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1.
Artigo em Inglês | MEDLINE | ID: mdl-33013696

RESUMO

Calcitonin is a small peptide hormone secreted from the parafollicular cells of the thyroid gland in response to an increase in serum calcium. The inhibition of osteoclastic resorption is the main mechanism by which calcitonin quickly decreases circulating calcium levels. Although calcitonin pharmacologically acts on osteoclasts to prevent bone resorption, the results of studies on genetically modified animals have shown that the physiological effect of calcitonin is in the inhibition of osteoblastic bone formation. Because the calcitonin receptor is only expressed in osteoclasts, the effect of calcitonin on osteoblasts maybe indirect and mediated via osteoclasts. Wnt ligands are involved in various aspects of skeletal biology, including bone remodeling and endochondral bone formation. Wnt10b has recently been recognized as a clastokine, and is potentially a therapeutic target for treating bone disorders. However, the extent to which Wnt signaling is involved in bone physiology and disease is not yet fully understood. We hypothesize that calcitonin indirectly increases osteoblastic bone formation by inducing Wnt10b expression in osteoclasts. Micro-CT analysis revealed reduced bone loss in calcitonin-treated ovariectomized rats. The serum of animals treated with calcitonin had decreased TRAP5b and CTX-1 but increased osteocalcin, P1NP, and Wnt10b. Immunohistochemistry staining showed that the level of Wnt10b in the femur was increased in calcitonin-treated groups as compared with control groups. Hematopoietic mononuclear cells were separated from rat femur and tibia bone marrow, and were induced into osteoclasts following treatment with M-CSF and RANKL. In these cells, immunoconfocal microscopy and Western blot analysis showed that calcitonin induced an increase in Wnt10b expression. In a culture of osteoblasts isolated from neonatal rat calvariae, the calcitonin-treated osteoclast supernatant showed an increase in mineralization, as indicated by ALP and alizarin red staining. Taken together, these results indicate that calcitonin induces bone formation by increasing the expression of Wnt10b in osteoclasts in ovariectomy-induced osteoporotic rats. The present study provides in-depth information about the effects of calcitonin on bone remodeling and will thus help in the development of future potential therapeutic strategies for postmenopausal osteoporosis.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Calcitonina/farmacologia , Fêmur/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Proteínas Wnt/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Calcitonina/uso terapêutico , Feminino , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Osteoclastos/metabolismo , Osteoporose/diagnóstico por imagem , Osteoporose/etiologia , Ovariectomia/efeitos adversos , Ratos , Ratos Sprague-Dawley , Microtomografia por Raio-X
2.
J Bone Miner Metab ; 36(5): 508-518, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28983668

RESUMO

Osteoporosis is a major health problem in postmenopausal women and the elderly that leads to fractures associated with substantial morbidity and mortality. Current osteoporosis therapies have significant drawbacks, and the risk of fragility fractures has not yet been eliminated. There remains an unmet need for a broader range of therapeutics. Previous studies have shown that YC-1 has important regulatory functions in the cardiovascular and nervous systems. Many of the YC-1 effector molecules in platelets, smooth muscle cells and neurons, such as cGMP and µ-calpain, also have important functions in osteoclasts. In this study, we explored the effects of YC-1 on bone remodeling and determined the potential of YC-1 as a treatment for postmenopausal osteoporosis. Micro-computed tomography of lumbar vertebrae showed that YC-1 significantly improved trabecular bone microarchitecture in ovariectomized rats compared with sham-operated rats. YC-1 also significantly reversed the increases in serum bone resorption and formation in these rats, as measured by enzyme immunoassays for serum CTX-1 and P1NP, respectively. Actin ring and pit formation assays and TRAP staining analysis showed that YC-1 inhibited osteoclast activity and survival. YC-1 induced extrinsic apoptosis in osteoclasts by activating caspase-3 and caspase-8. In osteoclasts, YC-1 stimulated µ-calpain activity and inhibited Src activity. Our findings provide proof-of-concept for YC-1 as a novel antiresorptive treatment strategy for postmenopausal osteoporosis, confirming an important role of nitric oxide/cGMP/protein kinase G signaling in bone.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/patologia , Indazóis/uso terapêutico , Osteoclastos/patologia , Ovariectomia , Actinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/enzimologia , Calpaína/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/enzimologia , Osteoclastos/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Microtomografia por Raio-X , Quinases da Família src/metabolismo
3.
Cell Transplant ; 24(8): 1555-70, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25198179

RESUMO

Type 1 diabetes mellitus is caused by T-cell-mediated autoimmune destruction of pancreatic ß-cells. Systemic administration of mesenchymal stem cells (MSCs) brings about their incorporation into a variety of tissues with immunosuppressive effects, resulting in regeneration of pancreatic islets. We previously showed that human MSCs isolated from Wharton's jelly (WJ-MSCs) represent a potential cell source to treat diabetes. However, the underlying mechanisms are unclear. The purpose of this study was to discern whether undifferentiated WJ-MSCs can differentiate into pancreatic insulin-producing cells (IPCs) and modify immunological responses in nonobese diabetic (NOD) mice. Undifferentiated WJ-MSCs underwent lentiviral transduction to express green fluorescent protein (GFP) and then were injected into the retro-orbital venous sinus of NOD mice. Seven days after transplantation, fluorescent islet-like cell clusters in the pancreas were apparent. WJ-MSC-GFP-treated NOD mice had significantly lower blood glucose and higher survival rates than saline-treated mice. Systemic and local levels of autoaggressive T-cells, including T helper 1 cells and IL-17-producing T-cells, were reduced, and regulatory T-cell levels were increased. Furthermore, anti-inflammatory cytokine levels were increased, and dendritic cells were decreased. At 23 days, higher human C-peptide and serum insulin levels and improved glucose tolerance were found. Additionally, WJ-MSCs-GFP differentiated into IPCs as shown by colocalization of human C-peptide and GFP in the pancreas. Significantly more intact islets and less severe insulitis were observed. In conclusion, undifferentiated WJ-MSCs can differentiate into IPCs in vivo with immunomodulatory effects and repair the destroyed islets in NOD mice.


Assuntos
Diabetes Mellitus Experimental/terapia , Células Secretoras de Insulina/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Linfócitos T/imunologia , Geleia de Wharton/citologia , Animais , Autoimunidade , Glicemia/análise , Peptídeo C/sangue , Diferenciação Celular , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Experimental/mortalidade , Diabetes Mellitus Experimental/patologia , Feminino , Humanos , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Taxa de Sobrevida , Linfócitos T/citologia , Linfócitos T/metabolismo
4.
J Neuroimmunol ; 250(1-2): 18-26, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22683190

RESUMO

OBJECTIVES: We previously found that antibodies in Tourette's syndrome (TS) patients' sera reacted with a 120 kDa protein from rat brain tissue. Here, we sought to identify this protein and determine if it was involved in TS pathogenesis. METHODS: The 120 kDa protein was identified using immunoprecipitation, Western blotting, and mass spectrometry. ELISAs were used to quantify anti-120 kDa protein antibodies in serum of interest using samples from 32 TS patients, 47 patients with attention deficit hyperactivity disorder (ADHD) and 14 healthy controls. Involvement of the 120 kDa protein in TS was confirmed using co-localisation assays with GH3 cells. TS sera were micro-infused into SD rats' brain striatum and their stereotypical behaviours were monitored. RESULTS: The brain protein was identified as hyperpolarisation-activated cyclic nucleotide channel 4 (HCN4). TS patients' sera contained significantly more anti-HCN4 antibodies than ADHD patient and control sera. After microinfusing TS serum, SD rats exhibited increased stereotyped tic behaviours, which were correlated with the amount of infused anti-HCN4 antibody. CONCLUSIONS: Anti-HCN4 antibodies in the brain might contribute to the pathogenesis of tic symptoms in TS patients. However, further studies are needed to investigate the validity of this animal model of TS induced by microinfusing anti-HCN4 antibody.


Assuntos
Autoanticorpos/imunologia , Autoimunidade/imunologia , Canais de Cátion Regulados por Nucleotídeos Cíclicos/imunologia , Proteínas Musculares/imunologia , Síndrome de Tourette/imunologia , Adolescente , Animais , Autoanticorpos/sangue , Autoantígenos/imunologia , Western Blotting , Criança , Ensaio de Imunoadsorção Enzimática , Feminino , Imunofluorescência , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Imunoprecipitação , Masculino , Canais de Potássio , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Síndrome de Tourette/sangue
5.
Res Vet Sci ; 86(2): 261-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18752819

RESUMO

Normal C3H/HeN female mice were used to develop an animal model of Taenia saginata asiatica oncosphere infection. The host cellular immune response in this model was analyzed by a cytokine enzyme-linked immunosorbent assay (cytokine ELISA) and flow cytometry. Tumor-like cysts containing cysticerci were recovered from the inoculation sites of female mice 7 weeks postinfection with the T. saginata asiatica oncospheres. A sharp increase and sustained elevation in the ability of spleen cells to produce interferon-gamma and interleukin (IL)-2 revealed that cellular immunity played an important role during the infection. An immediate increase in the levels of IL-6 at 1 week postinfection indicated the induction of a local acute inflammatory response. However, no significant change in the levels of IL-10 indicated that Th2 cells were not involved in this immune response. The patterns of cell distribution revealed by flow cytometry also supported the same finding. These results suggested that Th1 cells played a major role in the immune response in C3H/HeN mice during the early stages of the oncosphere infection and that the Th2 response was not induced during the stage of cysticercus formation.


Assuntos
Taenia saginata/imunologia , Teníase/imunologia , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imunidade Celular/imunologia , Interferon gama/imunologia , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Projetos Piloto , Baço/imunologia , Baço/parasitologia , Linfócitos T/imunologia , Teníase/parasitologia
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