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1.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502245

RESUMO

Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology.


Assuntos
Desenvolvimento Ósseo , Osteocalcina/metabolismo , Osteoporose/patologia , Vitamina K/metabolismo , Animais , Humanos , Osteoporose/metabolismo
2.
Int J Pharm ; 608: 121060, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500057

RESUMO

Osteoporosis is a major cause of morbidity, mortality, and economic burden worldwide. Despite being an effective in combating the bone-deteriorating disorders, bisphosphonates have several shortcomings including poor and variable bioavailability, low permeability, high toxicity, etc. In this study, we developed and optimized protransfersome formulation for the drug risedronate sodium (RIS-Na) with the goal of enhancing its bioavailability and hence patient compliance. Phase separation coacervation technique was utilized for development of optimized formulation. Optimization was achieved by using three-factor, three-level Box-Behnken design combined with Response Surface Methodology (RSM). This enabled us to decipher the effect of 3 independent variables (Phospholipid, Tween-80 and Sodium Deoxycholate) on three dependent parameters (entrapment efficiency, vesicle size and transdermal flux). Optimized formulation was further evaluated for pharmacokinetic and pharmacodynamic parameters. Smooth, spherical protransfersomes with a size of 260 ± 18 nm, having entrapment efficiency and flux of 80.4 ± 4.90% and 8.41 ± 0.148 µg/cm2/h, respectively were prepared. Ex vivo studies revealed a shorter lag time of 1.21 ± 0.18 h and higher flux associated with transdermal formulation. CLSM analysis further revealed better drug penetration (220 µm) through the skin in case of protransfersomes as compared to drug solution (72 µm). Additionally, biomechanical, biochemical, and histo-pathological studies further validated the results. Thus, it was concluded that protransfersome formulation has a great potential in providing better therapeutic efficacy of risedronate than its conventional counterpart.


Assuntos
Osteoporose , Absorção Cutânea , Administração Cutânea , Animais , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos , Humanos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Tamanho da Partícula , Ratos , Ratos Wistar , Pele/metabolismo
3.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502056

RESUMO

Skeletal tissue involves systemic adipose tissue metabolism and energy expenditure. MicroRNA signaling controls high-fat diet (HFD)-induced bone and fat homeostasis dysregulation remains uncertain. This study revealed that transgenic overexpression of miR-29a under control of osteocalcin promoter in osteoblasts (miR-29aTg) attenuated HFD-mediated body overweight, hyperglycemia, and hypercholesterolemia. HFD-fed miR-29aTg mice showed less bone mass loss, fatty marrow, and visceral fat mass together with increased subscapular brown fat mass than HFD-fed wild-type mice. HFD-induced O2 underconsumption, respiratory quotient repression, and heat underproduction were attenuated in miR-29aTg mice. In vitro, miR-29a overexpression repressed transcriptomic landscapes of the adipocytokine signaling pathway, fatty acid metabolism, and lipid transport, etc., of bone marrow mesenchymal progenitor cells. Forced miR-29a expression promoted osteogenic differentiation but inhibited adipocyte formation. miR-29a signaling promoted brown/beige adipocyte markers Ucp-1, Pgc-1α, P2rx5, and Pat2 expression and inhibited white adipocyte markers Tcf21 and Hoxc9 expression. The microRNA also reduced peroxisome formation and leptin expression during adipocyte formation and downregulated HFD-induced leptin expression in bone tissue. Taken together, miR-29a controlled leptin signaling and brown/beige adipocyte formation of osteogenic progenitor cells to preserve bone anabolism, which reversed HFD-induced energy underutilization and visceral fat overproduction. This study sheds light on a new molecular mechanism by which bone integrity counteracts HFD-induced whole-body fat overproduction.


Assuntos
Gordura Intra-Abdominal/metabolismo , Leptina/genética , MicroRNAs/metabolismo , Osteoblastos/metabolismo , Osteoporose/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leptina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Osteoblastos/citologia , Osteoporose/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Peroxissomos/metabolismo , Receptores Purinérgicos P2X5/genética , Receptores Purinérgicos P2X5/metabolismo , Simportadores/genética , Simportadores/metabolismo , Termogênese , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
4.
Nat Commun ; 12(1): 5330, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504093

RESUMO

Most autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME). The extent and nature of RME has been the subject of debate. Here we investigate the expression of several candidate RME genes in F1 hybrid mouse cells before and after differentiation, to define how they become persistently, monoallelically expressed. Clonal monoallelic expression is not present in embryonic stem cells, but we observe high frequencies of monoallelism in neuronal progenitor cells by assessing expression status in more than 200 clones. We uncover unforeseen modes of allelic expression that appear to be gene-specific and epigenetically regulated. This non-canonical allelic regulation has important implications for development and disease, including autosomal dominant disorders and opens up therapeutic perspectives.


Assuntos
Alelos , Desequilíbrio Alélico , Epigênese Genética , Doenças Musculares/genética , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/genética , Hidrolases Anidrido Ácido/genética , Hidrolases Anidrido Ácido/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Diferenciação Celular , Quimera , Células Clonais , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Dosagem de Genes , Frequência do Gene , Loci Gênicos , Impressão Genômica , Masculino , Camundongos , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Receptores de Ácido Caínico/genética , Receptores de Ácido Caínico/metabolismo
5.
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
6.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360948

RESUMO

Osteoporosis is one of the major bone disorders that affects both women and men, and causes bone deterioration and bone strength. Bone remodeling maintains bone mass and mineral homeostasis through the balanced action of osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively. The imbalance in bone remodeling is known to be the main cause of osteoporosis. The imbalance can be the result of the action of various molecules produced by one bone cell that acts on other bone cells and influence cell activity. The understanding of the effect of these molecules on bone can help identify new targets and therapeutics to prevent and treat bone disorders. In this article, we have focused on molecules that are produced by osteoblasts, osteocytes, and osteoclasts and their mechanism of action on these cells. We have also summarized the different pharmacological osteoporosis treatments that target different molecular aspects of these bone cells to minimize osteoporosis.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Osteoporose/metabolismo , Animais , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Humanos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/patologia
7.
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
8.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361085

RESUMO

A novel aptamer-based competitive drug screening platform for osteoporosis was devised in which fluorescence-labeled, sclerostin-specific aptamers compete with compounds from selected chemical libraries for the binding of immobilized recombinant human sclerostin to achieve high-throughput screening for potential small-molecule sclerostin inhibitors and to facilitate drug repurposing and drug discovery. Of the 96 selected inhibitors and FDA-approved drugs, six were shown to result in a significant decrease in the fluorescence intensity of the aptamer, suggesting a higher affinity toward sclerostin compared with that of the aptamer. The targets of these potential sclerostin inhibitors were correlated to lipid or bone metabolism, and several of the compounds have already been shown to be potential osteogenic activators, indicating that the aptamer-based competitive drug screening assay offered a potentially reliable strategy for the discovery of target-specific new drugs. The six potential sclerostin inhibitors suppressed the level of both intracellular and/or extracellular sclerostin in mouse osteocyte IDG-SW3 and increased alkaline phosphatase activity in IDG-SW3 cells, human bone marrow-derived mesenchymal stem cells and human fetal osteoblasts hFOB1.19. Potential small-molecule drug candidates obtained in this study are expected to provide new therapeutics for osteoporosis as well as insights into the structure-activity relationship of sclerostin inhibitors for rational drug design.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Aptâmeros de Nucleotídeos/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteócitos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Aptâmeros de Nucleotídeos/isolamento & purificação , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteócitos/citologia , Osteócitos/metabolismo , Osteoporose/metabolismo , Osteoporose/patologia
9.
Cells ; 10(7)2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34359938

RESUMO

Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca2+, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response.


Assuntos
Artrite/metabolismo , Doenças Cardiovasculares/metabolismo , Osteoporose/metabolismo , Pré-Albumina/metabolismo , Amiloide/química , Amiloide/metabolismo , Amiloidose/metabolismo , Animais , Humanos , Estresse Oxidativo , Pré-Albumina/química , Conformação Proteica , Estabilidade Proteica
10.
Nat Commun ; 12(1): 4974, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404802

RESUMO

Osteoporosis affects millions worldwide and is often caused by osteoclast induced bone loss. Here, we identify the cytoplasmic protein ELMO1 as an important 'signaling node' in osteoclasts. We note that ELMO1 SNPs associate with bone abnormalities in humans, and that ELMO1 deletion in mice reduces bone loss in four in vivo models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. Our transcriptomic analyses coupled with CRISPR/Cas9 genetic deletion identify Elmo1 associated regulators of osteoclast function, including cathepsin G and myeloperoxidase. Further, we define the 'ELMO1 interactome' in osteoclasts via proteomics and reveal proteins required for bone degradation. ELMO1 also contributes to osteoclast sealing zone on bone-like surfaces and distribution of osteoclast-specific proteases. Finally, a 3D structure-based ELMO1 inhibitory peptide reduces bone resorption in wild type osteoclasts. Collectively, we identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to osteoporosis and arthritis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doenças Ósseas Metabólicas/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Artrite/patologia , Reabsorção Óssea/metabolismo , Sistemas CRISPR-Cas , Feminino , Camundongos , Camundongos Knockout , Osteoprotegerina/deficiência , Ovariectomia , Transcriptoma , Microtomografia por Raio-X
11.
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
12.
J Biochem Mol Toxicol ; 35(9): e22837, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34227182

RESUMO

Rhaponticin is a constituent isolated from numerous medicinal herbs. It has been reported earlier that rhaponticin possesses numerous biological effects like antiallergic, antidiabetic, hepatoprotective, and antithrombosis. The goal of this exploration was to scrutinize the therapeutic potential of rhaponticin on ovariectomy (OVX)-triggered osteoporosis in rats. Female Sprague Dawley rats were arbitrarily allocated to a sham-operated control group I, group II, which underwent OVX, and groups III and IV that underwent OVX were administered with rhaponticin (10 and 20 mg/kg). Rhaponticin was supplemented orally after 4 weeks of OVX and continued for about 16 weeks. Our findings exhibit that rhaponticin prevented the BMD diminution of femurs, induced by OVX, and protected the worsening of trabecular microarchitecture that are assisted through a noteworthy decline in skeletal remodeling as noticed through the diminished status of bone markers in a dose-dependent manner (10 and 20 mg/kg). OVX rats treated with rhaponticin efficiently enhanced body weight, lipid profiles, uterine index, bone turnover markers, inflammatory markers, and augmented the incidence of calcium in the OVX rats. Rhaponticin was established to restrain the functions of acid phosphatase, estradiol, and bone gla protein in OVX rats. Also, rhaponticin displayed some beneficial effects on histomorphometric and histopathological examination. It was observed that tabular area and thickness were reinstated in sham control and rhaponticin-treated OVX rats. We recognized that rhaponticin did not induce a damaging outcome on the skeletal organization of OVX rats. Moreover, we denote that rhaponticin can be an exceptional agent for the treatment and deal with associated bone diseases.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osteoporose/prevenção & controle , Ovariectomia , Estilbenos/farmacologia , Animais , Osso Esponjoso/metabolismo , Osso Esponjoso/patologia , Feminino , Osteoporose/metabolismo , Osteoporose/patologia , Ratos , Ratos Sprague-Dawley
13.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207344

RESUMO

Osteoporosis is a chronic disease characterized by low bone mass caused by increased bone turnover and impaired bone microarchitecture. In treatment, we use antiresorptive or anabolic drugs, which usually have a unidirectional effect, i.e., they inhibit the activity of osteoclasts or stimulate the effect of osteoblasts. Strontium ranelate is an anti-osteoporosis drug with a unique mechanism of action (used primarily in postmenopausal women). Unlike other medicines, it has a multidirectional effect on bone tissue, intensifying osteoblastogenesis while inhibiting osteoclastogenesis. It turns out that this effect is demonstrated by strontium ions, an element showing physical and chemical similarity to calcium, the basic element that builds the mineral fraction of bone. As a result, strontium acts through the calcium-sensing receptor (CaSR) receptor in bone tissue cells. In recent years, there has been a significant increase in interest in the introduction of strontium ions in place of calcium ions in ceramics used as bone replacement materials for the treatment of bone fractures and defects caused by osteoporosis. The aim of this study was to summarize current knowledge about the role of strontium in the treatment of osteoporosis, its effects (in various forms), and the ways in which it is administered.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Osteoporose/tratamento farmacológico , Estrôncio/farmacologia , Animais , Conservadores da Densidade Óssea/uso terapêutico , Cálcio/metabolismo , Humanos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoporose/metabolismo , Estrôncio/uso terapêutico
14.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209461

RESUMO

Curcumin, an active component of the rhizome turmeric, has gained much attention as a plant-based compound with pleiotropic pharmacological properties. It possesses anti-inflammatory, antioxidant, hypoglycemic, antimicrobial, neuroprotective, and immunomodulatory activities. However, the health-promoting utility of curcumin is constrained due to its hydrophobic nature, water insolubility, poor bioavailability, rapid metabolism, and systemic elimination. Therefore, an innovative stride was taken, and complexes of metals with curcumin have been synthesized. Curcumin usually reacts with metals through the ß-diketone moiety to generate metal-curcumin complexes. It is well established that curcumin strongly chelates several metal ions, including boron, cobalt, copper, gallium, gadolinium, gold, lanthanum, manganese, nickel, iron, palladium, platinum, ruthenium, silver, vanadium, and zinc. In this review, the pharmacological, chemopreventive, and therapeutic activities of metal-curcumin complexes are discussed. Metal-curcumin complexes increase the solubility, cellular uptake, and bioavailability and improve the antioxidant, anti-inflammatory, antimicrobial, and antiviral effects of curcumin. Metal-curcumin complexes have also demonstrated efficacy against various chronic diseases, including cancer, arthritis, osteoporosis, and neurological disorders such as Alzheimer's disease. These biological activities of metal-curcumin complexes were associated with the modulation of inflammatory mediators, transcription factors, protein kinases, antiapoptotic proteins, lipid peroxidation, and antioxidant enzymes. In addition, metal-curcumin complexes have shown usefulness in biological imaging and radioimaging. The future use of metal-curcumin complexes may represent a new approach in the prevention and treatment of chronic diseases.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Artrite/tratamento farmacológico , Complexos de Coordenação/uso terapêutico , Curcumina/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Osteoporose/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Artrite/metabolismo , Artrite/patologia , Humanos , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Osteoporose/metabolismo , Osteoporose/patologia
15.
Biomed Pharmacother ; 139: 111697, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243614

RESUMO

Excessive osteoclast activity, along with relatively weak osteoblast function, is strongly associated with bone disease. Therefore, studies to identify novel anti-osteoporosis candidates with dual actions of inhibiting osteoclastogenesis and increasing osteoblastogenesis may provide an ideal approach for treating osteoporosis. Pitavastatin, an inhibitor of 3-hydroxy-3 methyl-glutaryl coenzyme A reductase, has demonstrated various pharmacological activities, including anti-inflammation, bone anabolic effects, vasodilation, and inhibition of revascularization; however, the precise effects and mechanisms of pitavastatin on the regulation of osteoblast and osteoclast activity need to be comprehensively elucidated. Herein, we demonstrated that pitavastatin is a potential candidate for treating osteoporosis by enhancing osteoblast differentiation and bone growth and inhibiting osteoclast differentiation and bone resorption. Pitavastatin exerted dose-dependent inhibitory effects on receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation, bone resorption, and osteoclast-specific marker gene expression. These inhibitory effects were achieved by inhibiting the Akt, NF-κB, and mitogen-activated protein kinase (p38, ERK, and JNK) signaling pathways, resulting in the downregulation of major transcription factors c-Fos and NFATc1. Furthermore, pitavastatin potentially stimulated osteoblast differentiation by activating alkaline phosphatase (ALP), enhancing mineralization by Alizarin Red S, and increasing the expression of osteoblastogenic marker genes such as runt-related transcription factor 2, ALP, osteocalcin, and collagen type 1 alpha. Furthermore, we evaluated the therapeutic potential of pitavastatin in ovariectomy-induced systematic bone loss based on micro-computed tomography and histological analysis of femurs. Our findings demonstrated a new function and mechanism for pitavastatin in bone remodeling, indicating its potential as a therapeutic candidate in treating osteoporosis by inhibiting osteoclastic resorption and promoting osteoblastic formation.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Ovariectomia/efeitos adversos , Quinolinas/farmacologia , Animais , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Biomolecules ; 11(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067783

RESUMO

Osteoclasts (OCs) are important cells that are involved in the regulation of bone metabolism and are mainly responsible for coordinating bone resorption with bone formation to regulate bone remodeling. The imbalance between bone resorption and formation significantly affects bone metabolism. When the activity of osteoclasts exceeds the osteoblasts, it results in a condition called osteoporosis, which is characterized by reduced bone microarchitecture, decreased bone mass, and increased occurrences of fracture. Molecules, including transcription factors, proteins, hormones, nucleic acids, such as non-coding RNAs, play an important role in osteoclast proliferation, differentiation, and function. In this review, we have highlighted the role of these molecules in osteoclasts regulation and osteoporosis. The developed therapeutics targeting these molecules for the treatment of osteoporosis in recent years have also been discussed with challenges faced in clinical application.


Assuntos
Produtos Biológicos/farmacologia , Osteoclastos/citologia , Osteoporose/patologia , Animais , Produtos Biológicos/uso terapêutico , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo
17.
Theranostics ; 11(14): 6717-6734, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093849

RESUMO

Rationale: Osteoporotic patients suffer symptoms of excessive osteoclastogenesis and impaired osteogenesis, resulting in a great challenge to treat osteoporosis-related bone defects. Based on the positive effect of rare earth elements on bone metabolism and bone regeneration, we try to prove the hypothesis that the La3+ dopants in lanthanum-substituted MgAl layered double hydroxide (La-LDH) nanohybrid scaffolds simultaneously activate osteogenesis and inhibit osteoclastogenesis. Methods: A freeze-drying technology was employed to construct La-LDH nanohybrid scaffolds. The in vitro osteogenic and anti-osteoclastogenic activities of La-LDH nanohybrid scaffolds were evaluated by using ovariectomized rat bone marrow stromal cells (rBMSCs-OVX) and bone marrow-derived macrophages (BMMs) as cell models. The in vivo bone regeneration ability of the scaffolds was investigated by using critical-size calvarial bone defect model of OVX rats. Results: La-LDH nanohybrid scaffolds exhibited three-dimensional macroporous structure, and La-LDH nanoplates arranged perpendicularly on chitosan organic matrix. The La3+ dopants in the scaffolds promote proliferation and osteogenic differentiation of rBMSCs-OVX by activating Wnt/ß-catenin pathway, leading to high expression of ALP, Runx-2, COL-1 and OCN genes. Moreover, La-LDH scaffolds significantly suppressed RANKL-induced osteoclastogenesis by inhibiting NF-κB signaling pathway. As compared with the scaffolds without La3+ dopants, La-LDH scaffolds provided more favourable microenvironment to induce new bone in-growth along macroporous channels. Conclusion: La-LDH nanohybrid scaffolds possessed the bi-directional regulation functions on osteogenesis and osteoclastogenesis for osteoporotic bone regeneration. The modification of La3+ dopants in bone scaffolds provides a novel strategy for osteoporosis-related bone defect healing.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Lantânio/farmacologia , Nanoestruturas/química , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Tecidos Suporte/química , Animais , Regeneração Óssea/genética , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Dioxigenases/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Lantânio/química , Macrófagos/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica de Transmissão , NF-kappa B/metabolismo , Nanoestruturas/ultraestrutura , Osteocalcina/metabolismo , Osteogênese/genética , Osteoporose/metabolismo , Ligante RANK/farmacologia , Ratos , Ratos Sprague-Dawley , Tomografia Computadorizada por Raios X , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
18.
FASEB J ; 35(7): e21740, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143911

RESUMO

Osteoporosis is the most common metabolic skeletal disease. It is characterized by the deterioration of the skeletal microarchitecture and bone loss, leading to ostealgia, and even bone fractures. Accumulating evidence has indicated that there is an inextricable relationship between the gut microbiota (GM) and bone homeostasis involving host-microbiota crosstalk. Any perturbation of the GM can play an initiating and reinforcing role in disrupting the bone remodeling balance during the development of osteoporosis. Although the GM is known to influence bone metabolism, the mechanisms associated with these effects remain unclear. Herein, we review the current knowledge of how the GM affects bone metabolism in health and disease, summarize the correlation between pathogen-associated molecular patterns of GM structural components and bone metabolism, and discuss the potential mechanisms underlying how GM metabolites regulate bone turnover. Deciphering the complicated relationship between the GM and bone health will provide new insights into the prevention and treatment of osteoporosis.


Assuntos
Osso e Ossos/metabolismo , Microbioma Gastrointestinal/fisiologia , Animais , Remodelação Óssea/fisiologia , Homeostase/fisiologia , Humanos , Osteoporose/metabolismo
19.
Molecules ; 26(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062884

RESUMO

Osteoporosis is a systemic metabolic bone disorder that is caused by an imbalance in the functions of osteoclasts and osteoblasts and is characterized by excessive bone resorption by osteoclasts. Targeting osteoclast differentiation and bone resorption is considered a good fundamental solution for overcoming bone diseases. ß-boswellic acid (ßBA) is a natural compound found in Boswellia serrata, which is an active ingredient with anti-inflammatory, anti-rheumatic, and anti-cancer effects. Here, we explored the anti-resorptive effect of ßBA on osteoclastogenesis. ßBA significantly inhibited the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by receptor activator of nuclear factor-B ligand (RANKL) and suppressed bone resorption without any cytotoxicity. Interestingly, ßBA significantly inhibited the phosphorylation of IκB, Btk, and PLCγ2 and the degradation of IκB. Additionally, ßBA strongly inhibited the mRNA and protein expression of c-Fos and NFATc1 induced by RANKL and subsequently attenuated the expression of osteoclast marker genes, such as OC-STAMP, DC-STAMP, ß3-integrin, MMP9, ATP6v0d2, and CtsK. These results suggest that ßBA is a potential therapeutic candidate for the treatment of excessive osteoclast-induced bone diseases such as osteoporosis.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Reabsorção Óssea , Regulação da Expressão Gênica , Osteoclastos/metabolismo , Fosfolipase C gama/metabolismo , Ligante RANK , Triterpenos/farmacologia , Animais , Boswellia , Diferenciação Celular , Técnicas de Cocultura , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Fosforilação , Transdução de Sinais
20.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34073015

RESUMO

Pentraxin 3 (PTX3) is a glycoprotein belonging to the humoral arm of innate immunity that participates in the body's defence mechanisms against infectious diseases. It has recently been defined as a multifunctional protein, given its involvement in numerous physiological and pathological processes, as well as in the pathogenesis of age-related diseases such as osteoporosis. Based on this evidence, the aim of our study was to investigate the possible role of PTX3 in both the osteoblastic differentiation and calcification process: to this end, primary osteoblast cultures from control and osteoporotic patients were incubated with human recombinant PTX3 (hrPTX3) for 72 h. Standard osteinduction treatment, consisting of ß-glycerophosphate, dexamethasone and ascorbic acid, was used as control. Our results showed that treatment with hrPTX3, as well as with the osteogenic cocktail, induced cell differentiation towards the osteoblastic lineage. We also observed that the treatment not only promoted an increase in cell proliferation, but also the formation of calcification-like structures, especially in primary cultures from osteoporotic patients. In conclusion, the results reported here suggest the involvement of PTX3 in osteogenic differentiation, highlighting its osteoinductive capacity, like the standard osteoinduction treatment. Therefore, this study opens new and exciting perspectives about the possible role of PTX3 as biomarker and therapeutic agent for osteoporosis.


Assuntos
Proteína C-Reativa/fisiologia , Osteoblastos , Osteogênese , Osteoporose/metabolismo , Componente Amiloide P Sérico/fisiologia , Calcificação Fisiológica , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Pessoa de Meia-Idade , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteoblastos/patologia , Cultura Primária de Células
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