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1.
Biochim Biophys Acta ; 1854(10 Pt B): 1687-93, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25862977

RESUMO

Protein phosphorylation is a nearly universal post-translation modification involved in a plethora of cellular events. Even though phosphorylation of extracellular proteins had been observed, the identity of the kinases that phosphorylate secreted proteins remained a mystery until only recently. Advances in genome sequencing and genetic studies have paved the way for the discovery of a new class of kinases that localize within the endoplasmic reticulum, Golgi apparatus and the extracellular space. These novel kinases phosphorylate proteins and proteoglycans in the secretory pathway and appear to regulate various extracellular processes. Mutations in these kinases cause human disease, thus underscoring the biological importance of phosphorylation within the secretory pathway. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.


Assuntos
Anormalidades Múltiplas/genética , Caseína Quinase I/genética , Fissura Palatina/genética , Exoftalmia/genética , Proteínas da Matriz Extracelular/genética , Microcefalia/genética , Osteosclerose/genética , Proteínas Tirosina Quinases/genética , Via Secretória/genética , Anormalidades Múltiplas/enzimologia , Animais , Caseína Quinase I/química , Caseína Quinase I/metabolismo , Fissura Palatina/enzimologia , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/genética , Exoftalmia/enzimologia , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/metabolismo , Complexo de Golgi/enzimologia , Complexo de Golgi/genética , Humanos , Microcefalia/enzimologia , Mutação , Osteosclerose/enzimologia , Fosforilação/genética , Conformação Proteica , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Especificidade por Substrato
2.
J Vet Intern Med ; 26(4): 935-44, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22805166

RESUMO

BACKGROUND: Erythrocytic pyruvate kinase (PK) deficiency, first documented in Basenjis, is the most common inherited erythroenzymopathy in dogs. OBJECTIVES: To report 3 new breed-specific PK-LR gene mutations and a retrospective survey of PK mutations in as mall and selected group of Beagles and West Highland White Terriers (WHWT). ANIMALS: Labrador Retrievers (2 siblings, 5 unrelated), Pugs (2 siblings, 1 unrelated), Beagles (39 anemic, 29 other),WHWTs (22 anemic, 226 nonanemic), Cairn Terrier (n = 1). METHODS: Exons of the PK-LR gene were sequenced from genomic DNA of young dogs (<2 years) with persistent highly regenerative hemolytic anemia. RESULTS: A nonsense mutation (c.799C>T) resulting in a premature stop codon was identified in anemic Labrador Retriever siblings that had osteosclerosis, high serum ferritin concentrations, and severe hepatic secondary hemochromatosis. Anemic Pug and Beagle revealed 2 different missense mutations (c.848T>C, c.994G>A, respectively) resulting in intolerable amino acid changes to protein structure and enzyme function. Breed-specific mutation tests were developed. Among the biased group of 248 WHWTs, 9% and 35% were homozygous (affected) and heterozygous, respectively, for the previously described mutation (mutant allele frequency 0.26). A PK-deficient Cairn Terrier had the same insertion mutation as the affected WHWTs. Of the selected group of 68 Beagles, 35% were PK-deficient and 3% were carriers (0.37). CONCLUSIONS AND CLINICAL IMPORTANCE: Erythrocytic PK deficiency is caused by different mutations in different dog breeds and causes chronic severe hemolytic anemia, hemosiderosis, and secondary hemochromatosis because of chronic hemolysis and, an as yet unexplained osteosclerosis. The newly developed breed-specific mutation assays simplify the diagnosis of PK deficiency.


Assuntos
Anemia Hemolítica/veterinária , Doenças do Cão/genética , Eritrócitos/enzimologia , Hemocromatose/veterinária , Mutação , Osteosclerose/veterinária , Piruvato Quinase/genética , Sequência de Aminoácidos , Anemia Hemolítica/enzimologia , Anemia Hemolítica/genética , Animais , Sequência de Bases , Códon sem Sentido , Doenças do Cão/sangue , Doenças do Cão/enzimologia , Cães , Feminino , Hemocromatose/sangue , Hemocromatose/enzimologia , Hemocromatose/genética , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Osteosclerose/sangue , Osteosclerose/enzimologia , Osteosclerose/genética , Piruvato Quinase/deficiência
3.
Intern Med ; 50(16): 1703-8, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21841329

RESUMO

A 62-year-old woman presented with a markedly increased serum ALP level of skeletal origin during a regular follow-up of chronic hepatitis C. Serum calcium, phosphorus, and intact-PTH levels were normal and bone turnover markers were increased. Her generalized bone density was diffusely increased. These findings were consistent with hepatitis C-associated osteosclerosis (HCAO). She underwent cholecystectomy, as gallbladder cancer was suspected; however, histopathological findings demonstrated xanthogranulomatous cholecystitis. After cholecystectomy, serum ALP level and bone turnover markers were gradually decreased. This may indicate the existence of a novel osteogenic factor in the gallbladder in HCAO.


Assuntos
Colecistite/diagnóstico , Granuloma/diagnóstico , Hepatite C Crônica/diagnóstico , Osteosclerose/complicações , Xantomatose/diagnóstico , Fosfatase Alcalina/sangue , Colecistite/complicações , Colecistite/enzimologia , Feminino , Granuloma/complicações , Granuloma/enzimologia , Hepatite C Crônica/complicações , Hepatite C Crônica/enzimologia , Humanos , Pessoa de Meia-Idade , Osteosclerose/diagnóstico , Osteosclerose/enzimologia , Xantomatose/complicações , Xantomatose/enzimologia
4.
Bone ; 47(4): 795-803, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20638491

RESUMO

INTRODUCTION: Breast cancer metastases to bone are common in advanced stage disease. We have recently demonstrated that vitamin D deficiency enhances breast cancer growth in an osteolytic mouse model of breast cancer metastasis. In this study, we examined the effects of vitamin D deficiency on tumor growth in an osteosclerotic model of intra-skeletal breast cancer in mice. METHODS: The effects of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] on proliferation and apoptosis of MCF-7 breast cancer cells, and changes in the expression of genes within the vitamin D metabolic pathway (VDR, 1α- and 24-hydroxylase) were examined in vitro. MCF-7 breast cancer cells were injected intra-tibially into vitamin D deficient and vitamin D sufficient mice co-treated with and without osteoprotegerin (OPG). The development of tumor-related lesions was monitored via serial X-ray analysis. Tumor burden and indices of proliferation and apoptosis were determined by histology along with markers of bone turnover and serum intact PTH levels. RESULTS: In vitro, MCF-7 cells expressed critical genes for vitamin D signalling and metabolism. Treatment with 1,25(OH)(2)D(3) inhibited cell growth and proliferation, and increased apoptosis. In vivo, osteosclerotic lesions developed faster and were larger at endpoint in the tibiae of vitamin D deficient mice compared to vitamin D sufficient mice (1.49±0.08 mm(2) versus 1.68±0.15 mm(2), P<0.05). Tumor area was increased by 55.8% in vitamin D deficient mice (0.81±0.13 mm(2) versus 0.52±0.11 mm(2) in vitamin D sufficient mice). OPG treatment inhibited bone turnover and caused an increase in PTH levels, while tumor burden was reduced by 90.4% in vitamin D sufficient mice and by 92.6% in vitamin D deficient mice. Tumor mitotic activity was increased in the tibiae of vitamin D deficient mice and apoptosis was decreased, consistent with faster growth. CONCLUSION: Vitamin D deficiency enhances both the growth of tumors and the tumor-induced osteosclerotic changes in the tibiae of mice following intratibial implantation of MCF-7 cells. Enhancement of tumor growth appears dependent on increased bone resorption rather than increased bone formation induced by these tumors.


Assuntos
Neoplasias Ósseas/complicações , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Osteosclerose/complicações , Deficiência de Vitamina D/complicações , Ensaios Antitumorais Modelo de Xenoenxerto , Fosfatase Ácida/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/fisiopatologia , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Neoplasias da Mama/genética , Calcitriol/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoenzimas/metabolismo , Camundongos , Osteólise/complicações , Osteólise/patologia , Osteosclerose/enzimologia , Osteosclerose/patologia , Radiografia , Fosfatase Ácida Resistente a Tartarato , Carga Tumoral/efeitos dos fármacos , Deficiência de Vitamina D/patologia
5.
J Bone Miner Res ; 25(11): 2515-26, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20499337

RESUMO

Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss-of-function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB-CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss-of-function mutation in CLCN7 [Albers-Schönberg disease (A-SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age-appropriate controls, were persistent and essentially concordant in A-SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A-SD. LDH isoenzyme quantitation showed excesses of LDH-2, -3, and -4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate-induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP-5b and BB-CK also were markedly elevated in A-SD. Hence, high serum levels of several enzymes characterize A-SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency.


Assuntos
Aspartato Aminotransferases/sangue , Canais de Cloreto/deficiência , L-Lactato Desidrogenase/sangue , Osteosclerose/sangue , Osteosclerose/enzimologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Canais de Cloreto/metabolismo , Intervalos de Confiança , Creatina Quinase/sangue , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Isoenzimas/sangue , Masculino , Tamanho do Órgão , Osteopetrose/sangue , Osteopetrose/diagnóstico , Osteopetrose/enzimologia , Osteopetrose/patologia , Osteosclerose/diagnóstico , Osteosclerose/patologia , Valores de Referência
6.
Clin Pharmacol Ther ; 83(1): 172-6, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18073778

RESUMO

Osteoporosis is characterized by low bone mass with skeletal fragility and an increased risk of fracture. This bone loss is brought about by an imbalance between bone resorption and formation. Cathepsin K is the most abundant cysteine protease expressed in the osteoclast and is believed to be instrumental in bone matrix degradation necessary for bone resorption. Cathepsin K inhibitors represent a novel target for developing agents to treat osteoporosis and other disorders characterized by increased bone resorption.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Osteosclerose/tratamento farmacológico , Animais , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Catepsina K , Catepsinas/metabolismo , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/uso terapêutico , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Camundongos , Camundongos Knockout , Osteosclerose/enzimologia , Osteosclerose/fisiopatologia , Ovariectomia , Primatas , Coelhos , Ratos , Resultado do Tratamento
7.
Br J Haematol ; 123(3): 539-41, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14617021

RESUMO

It is proposed that a locally active, intrinsic renin-angiotensin system (RAS) exists in the bone marrow (BM) and plays a role in regulating haematopoiesis. Angiotensin II type I receptor has been detected on erythroid burst-forming unit-derived cells; its antagonist losartan and angiotensin I-converting enzyme (ACE) inhibitors can suppress erythropoiesis. The possible role of ACE/RAS in BM was investigated by evaluating ACE expression in normal BM, several myeloproliferative disorders and myelodysplasia. Immunohistochemical studies showed that erythroid elements expressed ACE protein in both normal and disturbed haematopoiesis. The presence of ACE in erythroid cells suggests another mechanism for direct ACE inhibitor activity in erythropoiesis.


Assuntos
Células Precursoras Eritroides/enzimologia , Transtornos Mieloproliferativos/enzimologia , Peptidil Dipeptidase A/análise , Anemia Refratária/enzimologia , Anemia Refratária com Excesso de Blastos/enzimologia , Anemia Sideroblástica/enzimologia , Humanos , Imuno-Histoquímica/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Osteosclerose/enzimologia
8.
FEBS Lett ; 401(2-3): 207-12, 1997 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-9013888

RESUMO

We examined the pathogenetic mechanism underlying the lack of bone resorption in osteosclerotic oc/oc mice. An immunoelectron microscopic analysis revealed that in the osteoclasts of these mice, no ruffled borders formed, and that vacuolar H+-ATPase (V-ATPase) was present throughout the cytoplasm but not on the apical membranes. The activity of V-ATPase in oc/oc mice was similar to that in normal mice. In normal spleen cell-derived osteoclast-like cells (OCLs), immunoreactivity for V-ATPase was detected in association with Triton X-100-insoluble cellular structure, but not in oc/oc spleen cell-derived OCLs. Moreover, in renal proximal convoluted tubules of oc/oc mice, the basal striation did not form. These results suggest that osteosclerosis in oc/oc mice is possibly due to the dissociation of V-ATPase and cytoskeleton in osteoclasts.


Assuntos
Adenosina Trifosfatases/metabolismo , Citoesqueleto/enzimologia , Osteoclastos/enzimologia , Osteosclerose/enzimologia , Animais , Reabsorção Óssea , Células Cultivadas , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/ultraestrutura , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Osteoclastos/ultraestrutura , Baço/citologia , Baço/metabolismo , Baço/ultraestrutura , Vacúolos/enzimologia
9.
Klin Wochenschr ; 67(7): 402-7, 1989 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-2787445

RESUMO

A patient with peripheral T-cell Lymphoma and acquired, systemic osteosclerosis is described. Bone histology showed a spectacular activation of osteoblasts accompanyed by massive new bone formation. Alkaline phosphatase in serum was elevated and increased to greater than 2000 U/l when the lymphoma became refractory to chemotherapy. In the patient's serum an osteoblast-activating factor could be demonstrated using a rat osteogenic osteosarcoma cell line (ROS 17/2.8). The factor was absent during remission of the tumor. We conclude that osteosclerosis was a paraneoplastic syndrome in this patient due to the secretion of an osteoblast-stimulating factor by the T-cell lymphoma. This situation is similar to the secretion of osteoclast-activating factors described in B-cell lymphomas, particularly multiple myeloma. The characterization of such a factor could be of therapeutic relevance.


Assuntos
Linfocinas/sangue , Linfoma não Hodgkin/enzimologia , Osteosclerose/enzimologia , Síndromes Paraneoplásicas/enzimologia , Linfócitos T , Adulto , Fosfatase Alcalina/sangue , Animais , Medula Óssea/patologia , Neoplasias Ósseas/patologia , Osso e Ossos/patologia , Linhagem Celular , Humanos , L-Lactato Desidrogenase/sangue , Linfoma não Hodgkin/patologia , Masculino , Osteossarcoma/patologia , Síndromes Paraneoplásicas/patologia , Ratos
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