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1.
Nutrients ; 13(8)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34444982

RESUMO

Several natural compounds, such as vitamin K2, have been highlighted for their positive effects on bone metabolism. It has been proposed that skeletal disorders, such as osteoporosis, may benefit from vitamin K2-based therapies or its regular intake. However, further studies are needed to better clarify the effects of vitamin K2 in bone disorders. To this aim, we developed in vitro a three-dimensional (3D) cell culture system one step closer to the bone microenvironment based on co-culturing osteoblasts and osteoclasts precursors obtained from bone specimens and peripheral blood of the same osteoporotic patient, respectively. Such a 3-D co-culture system was more informative than the traditional 2-D cell cultures when responsiveness to vitamin K2 was analyzed, paving the way for data interpretation on single patients. Following this approach, the anabolic effects of vitamin K2 on the osteoblast counterpart were found to be correlated with bone turnover markers measured in osteoporotic patients' sera. Overall, our data suggest that co-cultured osteoblasts and osteoclast precursors from the same osteoporotic patient may be suitable to generate an in vitro 3-D experimental model that potentially reflects the individual's bone metabolism and may be useful to predict personal responsiveness to nutraceutical or drug molecules designed to positively affect bone health.


Assuntos
Osso e Ossos/efeitos dos fármacos , Nutrientes/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose , Medicina de Precisão/métodos , Vitamina K 2/farmacologia , Biomarcadores/sangue , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Células Cultivadas , Técnicas de Cocultura/métodos , Feminino , Humanos , Masculino , Modelos Biológicos , Nutrientes/uso terapêutico , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Modelagem Computacional Específica para o Paciente , Vitamina K 2/uso terapêutico , Vitaminas/farmacologia , Vitaminas/uso terapêutico
2.
FASEB J ; 35(9): e21837, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34383985

RESUMO

Overwhelming evidence indicates that excessive stimulation of innate immune receptors of the NOD-like receptor (NLR) family causes significant damage to multiple tissues, yet the role of these proteins in bone metabolism is not well known. Here, we studied the interaction between the NLRP3 and NLRC4 inflammasomes in bone homeostasis and disease. We found that loss of NLRP3 or NLRC4 inflammasome attenuated osteoclast differentiation in vitro. At the tissue level, lack of NLRP3, or NLRC4 to a lesser extent, resulted in higher baseline bone mass compared to wild-type (WT) mice, and conferred protection against LPS-induced inflammatory osteolysis. Bone mass accrual in mutant mice correlated with lower serum IL-1ß levels in vivo. Unexpectedly, the phenotype of Nlrp3-deficient mice was reversed upon loss of NLRC4 as bone mass was comparable between WT mice and Nlrp3;Nlrc4 knockout mice. Thus, although bone homeostasis is perturbed to various degrees by the lack of NLRP3 or NLRC4, this tissue appears to function normally upon compound loss of the inflammasomes assembled by these receptors.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Diferenciação Celular/fisiologia , Homeostase/fisiologia , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/metabolismo , Osteólise/metabolismo
3.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360623

RESUMO

Investigations in male patients with fertility disorders revealed a greater risk of osteoporosis. The rodent model of experimental autoimmune-orchitis (EAO) was established to analyze the underlying mechanisms of male infertility and causes of reduced testosterone concentration. Hence, we investigated the impact of testicular dysfunction in EAO on bone status. Male mice were immunized with testicular homogenate in adjuvant to induce EAO (n = 5). Age-matched mice were treated with adjuvant alone (adjuvant, n = 6) or remained untreated (control, n = 7). Fifty days after the first immunization specimens were harvested. Real-time reverse transcription-PCR indicated decreased bone metabolism by alkaline phosphatase and Cathepsin K as well as remodeling of cell-contacts by Connexin-43. Micro computed tomography demonstrated a loss of bone mass and mineralization. These findings were supported by histomorphometric results. Additionally, biomechanical properties of femora in a three-point bending test were significantly altered. In summary, the present study illustrates the induction of osteoporosis in the investigated mouse model. However, results suggest that the major effects on bone status were mainly caused by the complete Freund's adjuvant rather than the autoimmune-orchitis itself. Therefore, the benefit of the EAO model to transfer laboratory findings regarding bone metabolism in context with orchitis into a clinical application is limited.


Assuntos
Doenças Autoimunes/complicações , Osso e Ossos/metabolismo , Orquite/complicações , Osteoporose/imunologia , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Doenças Autoimunes/fisiopatologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Orquite/metabolismo , Orquite/patologia , Orquite/fisiopatologia , Osteoporose/diagnóstico por imagem , Microtomografia por Raio-X
4.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445256

RESUMO

Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxytocin is synthetized by osteoblasts, and this synthesis is stimulated by estrogen. Animal studies demonstrate a direct action of oxytocin on bone, as the systemic administration of oxytocin prevents and reverses the bone loss induced by estrogen deficiency. Although oxytocin is involved in bone formation in both sexes during development, oxytocin treatment has no effect on male osteoporosis, underlining the importance of estrogen that amplifies its local autocrine and paracrine secretion. There are few human data showing a decrease in the oxytocin serum level in anorexia nervosa independently of estrogen and in amenorrheic women associated with impaired bone microarchitecture; in post-menopausal women a higher oxytocin serum level is associated with higher bone density, but not in osteoporotic men. Oxytocin displays many effects that may be beneficial in the management of osteoporosis, cardiovascular diseases, cognitive disorders, breast cancer, diabetes and body fat gain, all age-related diseases affecting elderly women, opening exciting therapeutic perspectives, although the issue is to find a single route, dosage and schedule able to reach all these targets.


Assuntos
Comunicação Autócrina , Densidade Óssea , Osso e Ossos/metabolismo , Ocitocina/metabolismo , Comunicação Parácrina , Caracteres Sexuais , Amenorreia/metabolismo , Animais , Anorexia Nervosa/metabolismo , Osso e Ossos/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Estrogênios/deficiência , Estrogênios/metabolismo , Feminino , Humanos , Masculino , Osteoporose Pós-Menopausa/metabolismo
5.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445808

RESUMO

Magnesium (Mg) is a pivotal and very complex component of healthy aging in the cardiovascular-muscle-bone triad. Low Mg levels and low Mg intake are common in the general aging population and are associated with poorer outcomes than higher levels, including vascular calcification, endothelial dysfunction, osteoporosis, or muscle dysfunction/sarcopenia. While Mg supplementation appears to reverse these processes and benefit the triad, more randomized clinical trials are needed. These will allow improvement of preventive and curative strategies and propose guidelines regarding the pharmaceutical forms and the dosages and durations of treatment in order to optimize and adapt Mg prescription for healthy aging and for older vulnerable persons with comorbidities.


Assuntos
Doenças Cardiovasculares/metabolismo , Magnésio/metabolismo , Osteoporose/metabolismo , Sarcopenia/metabolismo , Envelhecimento/metabolismo , Animais , Osso e Ossos/metabolismo , Envelhecimento Saudável/metabolismo , Humanos , Força Muscular/fisiologia , Músculo Esquelético/metabolismo
6.
Am J Hum Genet ; 108(9): 1710-1724, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450031

RESUMO

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.


Assuntos
Osso e Ossos/metabolismo , Complexo I de Proteína do Envoltório/genética , Proteína Coatomer/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Osteoporose/genética , Animais , Ácido Ascórbico/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Pré-Escolar , Complexo I de Proteína do Envoltório/deficiência , Proteína Coatomer/química , Proteína Coatomer/deficiência , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Embrião não Mamífero , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Complexo de Golgi , Haploinsuficiência , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Índice de Gravidade de Doença , Peixe-Zebra
7.
Nutrients ; 13(8)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34444729

RESUMO

Epidemiologic studies showed that higher vitamin K (VK) consumption correlates with a reduced risk of osteoporosis, yet the dispute remains about whether VK is effective in improving bone mineral density (BMD). We sought to discover the anti-osteoporotic effect of menaquinone-4 (MK-4) and evaluate the expression of critical genes related to bone formation and bone resorption pathways in the body. Fifty female C57BL/6 mice (aged 13 weeks) were randomly arranged to a sham-operated group (SHAM, treated with corn oil) and four ovariectomized groups that were administered corn oil (OVX group), estradiol valerate (EV, 2 mg/kg body weight as the positive control), low or high doses of VK (LVK and HVK; 20 and 40 mg MK-4/kg body weight, respectively) by gavage every other day for 12 weeks. Body and uterine weight, serum biochemical indicators, bone microarchitecture, hematoxylin-eosin (HE) staining, and the mRNA expression of critical genes related to bone formation and bone resorption pathways were assessed. Either dose of MK-4 supplementation increased the alkaline phosphatase (ALP), decreased the undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase (TRACP, p < 0.05) levels, and presented higher BMD, percent bone volume (BV/TV), trabecular thickness (Tb.Th), and lower trabecular separation (Tb.Sp) and structure model index (SMI, p < 0.05) compared with the OVX group. Additionally, both doses of MK4 increased the mRNA expression of Runx2 and Bmp2 (p < 0.05), whereas the doses down-regulated Pu.1 and Nfatc1 (p < 0.05) mRNA expression, the high dose decreased Osx and Tgfb (p < 0.05) mRNA expression, and the low dose decreased Mitd and Akt1 (p < 0.05) mRNA expression. These data show the dual regulatory effects of MK-4 on bone remodeling in ovariectomized mice: the promotion of bone anabolic activity and inhibition of osteoclast differentiation, which provides a novel idea for treating osteoporosis.


Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Vitamina K 2/análogos & derivados , Animais , Peso Corporal/efeitos dos fármacos , Remodelação Óssea/genética , Reabsorção Óssea/genética , Osso e Ossos/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Osteogênese/genética , Ovariectomia , Útero/efeitos dos fármacos , Vitamina K 2/administração & dosagem , Vitamina K 2/farmacologia
8.
Theranostics ; 11(16): 7715-7734, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335960

RESUMO

Rationale: Emerging evidence indicates that the growth of blood vessels and osteogenesis is tightly coordinated during bone development. However, the molecular regulators of intercellular communication in the bone microenvironment are not well studied. Therefore, we aim to investigate whether BMMSC-Exo promotes osteogenesis and angiogenesis via transporting lnc-H19 in the CBS- heterozygous mouse model. Methods: Using RT2 lncRNA PCR array screening, we identify a bone-specific, long noncoding RNA-H19 (lncRNA-H19/lnc-H19) in exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exo) during osteogenesis. Using bioinformatics analysis, we further discovered the seed sequence of miR-106a that could bind to lnc-H19. A luciferase reporter assay was performed to demonstrate the direct binding of miR-106a to the target gene angiopoietin 1 (Angpt1). We employed an immunocompromised Nude mouse model, to evaluate the effects of BMMSC-Exo on angiogenesis in vivo. Using a micro-CT scan, we monitored microstructural changes of bone in the experimental mice. Results: BMMSC-Exo possessed exosomal characteristics including exosome size, and typical markers including CD63, CD9, and TSD101. In vitro, BMMSC-Exo significantly promoted endothelial angiogenesis and osteogenesis. Mechanistic studies have shown that exosomal lnc-H19 acts as "sponges" to absorb miR-106 and regulate the expression of angiogenic factor, Angpt1 that activates lnc-H19/Tie2-NO signaling in mesenchymal and endothelial cells. Both of these effects on osteogenesis and angiogenesis are inhibited by antagonizing Tie2 signaling. Treatment of BMMSC-Exo also restored the bone formation and mechanical quality in vivo. Conclusion: These findings provide a novel insight into how the extracellular role of exosomal lnc-H19 affects osteogenesis and angiogenesis through competing endogenous RNA networks.


Assuntos
MicroRNAs/genética , Osteogênese/genética , RNA Longo não Codificante/genética , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Angiopoietina-1/fisiologia , Animais , Osso e Ossos/metabolismo , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Exossomos/genética , Genes Supressores de Tumor , Células-Tronco Mesenquimais/metabolismo , Camundongos , Neovascularização Patológica/genética , Óxido Nítrico/metabolismo , RNA Longo não Codificante/metabolismo , Receptor TIE-2/metabolismo , Receptor TIE-2/fisiologia , Transdução de Sinais/genética
9.
Theranostics ; 11(16): 7735-7754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335961

RESUMO

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the "vicious cycle" of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle, we orthogonally targeted nanomicelles (NM) loaded with non-therapeutic doses of a photosensitizer, titanocene (TC), to VLA-4 (α4ß1, CD49d/CD29) expressing MMC (MM1.S) and αvß3 (CD51/CD61) expressing OC. Concurrently, a non-lethal dose of a radiopharmaceutical, 18F-fluorodeoxyglucose ([18F]FDG) administered systemically interacted with TC (radionuclide stimulated therapy, RaST) to generate cytotoxic reactive oxygen species (ROS). The in vitro and in vivo effects of RaST were characterized in MM1.S cell line, as well as in xenograft and isograft MM animal models. Results: Our data revealed that RaST induced non-enzymatic hydroperoxidation of cellular lipids culminating in mitochondrial dysfunction, DNA fragmentation, and caspase-dependent apoptosis of MMC using VLA-4 avid TC-NMs. RaST upregulated the expression of BAX, Bcl-2, and p53, highlighting the induction of apoptosis via the BAK-independent pathway. The enhancement of multicopper oxidase enzyme F5 expression, which inhibits lipid hydroperoxidation and Fenton reaction, was not sufficient to overcome RaST-induced increase in the accumulation of irreversible function-perturbing α,ß-aldehydes that exerted significant and long-lasting damage to both DNA and proteins. In vivo, either VLA-4-TC-NM or αvß3-TC-NMs RaST induced a significant therapeutic effect on immunocompromised but not immunocompetent MM-bearing mouse models. Combined treatment with both VLA-4-TC-NM and αvß3-TC-NMs synergistically inhibited osteolysis, reduced tumor burden, and prevented rapid relapse in both in vivo models of MM. Conclusions: By targeting MM and bone cells simultaneously, combination RaST suppressed MM disease progression through a multi-prong action on the vicious cycle of bone cancer. Instead of using the standard multidrug approach, our work reveals a unique photophysical treatment paradigm that uses nontoxic doses of a single light-sensitive drug directed orthogonally to cancer and bone cells, followed by radionuclide-stimulated generation of ROS to inhibit tumor progression and minimize osteolysis in both immunocompetent murine and immunocompromised human MM models.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Compostos Organometálicos/farmacologia , Osteoclastos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Medula Óssea/metabolismo , Neoplasias Ósseas , Osso e Ossos/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fluordesoxiglucose F18/farmacologia , Humanos , Cadeias alfa de Integrinas/efeitos dos fármacos , Cadeias alfa de Integrinas/metabolismo , Camundongos , Mieloma Múltiplo/metabolismo , Compostos Organometálicos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteólise/patologia , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Nanomedicina Teranóstica/métodos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298935

RESUMO

In vitro evaluation of bone graft materials is generally performed by analyzing the interaction with osteoblasts or osteoblast precursors. In vitro bone models comprising different cell species can give specific first information on the performance of those materials. In the present study, a 3D co-culture model was established comprising primary human osteoblasts, osteoclasts and osteocytes. Osteocytes were differentiated from osteoblasts embedded in collagen gels and were cultivated with osteoblast and osteoclasts seeded in patterns on a porous membrane. This experimental setup allowed paracrine signaling as well as separation of the different cell types for final analysis. After 7 days of co-culture, the three cell species showed their typical morphology and gene expression of typical markers like ALPL, BSPII, BLGAP, E11, PHEX, MEPE, RANKL, ACP5, CAII and CTSK. Furthermore, relevant enzyme activities for osteoblasts (ALP) and osteoclasts (TRAP, CTSK, CAII) were detected. Osteoclasts in triple culture showed downregulated TRAP (ACP5) and CAII expression and decreased TRAP activity. ALP and BSPII expression of osteoblasts in triple culture were upregulated. The expression of the osteocyte marker E11 (PDPN) was unchanged; however, osteocalcin (BGLAP) expression was considerably downregulated both in osteoblasts and osteocytes in triple cultures compared to the respective single cultures.


Assuntos
Osso e Ossos/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteócitos/metabolismo , Idoso , Diferenciação Celular/genética , Células Cultivadas , Técnicas de Cocultura , Colágeno/metabolismo , Regulação para Baixo/genética , Feminino , Expressão Gênica/genética , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Regulação para Cima/genética
11.
Aging (Albany NY) ; 13(13): 17370-17379, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34198266

RESUMO

In this study, we used bioinformatics and an in vitro cellular model of glucocorticoid-induced osteoporosis to investigate mechanisms underlying the beneficial effects of baicalein (BN) against osteoporosis. STITCH database analysis revealed 30 BN-targeted genes, including AKT1, CCND1, MTOR, and PTEN. Functional enrichment analysis demonstrated that BN-targeted genes were enriched in 49 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. MIRWALK2.0 database analysis identified 110 enriched KEGG pathways related to osteoporosis. A Venn diagram demonstrated that 26 KEGG pathways were common between osteoporosis and BN-targeted genes. The top 5 common KEGG pathways were prostate cancer, bladder cancer, glioma, pathways in cancer, and melanoma. BN-targeted genes in the top 5 shared KEGG pathways were involved in PI3K-AKT, MAPK, p53, ErbB, and mTOR signaling pathways. In addition, glucocorticoid-induced osteoporosis in MC3T3-E1 cells was partially reversed by BN through inhibition of AKT, which, by upregulating FOXO1, enhanced expression of bone turnover markers (ALP, OCN, Runx2, and Col 1) and extracellular matrix mineralization. These findings demonstrate that BN suppresses osteoporosis via an AKT/FOXO1 signaling pathway.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Flavanonas/farmacologia , Proteína Forkhead Box O1/genética , Osteoporose/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Células 3T3 , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Calcificação Fisiológica/genética , Ciclina D1/genética , Bases de Dados Factuais , Matriz Extracelular/metabolismo , Proteína Forkhead Box O1/efeitos dos fármacos , Glucocorticoides , Humanos , Camundongos , Osteoporose/induzido quimicamente , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética
12.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204176

RESUMO

Age-related bone disorders such as osteoporosis or osteoarthritis are a major public health problem due to the functional disability for millions of people worldwide. Furthermore, fractures are associated with a higher degree of morbidity and mortality in the long term, which generates greater financial and health costs. As the world population becomes older, the incidence of this type of disease increases and this effect seems notably greater in those countries that present a more westernized lifestyle. Thus, increased efforts are directed toward reducing risks that need to focus not only on the prevention of bone diseases, but also on the treatment of persons already afflicted. Evidence is accumulating that dietary lipids play an important role in bone health which results relevant to develop effective interventions for prevent bone diseases or alterations, especially in the elderly segment of the population. This review focuses on evidence about the effects of dietary lipids on bone health and describes possible mechanisms to explain how lipids act on bone metabolism during aging. Little work, however, has been accomplished in humans, so this is a challenge for future research.


Assuntos
Envelhecimento/metabolismo , Osso e Ossos/metabolismo , Gorduras na Dieta/metabolismo , Animais , Autofagia/genética , Biomarcadores , Remodelação Óssea , Dieta , Instabilidade Genômica , Hormônios/metabolismo , Humanos , Osteíte/etiologia , Osteíte/metabolismo , Osteíte/patologia , Estresse Oxidativo
13.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208464

RESUMO

Piezo channels are mechanosensitive ion channels located in the cell membrane and function as key cellular mechanotransducers for converting mechanical stimuli into electrochemical signals. Emerged as key molecular detectors of mechanical forces, Piezo channels' functions in bone have attracted more and more attention. Here, we summarize the current knowledge of Piezo channels and review the research advances of Piezo channels' function in bone by highlighting Piezo1's role in bone cells, including osteocyte, bone marrow mesenchymal stem cell (BM-MSC), osteoblast, osteoclast, and chondrocyte. Moreover, the role of Piezo channels in bone diseases is summarized.


Assuntos
Osso e Ossos/metabolismo , Canais Iônicos/fisiologia , Animais , Doenças Ósseas , Condrócitos/metabolismo , Suscetibilidade a Doenças , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Canais Iônicos/agonistas , Canais Iônicos/antagonistas & inibidores , Canais Iônicos/química , Mecanotransdução Celular , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteócitos/metabolismo , Relação Estrutura-Atividade
14.
Nutrients ; 13(7)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210051

RESUMO

While in vitro and animal studies of osteoblastic and osteoclastic activity as well as bone resistance for copper are numerous, and the results encouraging in terms of regulation, human studies are scarce. The aim of this narrative review was to investigate the correlation of blood copper, daily copper intake, and copper supplementation with bone mineral density. This review included 10 eligible studies: five studies concerned copper blood levels, one study concerned daily copper intake, and four studies concerned copper supplementation. Blood copper levels did not show statistically significant differences in four of the studies analyzed, while only one study showed differences between osteoporotic and healthy women, although only with women between 45 and 59 years of age and not between 60 and 80 years of age. The dietary copper intake among women with or without osteoporosis did not show any differences. Only one study with a small sample of subjects carried out these assessments; therefore, it is a topic that the literature must deepen with further studies. The two studies that analyzed the integration of copper (2.5-3 mg/day) only showed good results in terms of slowing down bone mineral loss and reducing resorption markers, confirming the effectiveness of copper supplementation on bone metabolism.


Assuntos
Densidade Óssea/efeitos dos fármacos , Cobre/administração & dosagem , Cobre/sangue , Suplementos Nutricionais , Ingestão de Alimentos/fisiologia , Idoso , Idoso de 80 Anos ou mais , Reabsorção Óssea/sangue , Osso e Ossos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenômenos Fisiológicos da Nutrição , Osteoporose/sangue
15.
Electron. j. biotechnol ; 52: 52-58, July. 2021. tab, ilus
Artigo em Inglês | LILACS | ID: biblio-1283505

RESUMO

BACKGROUND: Osteoporosis attacks approximately 10% of the population worldwide. Sika Deer (Cervus nippon), one of China's precious traditional medicinal animals, has been widely recorded in ancient Chinese medical books and claimed for centuries to have numerous medical benefits including bone strengthening. This study aimed to find the use of Sika Deer bone in treating osteoporosis according to traditional records and to investigate the protective effect of Sika Deer bone polypeptide extract on glucocorticoidinduced osteoporosis (GIOP) in rats. RESULTS: Sika Deer bone polypeptide extract could increase serum Ca2+ and BGP, decrease serum P3+, ALP, PTH, and CT, but had no effect on serum NO in rats with GIOP. The immunohistochemical iNOS results of the rats' distal femur were negative in each group. Besides the model group, the eNOS color reaction in osteoblasts was strongly positive in the other three groups. CONCLUSIONS: Sika Deer bone polypeptide extract can improve pathological changes in the microstructure and stimulate the expression of eNOS in osteoblasts. The protective effect on bone might be mediated by eNOS-dependent NO generation.


Assuntos
Animais , Masculino , Ratos , Osteoporose/prevenção & controle , Peptídeos/farmacologia , Osso e Ossos/metabolismo , Cervos , Osteoblastos , Dexametasona , Ratos Wistar , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos
16.
Nutrients ; 13(5)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069053

RESUMO

A series of problems including osteopathy, abnormal serum data, and vascular calcification associated with chronic kidney disease (CKD) are now collectively called CKD-mineral bone disease (CKD-MBD). The pathophysiology of CKD-MBD is becoming clear with the emerging of αKlotho, originally identified as a progeria-causing protein, and bone-derived phosphaturic fibroblast growth factor 23 (FGF23) as associated factors. Meanwhile, compared with calcium and parathyroid hormone, which have long been linked with CKD-MBD, phosphate is now attracting more attention because of its association with complications and outcomes. Incidentally, as the pivotal roles of FGF23 and αKlotho in phosphate metabolism have been unveiled, how phosphate metabolism and hyperphosphatemia are involved in CKD-MBD and how they can be clinically treated have become of great interest. Thus, the aim of this review is reconsider CKD-MBD from the viewpoint of phosphorus, its involvement in the pathophysiology, causing complications, therapeutic approach based on the clinical evidence, and clarifying the importance of phosphorus management.


Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Fosfatos/metabolismo , Insuficiência Renal Crônica/complicações , Envelhecimento , Animais , Osso e Ossos/metabolismo , Cálcio/sangue , Fatores de Crescimento de Fibroblastos , Humanos , Hiperfosfatemia , Proteínas de Membrana/metabolismo , Hormônio Paratireóideo , Fósforo/sangue , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Calcificação Vascular
17.
Commun Biol ; 4(1): 658, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079065

RESUMO

It has not been well studied which cells and related mechanisms contribute to endochondral ossification. Here, we fate mapped the leptin receptor-expressing (LepR+) mesenchymal stem cells (MSCs) in different embryonic and adult extremities using Lepr-cre; tdTomato mice and investigated the underling mechanism using Lepr-cre; Ppp2r1afl/fl mice. Tomato+ cells appear in the primary and secondary ossification centers and express the hypertrophic markers. Ppp2r1a deletion in LepR+ MSCs reduces the expression of Runx2, Osterix, alkaline phosphatase, collagen X, and MMP13, but increases that of the mature adipocyte marker perilipin, thereby reducing trabecular bone density and enhancing fat content. Mechanistically, PP2A dephosphorylates Runx2 and BRD4, thereby playing a major role in positively and negatively regulating osteogenesis and adipogenesis, respectively. Our data identify LepR+ MSC as the cell origin of endochondral ossification during embryonic and postnatal bone growth and suggest that PP2A is a therapeutic target in the treatment of dysregulated bone formation.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteogênese/fisiologia , Proteína Fosfatase 2/metabolismo , Receptores para Leptina/metabolismo , Adipogenia , Animais , Densidade Óssea , Osso e Ossos/citologia , Osso e Ossos/embriologia , Osso e Ossos/metabolismo , Diferenciação Celular , Proliferação de Células , Condrogênese , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Fosforilação , Gravidez , Proteína Fosfatase 2/deficiência , Proteína Fosfatase 2/genética , Fatores de Transcrição/metabolismo
18.
Molecules ; 26(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063650

RESUMO

Coffee has been shown to attenuate sarcopenia, the age-associated muscle atrophy. Myostatin (MSTN), a member of the TGF-ß growth/differentiation factor superfamily, is a potent negative regulator of skeletal muscle mass, and MSTN-inhibition increases muscle mass or prevents muscle atrophy. This study, thus, investigated the presence of MSTN-inhibitory capacity in coffee extracts. The ethanol-extract of coffee silverskin (CSE) but not other extracts demonstrated anti-MSTN activity in a pGL3-(CAGA)12-luciferase reporter gene assay. CSE also blocked Smad3 phosphorylation induced by MSTN but not by GDF11 or Activin A in Western blot analysis, demonstrating its capacity to block the binding of MSTN to its receptor. Oral administration of CSE significantly increased forelimb muscle mass and grip strength in mice. Using solvent partitioning, solid-phase chromatography, and reverse-phase HPLC, two peaks having MSTN-inhibitory capacity were purified from CSE. The two peaks were identified as ßN-arachinoyl-5-hydroxytryptamide (C20-5HT) and ßN-behenoyl-5-hydroxytryptamide (C22-5HT) using mass spectrometry and NMR analysis. In summary, the results show that CSE has the MSTN-inhibitory capacity, and C20-5HT and C22-5HT are active components of CSE-suppressing MSTN activity, suggesting the potential of CSE, C20-5HT, and C22-5HT being developed as agents to combat muscle atrophy and metabolic syndrome.


Assuntos
Café/metabolismo , Músculo Esquelético/metabolismo , Músculos/efeitos dos fármacos , Miostatina/antagonistas & inibidores , Administração Oral , Animais , Glicemia/análise , Peso Corporal , Osso e Ossos/metabolismo , Etanol , Ácidos Graxos não Esterificados/metabolismo , Concentração Inibidora 50 , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/metabolismo , Solventes/química , Fator de Crescimento Transformador beta/metabolismo , Proteína Desacopladora 1/metabolismo
19.
Commun Biol ; 4(1): 683, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083709

RESUMO

In marine ecology, dietary interpretations of faunal assemblages often rely on nitrogen isotopes as the main or only applicable trophic level tracer. We investigate the geographic variability and trophic level isotopic discrimination factors of bone zinc 66Zn/64Zn ratios (δ66Zn value) and compared it to collagen nitrogen and carbon stable isotope (δ15N and δ13C) values. Focusing on ringed seals (Pusa hispida) and polar bears (Ursus maritimus) from multiple Arctic archaeological sites, we investigate trophic interactions between predator and prey over a broad geographic area. All proxies show variability among sites, influenced by the regional food web baselines. However, δ66Zn shows a significantly higher homogeneity among different sites. We observe a clear trophic spacing for δ15N and δ66Zn values in all locations, yet δ66Zn analysis allows a more direct dietary comparability between spatially and temporally distinct locations than what is possible by δ15N and δ13C analysis alone. When combining all three proxies, a more detailed and refined dietary analysis is possible.


Assuntos
Osso e Ossos/metabolismo , Cadeia Alimentar , Focas Verdadeiras/metabolismo , Ursidae/metabolismo , Isótopos de Zinco/análise , Animais , Regiões Árticas , Isótopos de Carbono/análise , Geografia , Biologia Marinha/métodos , Isótopos de Nitrogênio/análise , Reprodutibilidade dos Testes
20.
FASEB J ; 35(7): e21721, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118090

RESUMO

Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)--signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1S645P+/- ) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1S645P+/- animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.


Assuntos
Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Calcitriol/metabolismo , Transtornos do Crescimento/metabolismo , Janus Quinase 1/metabolismo , Transdução de Sinais/fisiologia , Animais , Remodelação Óssea/fisiologia , Proliferação de Células/fisiologia , Condrócitos/metabolismo , Condrócitos/fisiologia , Citocinas/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/fisiologia , Homeostase/fisiologia , Humanos , Inflamação/metabolismo , Rim/metabolismo , Rim/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Mutação/genética , Hormônio Paratireóideo/metabolismo , Fator de Transcrição STAT3/metabolismo
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