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1.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33322030

RESUMO

Mechanotransduction is a physiological process in which external mechanical stimulations are perceived, interpreted, and translated by cells into biochemical signals. Mechanical stimulations exerted by extracellular matrix stiffness and cell-cell contacts are continuously applied to living cells, thus representing a key pivotal trigger for cell homeostasis, survival, and function, as well as an essential factor for proper organ development and metabolism. Indeed, a deregulation of the mechanotransduction process consequent to gene mutations or altered functions of proteins involved in perceiving cellular and extracellular mechanics can lead to a broad range of diseases, from muscular dystrophies and cardiomyopathies to cancer development and metastatization. Here, we recapitulate the involvement of focal adhesion kinase (FAK) in the cellular conditions deriving from altered mechanotransduction processes.


Assuntos
Doenças Ósseas/metabolismo , Cardiomiopatias/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Mecanotransdução Celular , Animais , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos
2.
Medicine (Baltimore) ; 99(22): e20406, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481432

RESUMO

BACKGROUND: Structural and functional changes in subchondral bone have been recognized as a key factor in the development of related disease, and subchondral bone may be a new target for the treatment of osteoarthritis. The purpose of our present study is to investigate the global status and trends of subchondral bone research. METHOD: Publications related to the studies of subchondral bone from 1993 to 2018 were retrieved from the Science Citation Index-Expanded Web of Science database. The data source was studied and indexed by using bibliometric methodology. For visualized study, bibliographic coupling analysis, co-authorship analysis, co-citation analysis, co-occurrence analysis and the analysis of publication trends in subchondral bone research were conducted by VOS viewer and GraphPadPrism 5 software. RESULTS: A total of 4780 publications were included. There is an increasing trend of the relative research interests and number of publications per year globally. The cumulative number of publications about subchondral bone research followed the logistic growth model (Equation is included in full-text article.). The USA made the highest contributions to the global research with the most citations, the highest H-index, and the most total link strength, while Denmark had the highest average citation per item. The journal Osteoarthritis and Cartilage had the largest publication number. Boston University is the most contributive institution. Studies could be divided into 4 clusters: "Mechanism research", "Animal study", "Clinical study" and "Pathological features". Less efforts were put into clinical study. CONCLUSION: The number of publications about subchondral bone research would be increasing in the next years based on the current global trends. Attention should be drawn to the latest popular research, including "Mesenchymal stem-cells", "Autologous chondrocyte implantation", "Microfracture" and "Pain". Therefore, more and more efforts will be put into mechanism research on subchondral bone, which may inspire new clinical treatments for osteoarthritis and other related diseases based on subchondral bone.


Assuntos
Bibliometria , Pesquisa Biomédica/estatística & dados numéricos , Osso e Ossos/metabolismo , Cartilagem/metabolismo , Animais , Doenças Ósseas/metabolismo , Doenças das Cartilagens/metabolismo , Humanos
4.
Nat Commun ; 11(1): 114, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913286

RESUMO

Stem cell therapies are limited by poor cell survival and engraftment. A hurdle to the use of materials for cell delivery is the lack of understanding of material properties that govern transplanted stem cell functionality. Here, we show that synthetic hydrogels presenting integrin-specific peptides enhance the survival, persistence, and osteo-reparative functions of human bone marrow-derived mesenchymal stem cells (hMSCs) transplanted in murine bone defects. Integrin-specific hydrogels regulate hMSC adhesion, paracrine signaling, and osteoblastic differentiation in vitro. Hydrogels presenting GFOGER, a peptide targeting α2ß1 integrin, prolong hMSC survival and engraftment in a segmental bone defect and result in improved bone repair compared to other peptides. Integrin-specific hydrogels have diverse pleiotropic effects on hMSC reparative activities, modulating in vitro cytokine secretion and in vivo gene expression for effectors associated with inflammation, vascularization, and bone formation. These results demonstrate that integrin-specific hydrogels improve tissue healing by directing hMSC survival, engraftment, and reparative activities.


Assuntos
Doenças Ósseas/terapia , Integrina alfa2beta1/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Doenças Ósseas/metabolismo , Doenças Ósseas/fisiopatologia , Medula Óssea/química , Medula Óssea/metabolismo , Regeneração Óssea , Adesão Celular , Sobrevivência Celular , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Hidrogéis/química , Integrina alfa2beta1/genética , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Peptídeos/metabolismo
5.
Int J Mol Sci ; 21(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973091

RESUMO

Forkhead box class O family member proteins (FoxOs) are evolutionarily conserved transcription factors for their highly conserved DNA-binding domain. In mammalian species, all the four FoxO members, FoxO1, FoxO3, FoxO4, and FoxO6, are expressed in different organs. In bone, the first three members are extensively expressed and more studied. Bone development, remodeling, and homeostasis are all regulated by multiple cell lineages, including osteoprogenitor cells, chondrocytes, osteoblasts, osteocytes, osteoclast progenitors, osteoclasts, and the intercellular signaling among these bone cells. The disordered FoxOs function in these bone cells contribute to osteoarthritis, osteoporosis, or other bone diseases. Here, we review the current literature of FoxOs for their roles in bone cells, focusing on helping researchers to develop new therapeutic approaches and prevent or treat the related bone diseases.


Assuntos
Osso e Ossos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Osteócitos/metabolismo , Fatores de Transcrição/metabolismo , Doenças Ósseas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem da Célula , Condrogênese/fisiologia , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Fatores de Transcrição Forkhead/classificação , Fatores de Transcrição Forkhead/genética , Células-Tronco Hematopoéticas , Osteoartrite/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/fisiologia , Osteoporose/metabolismo , Transdução de Sinais
6.
Med Sci Monit ; 26: e919159, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31996665

RESUMO

Osteopontin (OPN), a secreted phosphoprotein, is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of cell matrix proteins and participates in many biological activities. Studies have shown that OPN plays a role in bone metabolism and homeostasis. OPN not only is an important factor in neuron-mediated and endocrine-regulated bone mass, but also is involved in biological activities such as proliferation, migration, and adhesion of several bone-related cells, including bone marrow mesenchymal stem cells, hematopoietic stem cells, osteoclasts, and osteoblasts. OPN has been demonstrated to be closely related to the occurrence and development of many bone-related diseases, such as osteoporosis, rheumatoid arthritis, and osteosarcoma. As expected, the functions of OPN in the bone have become a research hotspot. In this article, we try to decipher the mechanism of OPN-regulated bone metabolism and bone diseases.


Assuntos
Doenças Ósseas/metabolismo , Osso e Ossos/metabolismo , Osteopontina/metabolismo , Animais , Desenvolvimento Ósseo , Osso e Ossos/patologia , Calcinose/patologia , Humanos , Tamanho do Órgão
7.
Biomater Sci ; 8(3): 884-896, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31822874

RESUMO

Recent studies on bone regeneration demonstrate the use of low cost and stable small molecules, which avoid the adverse effect and high cost of growth factors. Herein, we investigate the chemotactic, angiogenic and osteoinductive potential of a prostacyclin analogue, ONO-1301, when delivered through a biomimetic nanocomposite scaffold (nanohydroxyapatite-gelatin matrix reinforced with fibers) for bone tissue regeneration. The small molecule was loaded onto the scaffold in three different concentrations. There was burst release from all the groups of scaffolds within 24 h followed by a sustained release up to 14 days, but the concentration was dependent on loading percentage. ONO-1301 loaded scaffolds augmented the migration, proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs), but increasing the concentration beyond a certain dose did not show any effect. The osteoinduction was mediated through the prostaglandin I2 receptor and cyclic AMP (cAMP) signaling pathway. They also promoted new bone formation in large sized calvarial defects in rats compared to the scaffold alone, but did not show any impact on angiogenesis. Hence, this study suggests the chemotactic and osteoinductive capability of ONO-1301 for the repair and regeneration of critical sized bone defects.


Assuntos
Doenças Ósseas/terapia , AMP Cíclico/metabolismo , Nanocompostos/química , Piridinas/administração & dosagem , Tecidos Suporte/química , Animais , Doenças Ósseas/metabolismo , Doenças Ósseas/fisiopatologia , Regeneração Óssea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Piridinas/química , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
8.
Artigo em Inglês | MEDLINE | ID: mdl-31483238

RESUMO

BACKGROUND: Bone is an important tissue and its normal function requires tight coordination of transcriptional networks and signaling pathways, and many of these networks/ pathways are dysregulated in pathological conditions affecting cartilage and bones. Long non-coding RNA (lncRNA) refers to a class of RNAs with a length of more than 200 nucleotides, lack of protein-coding potential, and exhibiting a wide range of biological functions. Although studies on lcnRNAs are still in their infancy, they have emerged as critical players in bone biology and bone diseases. The functions and exact mechanism of bone-related lncRNAs have not been fully classified yet. OBJECTIVE: The objective of this article is to summarize the current literature on lncRNAs on the basis of their role in bone biology and diseases, focusing on their emerging molecular mechanism, pathological implications and therapeutic potential. DISCUSSION: A number of lncRNAs have been identified and shown to play important roles in multiple bone cells and bone disease. The function and mechanism of bone-related lncRNA remain to be elucidated. CONCLUSION: At present, majority of knowledge is limited to cellular levels and less is known on how lncRNAs could potentially control the development and homeostasis of bone. In the present review, we highlight some lncRNAs in the field of bone biology and bone disease. We also delineate some lncRNAs that might have deep impacts on understanding bone diseases and providing new therapeutic strategies to treat these diseases.


Assuntos
Desenvolvimento Ósseo , Doenças Ósseas/metabolismo , Remodelação Óssea , Osso e Ossos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Doenças Ósseas/genética , Doenças Ósseas/patologia , Doenças Ósseas/fisiopatologia , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais
9.
Aging Clin Exp Res ; 32(3): 363-371, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31119697

RESUMO

The skeleton is the framework and in charge of body configuration preservation. As a living tissue, bones are constantly being formed and absorbed. Osteoblasts and osteoclasts are the main bone cells and balance between their activities indicates bone health. Several mechanisms influence the bone turnover and RANKL/RANK/OPG pathway is one of them. This system, whose components are part of the tumor necrosis factor (TNF) superfamily, exists in many organs and could play a role in bone modeling and remodeling. RANKL/RANK pathway controls osteoclasts activity and formation. In addition, they are identified as key factors on bone turnover in different pathological situations. At the same time, OPG (RANKL's decoy receptor) plays role as a bone-protective factor by binding to RANKL and prevention of extra resorption. The lack of balance between RANKL and OPG could result in excessive bone resorption. Probiotics, the beneficial microorganisms for human health, entail bones in their advantages. Recent studies suggest that probiotics could reduce inflammatory factors (for example TNF-α and IL-1ß) and increase bone OPG expression. In addition, probiotics have shown to maintain bones in various ways. Although current evidence is not enough for definitive approval of probiotics' efficacy on RANKL/RANK/OPG, its positive responses from conducted studies are significant. Understanding of the probiotics' effects on RANKL/RANK/OPG pathway will help focus future studies, and assist in developing efficient treatment strategies.


Assuntos
Remodelação Óssea , Probióticos/farmacologia , Ligante RANK/metabolismo , Doenças Ósseas/metabolismo , Reabsorção Óssea/metabolismo , Humanos , Osteoblastos/metabolismo , Osteoclastos/metabolismo
10.
Sci Rep ; 9(1): 18175, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796797

RESUMO

Over the past years, the study about bone tissue engineering in the field of regenerative medicine has been a main research topic. Using three-dimensional (3D) porous degradable scaffold complexed with mesenchymal stem cells (MSCs) and growth factor gene to improve bone tissue repair and regeneration has raised much interest. This study mainly evaluated the osteogenesis of alveolar bone defects of animal in the following experimental groups: sham-operated (SO), 3D printed bioglass (3D-BG), 3D-BG with BMP-2 gene loaded CS (3D-BG + BMP/CS) and 3D-BG with rhesus marrow bone MSCs and BMP/CS (3D-BG + BMP/CS + rBMSCs). Simulated human bone defect with critical size of 10 × 10 × 5 mm were established in quadrumana - rhesus monkeys, and in vivo osteogenesis was characterized by X-ray, micro-Computed Tomography (mCT) and history. Our results revealed that 3D-BG + rBMSCs + BMP/CS scaffold could improve bone healing best by showing its promote osteogenic properties in vivo. Considering the great bone repair capacity of 3D-BG + BMP/CS + rBMSCs in humanoid primate rhesus monkeys, it could be a promising therapeutic strategy for surgery trauma or accidents, especially for alveolar bones defects.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Regeneração Óssea/fisiologia , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Cerâmica/farmacologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese/fisiologia , Animais , Doenças Ósseas/metabolismo , Doenças Ósseas/terapia , Proliferação de Células/fisiologia , Feminino , Macaca mulatta , Impressão Tridimensional , Engenharia Tecidual/métodos , Tecidos Suporte , Microtomografia por Raio-X/métodos
11.
Medicine (Baltimore) ; 98(51): e18431, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31861011

RESUMO

The aim of this study was to measure the urate volume within tophus and bone erosion volume using dual-energy computed tomography in patients with tophaceous gout. Furthermore, our study aims to quantitatively analyze the relationship between monosodium urate (MSU) crystal deposition and bone erosion according to the anatomic location of urate deposition.Seventy-seven subjects with chronic gout were positively identified for the presence of urate deposition. Only 27 subjects identified for the presence of urate in contact with bone erosion were included in this study. The urate volumes and associated erosion volumes were measured. The relationships between urate within tophus and bone erosion were separately analyzed according to the anatomic location of urate deposition.Twenty-seven subjects were all male (100%) with a median (interquartile range, IQR) age of 52 (45-61) years. From all the subjects, 103 tophi depositions were identified in contact with bone erosion, including 58/103 tophi that contained an intraosseous component and 45/103 nonintraosseous tophi. Tophi containing intraosseous components were larger than nonintraosseous tophi (urate volume: median [IQR] 45.64 [4.79-250.89] mm vs 19.32 [6.97-46.71] mm, P = .035) and caused greater bone erosion (erosion volume: 249.03 [147.08-845.33] mm vs 69.07 [32.88-111.24] mm, P < .001). Almost all erosion volumes were larger than urate volumes in nonperiarticular tophi, in contrast to most erosion volumes, which were less than urate volumes in the tophi that contained a periarticular component (odds ratio, 95% confidence interval: 74.00, 14.70-372.60; P < .001). Urate volume and erosion volume demonstrated positive correlations in intraosseous tophi, intraosseous-intra-articular-periarticular tophi, and intraosseous-intra-articular tophi (rs = 0.761, rs = 0.695, rs = 0.629, respectively, P < .05).MSU crystal deposition shows a promoting effect on the development of bone erosions in varying degrees, associated with the location of MSU crystals deposited in the joints. The intraosseous tophi contribute the most to bone erosions, followed by intra-articular tophi, and periarticular tophi.


Assuntos
Doenças Ósseas/etiologia , Gota/complicações , Ácido Úrico/metabolismo , Adulto , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/metabolismo , Gota/diagnóstico por imagem , Gota/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
12.
Int J Mol Sci ; 20(23)2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31810213

RESUMO

Mollusks have served as important sources of human food and medicine for a long time. Raw Pisidium coreanum, a freshwater bivalve of the phylum Mollusca, is used in traditional therapies in parts of Asia. However, the therapeutic effects of Pisidium coreanum on bone diseases are not known. We investigated the functional roles of Pisidium coreanum in osteoporotic bone diseases. Pisidium coreanum inhibited the differentiation of bone marrow-derived monocytic cells into mature osteoclasts in vitro. The ovariectomized mice that received oral administration of Pisidium coreanum showed improvements in both trabecular and cortical bones. This preventive activity of Pisidium coreanum against bone loss was due to limited osteoclast maturation with reduced osteoclast surface extent in trabecular bone tissue. The formation of large multinucleated osteoclasts in vitro was significantly decreased in response to Pisidium coreanum, consistent with the reduced expression levels of osteoclast markers and fusion-related genes, such as NFATc1, p65, integrin αvß3, DC-STAMP, OC-STAMP, Atp6v0d2, FAK, CD44, and MFR. These data suggest that Pisidium coreanum inhibits osteoclast differentiation by negatively regulating the fusion of mononuclear osteoclast precursors. Thus, our data demonstrate the ability of Pisidium coreanum to effectively prevent estrogen-deficient osteoporosis through inhibition of multinucleated osteoclast formation.


Assuntos
Bivalves , Doenças Ósseas/dietoterapia , Estrogênios/deficiência , Osteoporose/dietoterapia , Animais , Doenças Ósseas/metabolismo , Doenças Ósseas/fisiopatologia , Reabsorção Óssea/dietoterapia , Reabsorção Óssea/prevenção & controle , Diferenciação Celular/efeitos dos fármacos , Humanos , Camundongos , Osteoclastos/efeitos dos fármacos , Osteoporose/metabolismo , Alimentos Marinhos/análise
13.
Front Immunol ; 10: 2628, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787987

RESUMO

The innate immune system is equipped with a number of germ-line encoded soluble pattern recognition molecules (PRMs) that collectively mediate the humoral host response to infection and damage in cooperation with cells and tissues of the immune and non-immune compartments. Despite the impressive diversity in structure, source, and regulation across PRMs, these all share remarkably similar functions inasmuch as they recognize microbes and damaged tissues, activate complement, exert opsono-phagocytic activities, and regulate inflammation. The long pentraxin 3 (PTX3) is a prototypic soluble PRM. Long known as a major player in innate immunity, inflammation and matrix remodeling, only recently has PTX3 emerged as a mediator of bone homeostasis in rodents and humans. Ptx3-targeted mice exhibit reduced trabecular volume during bone development, and impaired callus mineralization following experimental fracture. The murine gene is expressed in vivo by non-hematopoietic periosteal cells in the early phases of fracture healing, and in vitro by maturing osteoblasts. Human osteoblasts do express the PTX3 protein, whose levels positively correlate with bone density in vivo and osteoblast proliferation and maturation in vitro, thus pointing to a role in bone deposition. Contrasting evidence, however, suggest osteoclastogenesis-promoting effects of PTX3, where its expression has been associated with periodontitis, arthritis, and bone metastasis, conditions hallmarked by inflammation and bone resorption. Here, we review past and recent literature on the functions exerted by this long pentraxin in bone biology, with major emphasis on physiological skeletal remodeling, fracture healing, and chronic diseases of the bone.


Assuntos
Osso e Ossos/fisiologia , Proteína C-Reativa/fisiologia , Componente Amiloide P Sérico/fisiologia , Animais , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Osso e Ossos/patologia , Proteína C-Reativa/genética , Doença Crônica , Consolidação da Fratura , Homeostase , Humanos , Componente Amiloide P Sérico/genética
14.
Chin Med J (Engl) ; 132(23): 2775-2782, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31856047

RESUMO

BACKGROUND: Despite a growing population of patients starting hemodialysis in China, little is known about markers of mineral bone disease (MBD) and their management. We present data on prevalence and correlates of hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism from the China Dialysis Outcomes and Practice Patterns Study (DOPPS), with evaluation of whether these laboratory markers triggered changes in management. METHODS: We compared the frequency of measurement and prevalence of poor control of MBD markers in China DOPPS with other DOPPS regions. We also used generalized estimating equations to assess correlates of MBD markers, and separate models to assess predictors of vitamin D and phosphate binder prescriptions in the China DOPPS. RESULTS: Severe hyperphosphatemia (>7 mg/dL) and secondary hyperparathyroidism (>600 pg/mL) were common (27% and 21% prevalence, respectively); both were measured infrequently (14.9% and 3.2% of patients received monthly measurements in China). Frequency of dialysis sessions was positively associated with hyperphosphatemia; presence of residual kidney function was negatively associated with both hyperphosphatemia and secondary hyperparathyroidism. Laboratory measures indicating poor control of MBD were not associated with subsequent prescription of active vitamin D or phosphate binder. CONCLUSIONS: There are substantial opportunities for improvement and standardization of MBD management in China. Development of country-specific guidelines may yield realistic targets and standardization of medication use accounting for availability and cost.


Assuntos
Hiperparatireoidismo Secundário/metabolismo , Hiperfosfatemia/metabolismo , Minerais/metabolismo , Diálise Renal , Adulto , Idoso , Doenças Ósseas/metabolismo , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/metabolismo
15.
Cells ; 8(12)2019 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-31847314

RESUMO

Nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of various genes involved in inflammation and the immune response. The activation of NF-κB occurs via two pathways: inflammatory cytokines, such as TNF-α and IL-1ß, activate the "classical pathway", and cytokines involved in lymph node formation, such as CD40L, activate the "alternative pathway". NF-κB1 (p50) and NF-κB2 (p52) double-knockout mice exhibited severe osteopetrosis due to the total lack of osteoclasts, suggesting that NF-κB activation is required for osteoclast differentiation. These results indicate that NF-κB may be a therapeutic target for inflammatory bone diseases, such as rheumatoid arthritis and periodontal disease. On the other hand, mice that express the dominant negative form of IκB kinase (IKK)-ß specifically in osteoblasts exhibited increased bone mass, but there was no change in osteoclast numbers. Therefore, inhibition of NF-κB is thought to promote bone formation. Taken together, the inhibition of NF-κB leads to "killing two birds with one stone": it suppresses bone resorption and promotes bone formation. This review describes the role of NF-κB in physiological bone metabolism, pathologic bone destruction, and bone regeneration.


Assuntos
Desenvolvimento Ósseo/fisiologia , Doenças Ósseas/metabolismo , NF-kappa B/metabolismo , Animais , Desenvolvimento Ósseo/genética , Doenças Ósseas/fisiopatologia , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Inflamação , NF-kappa B/fisiologia , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
16.
Cells ; 8(11)2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31731497

RESUMO

Androgens are not only essential for bone development but for the maintenance of bone mass. Therefore, conditions with androgen deficiency, such as male hypogonadism, androgen-insensitive syndromes, and prostate cancer with androgen deprivation therapy are strongly associated with bone loss and increased fracture risk. Here we summarize the skeletal effects of androgens-androgen receptors (AR) actions based on in vitro and in vivo studies from animals and humans, and discuss bone loss due to androgens/AR deficiency to clarify the molecular basis for the anabolic action of androgens and AR in bone homeostasis and unravel the functions of androgen/AR signaling in healthy and disease states. Moreover, we provide evidence for the skeletal benefits of androgen therapy and elucidate why androgens are more beneficial than male sexual hormones, highlighting their therapeutic potential as osteoanabolic steroids in improving bone fracture repair. Finally, the application of selective androgen receptor modulators may provide new approaches for the treatment of osteoporosis and fractures as well as building stronger bones in diseases dependent on androgens/AR status.


Assuntos
Androgênios/metabolismo , Doenças Ósseas/metabolismo , Osso e Ossos/metabolismo , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/metabolismo , Animais , Densidade Óssea/fisiologia , Modelos Animais de Doenças , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Osteoporose/metabolismo , Fatores Sexuais , Transdução de Sinais/fisiologia
17.
Fertil Steril ; 112(5): 775-781, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31731931

RESUMO

Human skeleton is a living tissue that performs structural and metabolic functions. It is not only the largest storehouse for calcium and other essential ions but also a depot for toxic chemicals faced by human body throughout life. Skeletal modeling starts at conception and then throughout life undergoes constant remodeling to adopt its shape and strength according to human needs. With the passage of time, like other tissues in the body, bones also bear the brunt of life and in this life long process loses its strength and vitality. Multiple genetic and environmental factors play an integral part in its formation, strength, and decline.


Assuntos
Remodelação Óssea/fisiologia , Osso e Ossos/citologia , Osso e Ossos/fisiologia , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Condrócitos/fisiologia , Dieta Saudável/tendências , Exercício Físico/fisiologia , Humanos , Osteoblastos/fisiologia , Osteoclastos/fisiologia
18.
Int J Mol Sci ; 20(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683648

RESUMO

Rheumatoid arthritis (RA) is a systemic disease that affects the osteoarticular system, associated with bone fragility and increased risk of fractures. Herein, we aimed to characterize the systemic impact of the rat collagen-induced arthritis (CIA) model and explore its combination with femoral bone defect (FD). The impact of CIA on endogenous mesenchymal stem/stromal cells (MSC) was also investigated. CIA induction led to enlarged, more proliferative, spleen and draining lymph nodes, with altered proportion of lymphoid populations. Upon FD, CIA animals increased the systemic myeloid cell proportions, and their expression of co-stimulatory molecules CD40 and CD86. Screening plasma cytokine/chemokine levels showed increased tumor necrosis factor-α (TNF-α), Interleukin (IL)-17, IL-4, IL-5, and IL-12 in CIA, and IL-2 and IL-6 increased in CIA and CIA+FD, while Fractalkine and Leptin were decreased in both groups. CIA-derived MSC showed lower metabolic activity and proliferation, and significantly increased osteogenic and chondrogenic differentiation markers. Exposure of control-MSC to TNF-α partially mimicked the CIA-MSC phenotype in vitro. In conclusion, inflammatory conditions of CIA led to alterations in systemic immune cell proportions, circulating mediators, and in endogenous MSC. CIA animals respond to FD, and the combined model can be used to study the mechanisms of bone repair in inflammatory conditions.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Doenças Ósseas/metabolismo , Citocinas/metabolismo , Sistema Imunitário/metabolismo , Mediadores da Inflamação/metabolismo , Animais , Células Cultivadas , Citocinas/sangue , Feminino , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/sangue , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Células Mieloides/metabolismo , Ratos Wistar
19.
FEBS J ; 286(24): 4832-4851, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31677330

RESUMO

Osteo-articular diseases are characterized by a dysregulation of joint and/or bone homeostasis. These include diseases affecting the joints originally, such as osteoarthritis and rheumatoid arthritis, or the bone, such as osteoporosis. Inflammation and the involvement of Wingless-related integration site (Wnt) signaling pathways are key pathophysiological features of these diseases resulting in tissue degradation by matrix-degrading enzymes, namely matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTs), secreted by the joint resident cells and/or by infiltrating immune cells. Activation of Wnt signaling pathways is modulated by different families of proteins, including Dickkopfs and the secreted Frizzled-related proteins (sFRPs). The sFRP family is composed of five secreted glycoproteins in mammals that regulate Wnt signaling in the extracellular compartment. Indeed, sFRPs are able to bind both to the soluble Wnt ligands and to their cell membrane receptors, the Frizzled proteins. Their expression profile is altered in osteo-articular diseases, suggesting that they could account for the abnormal activation of Wnt pathways. In the present article, we review how sFRPs are more than simple antagonists of the Wnt signaling pathways and discuss their pathophysiological relevance in the context of osteo-articular diseases. We detail their Wnt-dependent and their Wnt-independent roles, with a particular emphasis on their ability to modulate the inflammatory response and extracellular matrix (ECM) remodeling. We also discuss their potential therapeutic use with a focus on bone remodeling, osteo-articular cancers, and tissue engineering.


Assuntos
Doenças Ósseas/metabolismo , Osteoartrite/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Doenças Ósseas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Biológicos , Doenças Musculoesqueléticas/genética , Doenças Musculoesqueléticas/metabolismo , Osteoartrite/genética , Transporte Proteico/genética , Transporte Proteico/fisiologia , Proteínas Wnt/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
20.
Semin Immunopathol ; 41(5): 573-582, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31591677

RESUMO

Skeleton undergoes constant remodeling process to maintain healthy bone mass. However, in pathological conditions, bone remodeling is deregulated, resulting in unbalanced bone resorption and formation. Abnormal osteoclast formation and activation play a key role in osteolysis, such as in rheumatoid arthritis and osteoporosis. As potential therapeutic targets or biomarkers, miRNAs have gained rapidly growing research and clinical attention. miRNA-based therapeutics is recently entering a new era for disease treatment. Such progress is emerging in treatment of skeletal diseases. In this review, we discuss miRNA biogenesis, advances in the strategies for miRNA target identification, important miRNAs involved in osteoclastogenesis and disease models, their regulated mechanisms, and translational potential and challenges in bone homeostasis and related diseases.


Assuntos
Doenças Ósseas/etiologia , MicroRNAs/genética , Osteoclastos/metabolismo , Osteogênese/genética , Biossíntese de Proteínas , Doenças Ósseas/metabolismo , Doenças Ósseas/terapia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Interferência de RNA
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