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1.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360579

RESUMO

Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mortality worldwide. Multiple stem cell types have been safely transferred into failing human hearts, but the overall clinical cardiovascular benefits have been modest. Therefore, there is a dire need to understand the basic biology of stem cells to enhance therapeutic effects. Bmi1 is part of the polycomb repressive complex 1 (PRC1) that is involved in different processes including proliferation, survival and differentiation of stem cells. We isolated cortical bones stem cells (CBSCs) from bone stroma, and they express significantly high levels of Bmi1 compared to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs). Using lentiviral transduction, Bmi1 was knocked down in the CBSCs to determine the effect of loss of Bmi1 on proliferation and survival potential with or without Bmi1 in CBSCs. Our data show that with the loss of Bmi1, there is a decrease in CBSC ability to proliferate and survive during stress. This loss of functionality is attributed to changes in histone modification, specifically histone 3 lysine 27 (H3K27). Without the proper epigenetic regulation, due to the loss of the polycomb protein in CBSCs, there is a significant decrease in cell cycle proteins, including Cyclin B, E2F, and WEE as well as an increase in DNA damage genes, including ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR). In conclusion, in the absence of Bmi1, CBSCs lose their proliferative potential, have increased DNA damage and apoptosis, and more cell cycle arrest due to changes in epigenetic modifications. Consequently, Bmi1 plays a critical role in stem cell proliferation and survival through cell cycle regulation, specifically in the CBSCs. This regulation is associated with the histone modification and regulation of Bmi1, therefore indicating a novel mechanism of Bmi1 and the epigenetic regulation of stem cells.


Assuntos
Apoptose , Proliferação de Células , Osso Cortical/citologia , Epigênese Genética , Histonas/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Células-Tronco/citologia , Animais , Ciclo Celular , Diferenciação Celular , Células Cultivadas , Osso Cortical/lesões , Osso Cortical/metabolismo , Dano ao DNA , Histonas/genética , Camundongos , Camundongos Endogâmicos C57BL , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Células-Tronco/metabolismo
2.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207309

RESUMO

Secondary hyperparathyroidism and abnormalities in tryptophan (TRP) metabolism are commonly observed in chronic kidney disease (CKD). The present study aimed to establish potential interactions between endogenous parathyroid hormone (PTH) and activation of the bone kynurenine (KYN) pathway in relation to bone turnover and strength in young rats after one month (CKD-1) and three months (CKD-3) of experimental CKD. TRP, KYN, KYN/TRP ratio and bone turnover markers (BTMs) were measured in trabecular and cortical bone tissue. Expression of aryl hydrocarbon receptor (AhR) and the genes involved in osteogenesis was determined in femoral bone. Biomechanical testing of femoral diaphysis and femoral neck was also performed. Activation of the KYN pathway in trabecular bone during CKD development intensified the expression of genes related to osteogenesis, which led to a decrease in cyclic adenosine monophosphate (cAMP) and BTMs levels, resulting in a stiffer and mechanically weaker femoral neck. In contrast, reduction of the KYN pathway in cortical bone allowed to unblock the PTH-dependent anabolic activating transcription factor 4/parathyroid hormone 1 receptor (PTH1R/ATF4) axis, led to cAMP accumulation, better bone turnover and strength in the course of CKD development. In summary, the paracrine KYN pathway in bone can interfere with the anabolic effects of PTH on bone through disrupting PTH-dependent molecular signaling.


Assuntos
Fêmur/metabolismo , Cinurenina/metabolismo , Comunicação Parácrina , Hormônio Paratireóideo/metabolismo , Transdução de Sinais , Uremia/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Animais , Osso Esponjoso/metabolismo , Osso Cortical/metabolismo , AMP Cíclico/metabolismo , Masculino , Ratos , Ratos Wistar , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo
3.
PLoS One ; 16(4): e0250438, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33891630

RESUMO

Chronic kidney disease (CKD) causes bone loss, particularly in cortical bone, through formation of cortical pores which lead to skeletal fragility. Animal models of CKD have shown variability in the skeletal response to CKD between males and females suggesting sex may play a role in this variation. Our aim was to compare the impact of adenine-induced CKD on cortical parameters in skeletally mature male and female C57Bl/6 mice. After 10-weeks of adenine-induced CKD, both male and female adenine mice had high serum parathyroid hormone (PTH), high bone turnover, and cortical porosity compared to non-CKD controls. Both sexes had lower cortical thickness, but only male mice had lower cortical bone area. CKD imparted greater deficits in mechanical properties of male mice compared to female mice. These data demonstrate that both male and female mice develop high PTH/high bone turnover in response to adenine-induced CKD and that cortical bone phenotypes are slightly more severe in males, particularly in mechanical properties deficits.


Assuntos
Adenina/farmacologia , Doenças Ósseas Metabólicas/genética , Hormônio Paratireóideo/sangue , Insuficiência Renal Crônica/genética , Adenina/efeitos adversos , Animais , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/patologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso Cortical/metabolismo , Osso Cortical/patologia , Dieta , Modelos Animais de Doenças , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Fêmur/patologia , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fenótipo , Porosidade/efeitos dos fármacos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Caracteres Sexuais
4.
Sci Rep ; 11(1): 7012, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33782429

RESUMO

Bone is a biological composite material consisting of two main components: collagen and mineral. Collagen is the most abundant protein in vertebrates, which makes it of high clinical and scientific interest. In this paper, we compare the composition and structure of cortical bone demineralized using several protocols: ethylene-diamine-tetraacetic acid (EDTA), formic acid (CH2O2), hydrochloric acid (HCl), and HCl/EDTA mixture. The efficiencies of these four agents were investigated by assessing the remaining mineral quantities and collagen integrity with various experimental techniques. Raman spectroscopy results show that the bone demineralized by the CH2O2 agent has highest collagen quality parameter. The HCl/EDTA mixture removes the most mineral, but it affects the collagen secondary structure as amide II bands are shifted as observed by Fourier transform infrared spectroscopy. Thermogravimetric analysis reveals that HCl and EDTA are most effective in removing the mineral with bulk measurements. In summary, we conclude that HCl best demineralizes bone, leaving the well-preserved collagen structure in the shortest time. These findings guide on the best demineralization protocol to obtain high-quality collagen from bone for clinical and scientific applications.


Assuntos
Técnica de Desmineralização Óssea/classificação , Técnica de Desmineralização Óssea/métodos , Colágeno/química , Osso Cortical/metabolismo , Animais , Suínos
5.
Int J Mol Sci ; 22(4)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572215

RESUMO

Estrogen receptor-α knockout (ERKO) in female, but not male, mice results in an impaired osteogenic response to exercise, but the mechanisms behind this ability in males are unknown. We explored the main and interactive effects of ERKO and exercise on cortical geometry, trabecular microarchitecture, biomechanical strength, and sclerostin expression in male mice. At 12 weeks of age, male C57BL/6J ERKO and WT animals were randomized into two groups: exercise treatment (EX) and sedentary (SED) controls, until 22 weeks of age. Cortical geometry and trabecular microarchitecture were measured via µCT; biomechanical strength was assessed via three-point bending; sclerostin expression was measured via immunohistochemistry. Two-way ANOVA was used to assess sclerostin expression and trabecular microarchitecture; two-way ANCOVA with body weight was used to assess cortical geometry and biomechanical strength. ERKO positively impacted trabecular microarchitecture, and exercise had little effect on these outcomes. ERKO significantly impaired cortical geometry, but exercise was able to partially reverse these negative alterations. EX increased cortical thickness regardless of genotype. There were no effects of genotype or exercise on sclerostin expression. In conclusion, male ERKO mice retain the ability to build bone in response to exercise, but altering sclerostin expression is not one of the mechanisms involved.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Osso Cortical/crescimento & desenvolvimento , Receptor alfa de Estrogênio/genética , Osteogênese/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Remodelação Óssea/fisiologia , Osso Cortical/diagnóstico por imagem , Osso Cortical/metabolismo , Receptor alfa de Estrogênio/metabolismo , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Corrida/fisiologia , Microtomografia por Raio-X
6.
J Bone Miner Metab ; 39(3): 404-415, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33044569

RESUMO

INTRODUCTION: Bone mass was recently reported to be related to skeletal muscle mass in humans, and a decrease in cortical bone is a risk factor for osteoporosis. Because circulating myostatin is a factor that primarily controls muscle metabolism, this study examined the role of myostatin in bone mass-skeletal muscle mass interactions. METHODS: The subjects were 375 middle-aged community residents with no history of osteoporosis or sarcopenia who participated in a health check-up. Cortical bone thickness and cancellous bone density were measured by ultrasonic bone densitometry in a health check-up survey. The subjects were divided into those with low cortical bone thickness (LCT) or low cancellous bone density (LBD) and those with normal values (NCT/NBD). Bone metabolism markers (TRACP-5b, etc.), skeletal muscle mass, serum myostatin levels, and lifestyle were then compared between the groups. RESULTS: The percentage of diabetic participants, TRACP-5b, and myostatin levels were significantly higher, and the frequency of physical activity, skeletal muscle mass, grip strength, and leg strength were significantly lower in the LCT group than in the NCT group. The odds ratio (OR) of high myostatin levels in the LCT group compared with the NCT group was significant (OR 2.17) even after adjusting for related factors. Between the low cancellous bone density (LBD) and normal cancellous bone density (NBD) groups, significant differences were observed in the same items as between the LCT and NCT groups, but no significant differences were observed in skeletal muscle mass and blood myostatin levels. The myostatin level was significantly negatively correlated with cortical bone thickness and skeletal muscle mass. CONCLUSIONS: A decrease in cortical bone thickness was associated with a decrease in skeletal muscle mass accompanied by an increase in the blood myostatin level. Blood myostatin may regulate the bone-skeletal muscle relationship and serve as a surrogate marker of bone metabolism, potentially linking muscle mass to bone structure.


Assuntos
Biomarcadores/metabolismo , Osso Cortical/metabolismo , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Adulto , Densidade Óssea/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Tamanho do Órgão , Análise de Regressão
7.
J Biol Chem ; 296: 100177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33303631

RESUMO

Increasing evidence emphasizes the importance of chemokines and chemokine receptors as regulators of bone remodeling. The C-C chemokine receptor 3 (CCR3) is dramatically upregulated during osteoclastogenesis, but the role of CCR3 in osteoclast formation and bone remodeling in adult mice is unknown. Herein, we used bone marrow macrophages derived from adult male CCR3-proficient and CCR3-deficient mice to study the role of CCR3 in osteoclast formation and activity. CCR3 deficiency was associated with formation of giant hypernucleated osteoclasts, enhanced bone resorption when cultured on bone slices, and altered mRNA expression of related chemokine receptors and ligands. In addition, primary mouse calvarial osteoblasts isolated from CCR3-deficient mice showed increased mRNA expression of the osteoclast activator-related gene, receptor activator of nuclear factor kappa-B ligand, and osteoblast differentiation-associated genes. Microcomputed tomography analyses of femurs from CCR3-deficient mice revealed a bone phenotype that entailed less cortical thickness and volume. Consistent with our in vitro studies, the total number of osteoclasts did not differ between the genotypes in vivo. Moreover, an increased endocortical osteoid mineralization rate and higher trabecular and cortical bone formation rate was displayed in CCR3-deficient mice. Collectively, our data show that CCR3 deficiency influences osteoblast and osteoclast differentiation and that it is associated with thinner cortical bone in adult male mice.


Assuntos
Osso e Ossos/patologia , Osso Cortical/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Ligante RANK/metabolismo , Receptores CCR3/deficiência , Animais , Osso e Ossos/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Osso Cortical/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteoclastos/patologia , Receptores CCR3/genética , Receptores CCR3/metabolismo , Microtomografia por Raio-X/métodos
8.
PLoS One ; 15(12): e0243294, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33270744

RESUMO

OBJECTIVES: Mechanical and biochemical bone properties are influenced by muscles. However, the muscle-bone interaction has not been fully elucidated regarding the upper extremities. The objective of the present study was to evaluate the mechanical muscle-bone interaction at the forearm by evaluating the relationship between the properties of three-dimensional (3D) forearm cortical bone models derived from conventional computed tomography (CT) images and handgrip strength (HGS). METHODS: A total of 108 women (mean age, 75.2 ± 9.4 years; range, 62-101 years) with a distal radius fracture who took conventional CT scans for the assessment of the fracture were included in this study. Distal radius 3D models were reconstructed and the average cortical bone density (Cd) and thickness (Ct) of the region of interest (ROI), which might be affected by the forearm flexor muscles, were calculated using a 3D modeling software. Clinical parameters including HGS, lumbar and hip bone mineral densities (BMDs), and other demographic factors were also obtained. A multivariate linear regression analysis was performed to identify relevant factors associated with HGS. RESULTS: HGS was found to be independently associated with height and Cd, but no significant difference was found between HGS and Ct, age, weight, as well as lumber and hip BMDs. CONCLUSIONS: Cortical bone density might be associated with HGS, which is generated by the forearm flexor muscles. Hence, the mechanical muscle-bone interaction in the upper extremities could be supported by the present study.


Assuntos
Densidade Óssea , Osso Cortical , Força da Mão , Fraturas do Rádio , Rádio (Anatomia) , Tomografia Computadorizada por Raios X , Idoso , Idoso de 80 Anos ou mais , Osso Cortical/diagnóstico por imagem , Osso Cortical/metabolismo , Osso Cortical/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/metabolismo , Rádio (Anatomia)/fisiopatologia , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/metabolismo , Fraturas do Rádio/fisiopatologia , Estudos Retrospectivos
9.
Sci Rep ; 10(1): 21804, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311522

RESUMO

Previous studies examining the role of the histone deacetylase Hdac3 within myeloid cells demonstrated that Hdac3 promotes M2 activation and tissue healing in inflammatory conditions. Since myeloid lineage cells are required for proper bone formation and regeneration, in this study we examined the functions of Hdac3 during bone healing. Conditional deletion of Hdac3 within myeloid progenitors accelerates healing of cortical bone defects. Moreover, reduced osteoclast numbers within the defect site are correlated with Hdac3 suppression. Ex vivo osteoclastogenesis assays further demonstrate that Hdac3 deficiency limits osteoclastogenesis, the number of nuclei per cell and bone resorption, suggesting a defect in cell fusion. High throughput RNA sequencing identified the transmembrane protein Pmepa1 as a differentially expressed gene within osteoclast progenitor cells. Knockdown of Pmepa1 partially restores defects in osteoclastogenesis induced by Hdac3 deficiency. These results show that Hdac3 is required for optimal bone healing and osteoclast fusion, potentially via its regulation of Pmepa1 expression.


Assuntos
Regeneração Óssea , Osso Cortical/metabolismo , Deleção de Genes , Histona Desacetilases/deficiência , Proteínas de Membrana/metabolismo , Células Progenitoras Mieloides/metabolismo , Osteoclastos/metabolismo , Animais , Fusão Celular , Osso Cortical/lesões , Osso Cortical/patologia , Feminino , Histona Desacetilases/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Células Progenitoras Mieloides/patologia , Osteoclastos/patologia
10.
Sci Rep ; 10(1): 22367, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33353965

RESUMO

To investigate bone health and body composition in young women with long-duration type 1 diabetes (T1D) in relation to matched controls. Twenty-three Swedish women, age 19.2-27.9 years, with a T1D duration of 10 years or more were recruited from the Swedish National Diabetes Registry (NDR). An age-, gender- and geography-matched control group was recruited. Bone mass and body composition were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Data was retrieved from the NDR and SWEDIABKIDS registries. T1D individuals had a mean diabetes duration of 19 years. T1D individuals had reduced lean mass (40.0 ± 6.1 kg vs. 43.9 ± 4.9 kg) and were shorter (1.66 ± 0.06 m vs. 1.71 ± 0.06 m) although comparable BMI. Subjects with T1D had lower muscle area (P = 0.0045). No differences were observed for fractures; physical activity; total, lumbar spine or femur areal bone mineral density. The cortical bone strength strain index was lower for TD1 patients (1875 ± 399 mm3 vs. 2277 ± 332 mm3). In conclusion, young women with long-term diabetes duration showed reduced cortical bone strength, decreased periosteal circumference, endosteal circumference and altered body composition. These factors contribute to the health burden of TD1, which warrants further attention for advancing bone health in women with T1D.


Assuntos
Peso Corporal , Densidade Óssea , Osso Cortical , Diabetes Mellitus Tipo 1 , Sistema de Registros , Absorciometria de Fóton , Adulto , Osso Cortical/diagnóstico por imagem , Osso Cortical/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Humanos , Seio Sagital Superior , Suécia
11.
Front Endocrinol (Lausanne) ; 11: 567417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33071975

RESUMO

Bone possesses a highly complex hierarchical structure comprised of mineral (~45% by volume), organic matrix (~35%) and water (~20%). Water exists in bone in two forms: as bound water (BW), which is bound to bone mineral and organic matrix, or as pore water (PW), which resides in Haversian canals as well as in lacunae and canaliculi. Magnetic resonance (MR) imaging has been increasingly used for assessment of cortical and trabecular bone. However, bone appears as a signal void on conventional MR sequences because of its short T2*. Ultrashort echo time (UTE) sequences with echo times (TEs) 100-1,000 times shorter than those of conventional sequences allow direct imaging of BW and PW in bone. A series of quantitative UTE MRI techniques has been developed for bone evaluation. UTE and adiabatic inversion recovery prepared UTE (IR-UTE) sequences have been developed to quantify BW and PW. UTE magnetization transfer (UTE-MT) sequences have been developed to quantify collagen backbone protons, and UTE quantitative susceptibility mapping (UTE-QSM) sequences have been developed to assess bone mineral.


Assuntos
Densidade Óssea/fisiologia , Osso Cortical/diagnóstico por imagem , Osso Cortical/metabolismo , Imagem Ecoplanar/métodos , Imageamento por Ressonância Magnética/métodos , Animais , Humanos , Fatores de Tempo , Água/metabolismo , Microtomografia por Raio-X/métodos
12.
J Struct Biol ; 212(2): 107616, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920138

RESUMO

Various tissue types, including fibrous connective tissue, bone marrow, cartilage, woven and lamellar bone, coexist in healing bone. Similar to most bone tissue type, healing bone contains a lacuno-canalicular network (LCN) housing osteocytes. These cells are known to orchestrate bone remodeling in healthy bone by sensing mechanical strains and translating them into biochemical signals. The structure of the LCN is hypothesized to influence mineralization processes. Hence, the aim of the present study was to visualize and match spatial variations in the LCN topology with mineral characteristics, within and at the interfaces of the different tissue types that comprise healing bone. We applied a correlative multi-method approach to visualize the LCN architecture and quantify mineral particle size and orientation within healing femoral bone in a mouse osteotomy model (26 weeks old C57BL/6 mice). This approach revealed structural differences across several length scales during endochondral ossification within the following regions: calcified cartilage, bony callus, cortical bone and a transition zone between the cortical and callus region analyzed 21 days after the osteotomy. In this transition zone, we observed a continuous convergence of mineral characteristics and osteocyte lacunae shape as well as discontinuities in the lacunae volume and LCN connectivity. The bony callus exhibits a 34% higher lacunae number density and 40% larger lacunar volume compared to cortical bone. The presented correlations between LCN architecture and mineral characteristics improves our understanding of how bone develops during healing and may indicate a contribution of osteocytes to bone (re)modeling.


Assuntos
Remodelação Óssea/fisiologia , Fêmur/metabolismo , Fêmur/fisiologia , Minerais/metabolismo , Osteócitos/metabolismo , Osteócitos/fisiologia , Animais , Osso Cortical/metabolismo , Osso Cortical/fisiologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal/métodos
13.
JCI Insight ; 5(19)2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32870816

RESUMO

In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these 2 compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas control mice lost cortical bone between 8 and 24 months of age, mice lacking RANKL in osteocytes gained cortical bone during this period. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice but not in RANKL conditional knockout mice. Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Overexpression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Finally, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone.


Assuntos
Envelhecimento/patologia , Reabsorção Óssea/patologia , Senescência Celular , Osso Cortical/patologia , Osteócitos/patologia , Ligante RANK/fisiologia , Envelhecimento/metabolismo , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Osso Cortical/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteócitos/metabolismo
14.
Sci Rep ; 10(1): 13751, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792620

RESUMO

Bone tissues have trabecular bone with a high bone turnover and cortical bone with a low turnover. The mechanisms by which the turnover rate of these bone tissues is determined remain unclear. Osteocytes secrete sclerostin, a Wnt/ß-catenin signaling antagonist, and inhibit bone formation. We found that sclerostin expression in cortical bone is more marked than in trabecular bone in Sost reporter mice. Leukemia inhibitory factor (LIF) secreted from osteoclasts reportedly suppressed sclerostin expression and promoted bone formation. Here, we report that osteoclasts downregulate sclerostin expression in trabecular bone and promote bone turnover. Treatment of C57BL/6 mice with an anti-RANKL antibody eliminated the number of osteoclasts and LIF-positive cells in trabecular bone. The number of sclerostin-positive cells was increased in trabecular bone, while the number of ß-catenin-positive cells and bone formation were decreased in trabecular bone. Besides, Tnfsf11 heterozygous (Rankl+/-) mice exhibited a decreased number of LIF-positive cells and increased number of sclerostin-positive cells in trabecular bone. Rankl+/- mice exhibited a decreased number of ß-catenin-positive cells and reduced bone formation in trabecular bone. Furthermore, in cultured osteoclasts, RANKL stimulation increased Lif mRNA expression, suggesting that RANKL signal increased LIF expression. In conclusion, osteoclasts downregulate sclerostin expression and promote trabecular bone turnover.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Remodelação Óssea/fisiologia , Osso Esponjoso/metabolismo , Osteoclastos/metabolismo , Ligante RANK/genética , Animais , Anticorpos/imunologia , Biomarcadores Tumorais/metabolismo , Densidade Óssea , Osso Cortical/metabolismo , Fator Inibidor de Leucemia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligante RANK/imunologia , Regulação para Cima/genética , Via de Sinalização Wnt/fisiologia
15.
Biochem Biophys Res Commun ; 529(2): 186-190, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32703409

RESUMO

The long bone midshaft expands by forming primary osteons at the periosteal surface of cortical bone in humans and rodents. Osteoblastic bone formation in the vascular cavity in the center of primary osteons is delayed during cortical bone development. The mechanisms of the formation of primary osteons is not fully understood, however. Focusing on NOTCH1 signaling, an inhibitory signaling on osteoblastic bone formation, our immunohistochemical analysis revealed Delta like1 (DLL1), a ligand of NOTCH1, and the NOTCH1 intracellular domain (NICD, an activated form of NOTCH1) immunoreactivity, in the cuboidal osteoblasts lining the bone surface in the vascular cavity of primary osteons during postnatal growth in rats. Interestingly, five days after treatment of primary osteoblasts with ascorbic acid and ß glycerophosphate, protein levels of both DLL1 and NICD increased transiently, indicating that DLL1 activates NOTCH1 in primary cultured osteoblasts. Thus, the results imply that DLL1-NOTCH1 signaling in osteoblasts is associated with primary osteonal bone formation.


Assuntos
Osso Cortical/citologia , Peptídeos e Proteínas de Sinalização Intercelular/análise , Proteínas de Membrana/análise , Osteoblastos/citologia , Receptor Notch1/análise , Animais , Células Cultivadas , Osso Cortical/metabolismo , Masculino , Osteoblastos/metabolismo , Domínios Proteicos , Ratos , Ratos Wistar
16.
Magn Reson Imaging ; 71: 17-24, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32387394

RESUMO

PURPOSE: The purpose of our study was to use Dual-TR STE-MR protocol as a clinical tool for cortical bone free water quantification at 1.5 T and validate it by comparing the obtained results (MR-derived results) with dehydration results. METHODS: Human studies were compliant with HIPPA and were approved by the institutional review board. Short Echo Time (STE) MR imaging with different Repetition Times (TRs) was used for quantification of cortical bone free water T1 (T1free) and concentration (ρfree). The proposed strategy was compared with the dehydration technique in seven bovine cortical bone samples. The agreement between the two methods was quantified by using Bland and Altman analysis. Then we applied the technique on a cross-sectional population of thirty healthy volunteers (18F/12M) and examined the association of the biomarkers with age. RESULTS: The mean values of ρfree for bovine cortical bone specimens were quantified as 4.37% and 5.34% by using STE-MR and dehydration techniques, respectively. The Bland and Altman analysis showed good agreement between the two methods along with the suggestion of 0.99% bias between them. Strong correlations were also reported between ρfree (r2 = 0.62) and T1free and age (r2 = 0.8). The reproducibility of the method, evaluated in eight subjects, yielded an intra-class correlation of 0.95. CONCLUSION: STE-MR imaging with dual-TR strategy is a clinical solution for quantifying cortical bone ρfree and T1free.


Assuntos
Osso Cortical/diagnóstico por imagem , Osso Cortical/metabolismo , Imageamento por Ressonância Magnética , Água/metabolismo , Adulto , Animais , Bovinos , Estudos Transversais , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
17.
Analyst ; 145(10): 3713-3724, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32342066

RESUMO

Water is an important component of bone and plays a key role in its mechanical and structural integrity. Water molecules in bone are present in different locations, including loosely or tightly bound to the matrix and/or mineral (biological apatite) phases. Identification of water location and interactions with matrix components impact bone function but have been challenging to assess. Here, we used near infrared (NIR) spectroscopy to identify loosely and tightly bound water present in cortical bone. In hydrated samples, NIR spectra have two primary water absorption bands at frequencies of ∼5200 and 7000 cm-1. Using lyophilization and hydrogen-deuterium exchange assays, we showed that these absorption bands are primarily associated with loosely bound bone water. Using further demineralization assays, thermal denaturation, and comparison to standards, we found that these absorption bands have underlying components associated with water molecules tightly bound to bone. In dehydrated samples, the peak at ∼5200 cm-1 was assigned to a combination of water tightly bound to collagen and to mineral, whereas the peak at 7000 cm-1 was exclusively associated with tightly bound mineral water. We also found significant positive correlations between the NIR mineral absorption bands and the mineral content as determined by an established mid infrared spectroscopic parameter, phosphate/amide I. Moreover, the NIR water data showed correlation trends with tissue mineral density (TMD) in cortical bone tissues. These observations reveal the ability of NIR spectroscopy to non-destructively identify loosely and tightly bound water in bone, which could have further applications in biomineralization and biomedical studies.


Assuntos
Osso Cortical/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho , Água/metabolismo , Animais , Densidade Óssea , Colágeno/metabolismo , Osso Cortical/fisiologia , Humanos , Suínos
18.
Biomed Res Int ; 2020: 9467683, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149147

RESUMO

Yishen Bugu Ye (YSBGY), a traditional Chinese medicine comprising 12 types of medicinal herbs, is often prescribed in China to increase bone strength. In this study, the antiosteoporotic effects of YSBGY were investigated in C57BL/6 mice afflicted with dexamethasone- (Dex-) induced osteoporosis (OP). The results showed that YSBGY reduced the interstitial edema in the liver and kidney of mice with Dex-induced OP. It also increased the number of trabecular bone elements and chondrocytes in the femur, promoted cortical bone thickness and trabecular bone density, and modulated the OP-related indexes in the femur and tibia of OP mice. It also increased the serum concentrations of type I collagen, osteocalcin, osteopontin, bone morphogenetic protein-2, bone morphogenetic protein receptor type 2, C-terminal telopeptide of type I collagen, and runt-related transcription factor-2 and reduced those of tartrate-resistant acid phosphatase 5 and nuclear factor of activated T cells in these mice, suggesting that it improved osteoblast differentiation and suppressed osteoclast differentiation. The anti-inflammatory effect of YSBGY was confirmed by the increase in the serum concentrations of interleukin- (IL-) 33 and the decrease in concentrations of IL-1, IL-7, and tumor necrosis factor-α in OP mice. Furthermore, YSBGY enhanced the serum concentrations of superoxide dismutase and catalase in these mice, indicating that it also exerted antioxidative effects. This is the first study to confirm the antiosteoporotic effects of YSBGY in mice with Dex-induced OP, and it showed that these effects may be related to the YSBGY-induced modulation of the osteoblast/osteoclast balance and serum concentrations of inflammatory factors. These results provide experimental evidence supporting the use of YSBGY for supporting bone formation in the clinical setting.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Animais , Densidade Óssea , Proteína Morfogenética Óssea 2/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Osso Esponjoso , Colágeno Tipo I/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Osso Cortical/metabolismo , Osso Cortical/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteocalcina/metabolismo , Osteoclastos/metabolismo , Osteopontina/metabolismo , Osteoporose/diagnóstico por imagem , Osteoporose/patologia , Peptídeos , Superóxido Dismutase/sangue , Fosfatase Ácida Resistente a Tartarato/metabolismo
19.
J Clin Endocrinol Metab ; 105(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32067027

RESUMO

CONTEXT: It is important to identify patients at highest risk of fractures. OBJECTIVE: To compare the separate and combined performances of bone-related genetic risk scores (GRSs) for prediction of forearm, hip and vertebral fractures separately, as well as of trabecular and cortical bone microstructure parameters separately. DESIGN, SETTING, AND PARTICIPANTS: Using 1103 single nucleotide polymorphisms (SNPs) independently associated with estimated bone mineral density of the heel (eBMD), we developed a weighted GRS for eBMD and determined its contribution to fracture prediction beyond 2 previously developed GRSs for femur neck BMD (49 SNPs) and lumbar spine BMD (48 SNPs). Associations between these GRSs and forearm (ncases = 1020; ncontrols = 2838), hip (ncases = 1123; ncontrols = 2630) and vertebral (ncases = 288; ncontrols = 1187) fractures were evaluated in 3 Swedish cohorts. Associations between the GRSs and trabecular and cortical bone microstructure parameters (n = 426) were evaluated in the MrOS Sweden cohort. RESULTS: We found that eBMDGRS was the only significant independent predictor of forearm and vertebral fractures while both FN-BMDGRS and eBMDGRS were significant independent predictors of hip fractures. The eBMDGRS was the major GRS contributing to prediction of trabecular bone microstructure parameters while both FN-BMDGRS and eBMDGRS contributed information for prediction of cortical bone microstructure parameters. CONCLUSIONS: The eBMDGRS independently predicts forearm and vertebral fractures while both FN-BMDGRS and eBMDGRS contribute independent information for prediction of hip fractures. We propose that eBMDGRS captures unique information about trabecular bone microstructure useful for prediction of forearm and vertebral fractures. These findings may facilitate personalized medicine to predict site-specific fractures as well as cortical and trabecular bone microstructure separately.


Assuntos
Densidade Óssea/genética , Osso Esponjoso/patologia , Osso Cortical/patologia , Fraturas Ósseas/diagnóstico , Osteoporose/diagnóstico , Polimorfismo de Nucleotídeo Único , Fraturas da Coluna Vertebral/diagnóstico , Idoso , Osso Esponjoso/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Osso Cortical/metabolismo , Feminino , Seguimentos , Fraturas Ósseas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/genética , Prognóstico , Fatores de Risco , Fraturas da Coluna Vertebral/genética
20.
J Gerontol A Biol Sci Med Sci ; 75(5): 826-834, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32060555

RESUMO

Bone loss in aging is linked with chronic low-grade inflammation and the accumulation of marrowfat in animals and humans. Peroxisome proliferator-activated receptor gamma (PPARγ), an adipogenic regulator, plays key roles in these biological processes. However, studies of the roles of PPARγ in age-related bone loss and inflammation are lacking. We hypothesized that deletion of PPARγ in bone marrow mesenchymal lineage cells would reduce bone loss with aging, potentially through a reduction in fat-generated inflammatory responses and an increase in osteoblastic activity. In the present study, we show that mice deficient of PPARγ in Dermo1-expressing mesenchymal lineage cells (Dermo1-Cre:PPARγ fl/fl) have reduced fat mass and increased cortical bone thickness but that deficiency of PPARγ had limited effect on protection of trabecular bone with aging as demonstrated by dual-energy X-ray absorptiometry, µCT, and histomorphometric analyses. Conditional knockout of PPARγ reduced serum concentrations of adipokines, including adiponectin, resistin, and leptin, and reduced marrow stromal cell expression levels of inflammation-related genes. Inflammation genes involved in the interferon signaling pathway were reduced the most. These results demonstrate that disruption of the master adipogenic regulator, PPARγ, has a certain protective effect on aging-induced bone loss, suggesting that regulation of adipose function and modulation of interferon signaling are among the key mechanisms by which PPARγ regulates bone homeostasis during aging process.


Assuntos
Envelhecimento/fisiologia , Células-Tronco Mesenquimais/fisiologia , Osteoporose/etiologia , PPAR gama/fisiologia , Adipocinas/sangue , Animais , Linhagem da Célula , Células Cultivadas , Osso Cortical/metabolismo , Feminino , Interferon gama/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoporose/prevenção & controle
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