline phosphatase (ALP) and parathyroid hormone (PTH), mild hypocalcemia and hypophosphatemia. Moreover, significant elevated receptor activator of nuclear factor kappa-B ligand (RANKL) level, but normal ß-C-terminal telopeptide of type I collagen (ß-CTX) concentration were revealed. He was initially suspected of rickets, because the radiological examination also showed broadened epiphysis in his long bones. Supplementation with calcium and calcitriol alleviated biochemical abnormality. However, the patient gradually developed osteosclerosis which was inconformity with rickets. Considering that he was also presented with facial paralysis and nasal obstruction symptom, the diagnosis of craniometaphyseal dysplasia was suspected, and then was confirmed by the mutation analysis of ANKH of the proband and his family, which showed a de novo heterozygous mutation (C1124-1126delCCT) on exon 9. CONCLUSIONS: Our study revealed that obvious biochemical abnormality and rickets-like features might present as uncommon characteristics in CMD patients, and the calcium and calcitriol supplementation could alleviate biochemical abnormalities. Furthermore, although early osteoclast differentiation factor was excited in CMD patient, activity of osteoclast was still inert.


Assuntos
Doenças do Desenvolvimento Ósseo/complicações , Doenças do Desenvolvimento Ósseo/metabolismo , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/metabolismo , Hiperostose/complicações , Hiperostose/metabolismo , Hipertelorismo/complicações , Hipertelorismo/metabolismo , Raquitismo/complicações , Fosfatase Alcalina/metabolismo , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Éxons/genética , Feminino , Heterozigoto , Humanos , Hiperostose/genética , Hipertelorismo/genética , Hipocalcemia/complicações , Hipofosfatemia/complicações , Lactente , Masculino , Mutação , Hormônio Paratireóideo/metabolismo , Linhagem , Proteínas de Transporte de Fosfato/genética
18.
J Bone Miner Res ; 31(4): 874-81, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26751728

RESUMO

Mutations in the LRP4 gene, coding for a Wnt signaling coreceptor, have been found to cause several allelic conditions. Among these, two are characterized by a strong skeletal involvement, namely sclerosteosis and Cenani-Lenz syndrome. In this work, we evaluated the role of LRP4 in the pathophysiology of these diseases. First, we report a novel LRP4 mutation, leading to the substitution of arginine at position 1170 in glutamine, identified in a patient with sclerosteosis. This mutation is located in the central cavity of the third ß-propeller domain, which is in line with two other sclerosteosis mutations we previously described. Reporter assays demonstrate that this mutation leads to impaired sclerostin inhibition of Wnt signaling. Moreover, we compared the effect of this novel variant to mutations causing Cenani-Lenz syndrome and show that impaired membrane trafficking of the LRP4 protein is the likely mechanism underlying Cenani-Lenz syndrome. This is in contrast to sclerosteosis mutations, previously shown to impair the binding between LRP4 and sclerostin. In addition, to better understand the biology of LRP4, we investigated the circulating sclerostin levels in the serum of a patient suffering from sclerosteosis owing to a LRP4 mutation. We demonstrate that impaired sclerostin binding to the mutated LRP4 protein leads to dramatic increase in circulating sclerostin in this patient. With this study, we provide the first evidence suggesting that LRP4 is responsible for the retention of sclerostin in the bone environment in humans. These findings raise potential concerns about the utility of determining circulating sclerostin levels as a marker for other bone-related parameters. Although more studies are needed to fully understand the mechanism whereby LRP4 facilitates sclerostin action, it is clear that this protein represents a potent target for future osteoporosis therapies and an interesting alternative for the antisclerostin treatment currently under study.


Assuntos
Proteínas Morfogenéticas Ósseas , Marcadores Genéticos , Hiperostose , Proteínas Relacionadas a Receptor de LDL , Mutação de Sentido Incorreto , Sindactilia , Substituição de Aminoácidos , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Marcadores Genéticos/genética , Células HEK293 , Humanos , Hiperostose/genética , Hiperostose/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Ligação Proteica , Domínios Proteicos , Sindactilia/genética , Sindactilia/metabolismo
19.
Matrix Biol ; 49: 82-92, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26116392

RESUMO

One of the key regulators of endochondral ossification is Indian hedgehog (Ihh), which acts as a long-range morphogen in the developing skeletal elements. Previous studies have shown that the distribution and signaling activity of Ihh is regulated by the concentration of the extracellular glycosaminoglycan heparan sulfate (HS). An essential step during biosynthesis of HS is the epimerization of D-glucuronic to L-iduronic acid by the enzyme glucuronyl C5-epimerase (Hsepi or Glce). Here we have investigated chondrocyte differentiation in Glce deficient mice and found increased regions of proliferating chondrocytes accompanied by a delayed onset of hypertrophic differentiation. In addition, we observed increased expression levels of the Ihh target genes Patched1 (Ptch1) and Parathyroid hormone related peptide (Pthrp; Parathyroid hormone like hormone (Pthlh)) indicating elevated Ihh signaling. We further show that Ihh binds with reduced affinity to HS isolated from Glce(-/-) mice. Together our results strongly indicate that not only the level, but also the structure of HS is critical in regulating the distribution and signaling activity of Ihh in chondrocytes.


Assuntos
Carboidratos Epimerases/deficiência , Condrócitos/citologia , Proteínas Hedgehog/metabolismo , Heparitina Sulfato/química , Racemases e Epimerases/deficiência , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Embrião de Mamíferos/citologia , Heparitina Sulfato/metabolismo , Hiperostose/genética , Hiperostose/metabolismo , Camundongos , Transdução de Sinais
20.
Clin Genet ; 89(2): 205-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26283468

RESUMO

Sclerosteosis, characterized by the hyperostosis of cranial and tubular bones, is a rare autosomal recessive hereditary disorder caused by mutation of SOST gene. Four nonsense mutations of SOST have been identified worldwide. Here, we report two affected siblings who carried a novel nonsense mutation of SOST in a consanguineous family from China. The proband manifested typical symptoms of sclerosteosis, whereas the symptoms were absent in another affected sibling. Two nucleotide substitutions in exon 2 of SOST were identified, c.444_445TC>AA, resulting in a premature stop codon, p.Cys148→Stop. This truncated mutation loses 66 amino acid residues which contain 3 cysteine residues of the cysteine-knot motif, leading to loss of function of SOST. The symptoms of sclerosteosis may be clinically heterogeneous in some patients, even with the same mutation. Our results support the notion that founder effects from the ancestors contribute to the disease onset.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Códon sem Sentido/genética , Consanguinidade , Marcadores Genéticos/genética , Hiperostose/genética , Mutação/genética , Sindactilia/genética , Adulto , Sequência de Bases , Família , Feminino , Homozigoto , Humanos , Hiperostose/diagnóstico por imagem , Recém-Nascido , Masculino , Dados de Sequência Molecular , Linhagem , Radiografia , Sindactilia/diagnóstico por imagem , Adulto Jovem
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