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1.
Endocrinol Diabetes Metab ; 7(1): e440, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37505196

RESUMO

INTRODUCTION: Gut microbiota (GM) is the collection of small organisms such as bacteria, fungi, bacteriophages and protozoans living in the intestine in symbiotics relation within their host. GM regulates host metabolism by various mechanisms. METHODS: This review aims to consolidate current information for physicians on the effect of GM on bone health. For this, an online search of the literature was conducted using the keywords gut microbiota, bone mass, osteoporosis, Lactobacillus and sex steroid. RESULTS AND CONCLUSIONS: There is a considerable degree of variation in bone mineral density (BMD) within populations, and it is estimated that a significant component of BMD variability is due to genetics. However, the remaining causes of bone mass variance within populations remain largely unknown. A well-recognized cause of phenotypic variation in bone mass is the composition of the microbiome. Studies have shown that germ-free (GF) mice have higher bone mass compared to conventionally raised (CR) mice. Furthermore, GM dysbiosis, also called dysbacteriosis, is defined as any alteration in the composition of the microbial community that has been colonized in the host intestine and associated with the development of bone diseases. For instance, postmenopausal osteoporosis (PMO) and diabetes. GM can be modulated by several factors such as genetics, age, drugs, food habits and probiotics. Probiotics are defined as viable bacteria that confer health benefits by modulating GM when administered in adequate quantity. Lactobacillus rhamnosus GG (LGG) is a great example of such a probiotic. LGG has been shown to regulate bone mass in healthy mice as well as ovariectomized (OVX) mice via two different mechanisms. This review will focus on the literature regarding the mechanism by which GM and probiotic LGG regulate bone mass in healthy mice as well as in OVX mice, a model of PMO.


Assuntos
Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Probióticos , Camundongos , Animais , Lactobacillus/metabolismo , Probióticos/farmacologia
4.
J Clin Invest ; 131(4)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586672

RESUMO

Estrogen deficiency causes a gut microbiome-dependent expansion of BM Th17 cells and TNF-α-producing T cells. The resulting increased BM levels of IL-17a (IL-17) and TNF stimulate RANKL expression and activity, causing bone loss. However, the origin of BM Th17 cells and TNF+ T cells is unknown. Here, we show that ovariectomy (ovx) expanded intestinal Th17 cells and TNF+ T cells, increased their S1P receptor 1-mediated (S1PR1-mediated) egress from the intestine, and enhanced their subsequent influx into the BM through CXCR3- and CCL20-mediated mechanisms. Demonstrating the functional relevance of T cell trafficking, blockade of Th17 cell and TNF+ T cell egress from the gut or their influx into the BM prevented ovx-induced bone loss. Therefore, intestinal T cells are a proximal target of sex steroid deficiency relevant for bone loss. Blockade of intestinal T cell migration may represent a therapeutic strategy for the treatment of postmenopausal bone loss.


Assuntos
Movimento Celular/imunologia , Intestinos , Osteoporose Pós-Menopausa , Ovariectomia , Células Th17/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Quimiocina CCL20/genética , Quimiocina CCL20/imunologia , Feminino , Humanos , Intestinos/imunologia , Intestinos/microbiologia , Camundongos , Camundongos Knockout , Osteoporose Pós-Menopausa/imunologia , Osteoporose Pós-Menopausa/microbiologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Fator de Necrose Tumoral alfa/genética
5.
Elife ; 102021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33432923

RESUMO

Genetic factors account for the majority of the variance of human bone mass, but the contribution of non-genetic factors remains largely unknown. By utilizing maternal/offspring transmission, cohabitation, or fecal material transplantation (FMT) studies, we investigated the influence of the gut microbiome on skeletal maturation. We show that the gut microbiome is a communicable regulator of bone structure and turnover in mice. In addition, we found that the acquisition of a specific bacterial strain, segmented filamentous bacteria (SFB), a gut microbe that induces intestinal Th17 cell expansion, was sufficient to negatively impact skeletal maturation. These findings have significant translational implications, as the identification of methods or timing of microbiome transfer may lead to the development of bacteriotherapeutic interventions to optimize skeletal maturation in humans. Moreover, the transfer of SFB-like microbes capable of triggering the expansion of human Th17 cells during therapeutic FMT procedures could lead to significant bone loss in fecal material recipients.


Assuntos
Microbioma Gastrointestinal , Esqueleto/crescimento & desenvolvimento , Animais , Transplante de Microbiota Fecal , Fezes/microbiologia , Feminino , Camundongos
6.
J Clin Invest ; 130(4): 1767-1781, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917685

RESUMO

Parathyroid hormone (PTH) is a critical regulator of skeletal development that promotes both bone formation and bone resorption. Using microbiota depletion by wide-spectrum antibiotics and germ-free (GF) female mice, we showed that the microbiota was required for PTH to stimulate bone formation and increase bone mass. Microbiota depletion lowered butyrate levels, a metabolite responsible for gut-bone communication, while reestablishment of physiologic levels of butyrate restored PTH-induced anabolism. The permissive activity of butyrate was mediated by GPR43 signaling in dendritic cells and by GPR43-independent signaling in T cells. Butyrate was required for PTH to increase the number of bone marrow (BM) regulatory T cells (Tregs). Tregs stimulated production of the osteogenic Wnt ligand Wnt10b by BM CD8+ T cells, which activated Wnt-dependent bone formation. Together, these data highlight the role that butyrate produced by gut luminal microbiota plays in triggering regulatory pathways, which are critical for the anabolic action of PTH in bone.


Assuntos
Butiratos/metabolismo , Microbioma Gastrointestinal , Osteogênese , Hormônio Paratireóideo/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Camundongos Knockout , Hormônio Paratireóideo/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Linfócitos T Reguladores/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
7.
J Bone Miner Res ; 34(2): 349-360, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30399207

RESUMO

Primary hyperparathyroidism (PHPT) is a condition where elevated PTH levels lead to bone loss, in part through increased production of the osteoclastogenic factor IL-17A, by bone marrow (BM) T-helper 17 (Th17) cells, a subset of helper CD4+ T cells. In animals, PHPT is modeled by continuous PTH treatment (cPTH). In mice, an additional critical action of cPTH is the capacity to increase the production of RANKL by osteocytes. However, a definitive link between IL-17A and osteocytic expression of RANKL has not been made. Here we show that cPTH fails to induce cortical and trabecular bone loss and causes less intense bone resorption in conditional knock-out (IL-17RAΔOCY ) male and female mice lacking the expression of IL-17A receptor (IL-17RA) in dentin matrix protein 1 (DMP1)-8kb-Cre-expressing cells, which include osteocytes and some osteoblasts. Therefore, direct IL-17RA signaling in osteoblasts/osteocytes is required for cPTH to exert its bone catabolic effects. In addition, in vivo, silencing of IL-17RA signaling in in DMP1-8kb-expressing cells blunts the capacity of cPTH to stimulate osteocytic RANKL production, indicating that cPTH augments osteocytic RANKL expression indirectly, via an IL-17A/IL-17RA-mediated mechanism. Thus, osteocytic production of RANKL and T cell production of IL-17A are both critical for the bone catabolic activity of cPTH. © 2018 American Society for Bone and Mineral Research.


Assuntos
Reabsorção Óssea/metabolismo , Osteócitos/metabolismo , Hormônio Paratireóideo/metabolismo , Ligante RANK/biossíntese , Receptores de Interleucina-17/metabolismo , Transdução de Sinais , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/metabolismo , Hiperparatireoidismo Primário/patologia , Interleucina-17/genética , Interleucina-17/metabolismo , Camundongos , Camundongos Knockout , Osteócitos/patologia , Hormônio Paratireóideo/genética , Ligante RANK/genética , Receptores de Interleucina-17/genética
8.
Immunity ; 49(6): 1116-1131.e7, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30446387

RESUMO

Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells. Interaction of BM CD8+ T cells with Treg cells resulted in increased secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8+ cells, which drove expression of Wnt10b. Reducing Treg cell numbers, or reconstitution of TCRß-/- mice with CD8+ T cells from Wnt10b-/- mice, prevented butyrate-induced bone formation and bone mass acquisition. Thus, butyrate concentrations regulate bone anabolism via Treg cell-mediated regulation of CD8+ T cell Wnt10b production.


Assuntos
Butiratos/farmacologia , Osteogênese/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Proteínas Wnt/metabolismo , Animais , Butiratos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Comunicação Celular , Proliferação de Células/efeitos dos fármacos , Feminino , Lacticaseibacillus rhamnosus/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Probióticos/administração & dosagem , Probióticos/metabolismo , Linfócitos T Reguladores/citologia , Proteínas Wnt/genética
9.
EMBO Rep ; 19(1): 156-171, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29158349

RESUMO

Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration, but the cellular and molecular mechanisms of action of iPTH are largely unknown. Here, we show that Teriparatide and iPTH cause a ~two-threefold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents the increase in bone formation and trabecular bone volume and structure induced by iPTH Therefore, increasing the number of Tregs is a pivotal mechanism by which iPTH exerts its bone anabolic activity. Increasing Tregs pharmacologically may represent a novel bone anabolic therapy, while iPTH-induced Treg increase may find applications in inflammatory conditions and transplant medicine.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Teriparatida/uso terapêutico , Idoso , Animais , Biomarcadores/metabolismo , Cálcio/uso terapêutico , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Sialoproteína de Ligação à Integrina/genética , Sialoproteína de Ligação à Integrina/metabolismo , Contagem de Linfócitos , Camundongos , Osteocalcina/genética , Osteocalcina/metabolismo , Osteoporose Pós-Menopausa/genética , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Ovariectomia , Fator de Transcrição Sp7/genética , Fator de Transcrição Sp7/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico
10.
J Clin Invest ; 126(6): 2049-63, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27111232

RESUMO

A eubiotic microbiota influences many physiological processes in the metazoan host, including development and intestinal homeostasis. Here, we have shown that the intestinal microbiota modulates inflammatory responses caused by sex steroid deficiency, leading to trabecular bone loss. In murine models, sex steroid deficiency increased gut permeability, expanded Th17 cells, and upregulated the osteoclastogenic cytokines TNFα (TNF), RANKL, and IL-17 in the small intestine and the BM. In germ-free (GF) mice, sex steroid deficiency failed to increase osteoclastogenic cytokine production, stimulate bone resorption, and cause trabecular bone loss, demonstrating that the gut microbiota is central in sex steroid deficiency-induced trabecular bone loss. Furthermore, we demonstrated that twice-weekly treatment of sex steroid-deficient mice with the probiotics Lactobacillus rhamnosus GG (LGG) or the commercially available probiotic supplement VSL#3 reduces gut permeability, dampens intestinal and BM inflammation, and completely protects against bone loss. In contrast, supplementation with a nonprobiotic strain of E. coli or a mutant LGG was not protective. Together, these data highlight the role that the gut luminal microbiota and increased gut permeability play in triggering inflammatory pathways that are critical for inducing bone loss in sex steroid-deficient mice. Our data further suggest that probiotics that decrease gut permeability have potential as a therapeutic strategy for postmenopausal osteoporosis.


Assuntos
Microbioma Gastrointestinal/fisiologia , Hormônios Esteroides Gonadais/deficiência , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/prevenção & controle , Probióticos/farmacologia , Animais , Remodelação Óssea , Fenômenos Fisiológicos do Sistema Digestório , Modelos Animais de Doenças , Feminino , Vida Livre de Germes , Humanos , Interleucina-17/metabolismo , Lacticaseibacillus rhamnosus , Camundongos , Camundongos Endogâmicos C57BL , Osteoporose Pós-Menopausa/patologia , Permeabilidade , Ligante RANK/metabolismo , Células Th17/imunologia , Fator de Necrose Tumoral alfa/metabolismo
11.
J Bone Miner Res ; 31(5): 949-63, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26614970

RESUMO

Hydrogen sulfide (H2 S) is a gasotransmitter known to regulate bone formation and bone mass in unperturbed mice. However, it is presently unknown whether H2 S plays a role in pathologic bone loss. Here we show that ovariectomy (ovx), a model of postmenopausal bone loss, decreases serum H2 S levels and the bone marrow (BM) levels of two key H2 S-generating enzymes, cystathione ß-synthase (CBS) and cystathione γ-lyase (CSE). Treatment with the H2 S-donor GYY4137 (GYY) normalizes serum H2 S in ovx mice, increases bone formation, and completely prevents the loss of trabecular bone induced by ovx. Mechanistic studies revealed that GYY increases murine osteoblastogenesis by activating Wnt signaling through increased production of the Wnt ligands Wnt16, Wnt2b, Wnt6, and Wnt10b in the BM. Moreover, in vitro treatment with 17ß-estradiol upregulates the expression of CBS and CSE in human BM stromal cells (hSCs), whereas an H2 S-releasing drug induces osteogenic differentiation of hSCs. In summary, regulation of H2 S levels is a novel mechanism by which estrogen stimulates osteoblastogenesis and bone formation in mice and human cells. Blunted production of H2 S contributes to ovx-induced bone loss in mice by limiting the compensatory increase in bone formation elicited by ovx. Restoration of H2 S levels is a potential novel therapeutic approach for postmenopausal osteoporosis. © 2015 American Society for Bone and Mineral Research.


Assuntos
Estrogênios/deficiência , Sulfeto de Hidrogênio/metabolismo , Osteogênese , Osteoporose Pós-Menopausa/metabolismo , Via de Sinalização Wnt , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Humanos , Camundongos , Osteoporose Pós-Menopausa/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Proteínas Wnt/metabolismo
12.
Cell Metab ; 22(5): 799-810, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26456334

RESUMO

Primary hyperparathyroidism (PHPT) is a common cause of bone loss that is modeled by continuous PTH (cPTH) infusion. Here we show that the inflammatory cytokine IL-17A is upregulated by PHPT in humans and cPTH in mice. In humans, IL-17A is normalized by parathyroidectomy. In mice, treatment with anti-IL-17A antibody and silencing of IL-17A receptor IL-17RA prevent cPTH-induced osteocytic and osteoblastic RANKL production and bone loss. Mechanistically, cPTH stimulates conventional T cell production of TNFα (TNF), which increases the differentiation of IL-17A-producing Th17 cells via TNF receptor 1 (TNFR1) signaling in CD4(+) cells. Moreover, cPTH enhances the sensitivity of naive CD4(+) cells to TNF via GαS/cAMP/Ca(2+) signaling. Accordingly, conditional deletion of GαS in CD4(+) cells and treatment with the calcium channel blocker diltiazem prevents Th17 cell expansion and blocks cPTH-induced bone loss. Neutralization of IL-17A and calcium channel blockers may thus represent novel therapeutic strategies for hyperparathyroidism.


Assuntos
Doenças Ósseas Metabólicas/metabolismo , Hiperparatireoidismo Primário/metabolismo , Interleucina-17/metabolismo , Animais , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/patologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Humanos , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/tratamento farmacológico , Hiperparatireoidismo Primário/patologia , Interleucina-17/biossíntese , Camundongos , Receptores Tipo I de Fatores de Necrose Tumoral/biossíntese , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/biossíntese
13.
J Bone Miner Res ; 30(4): 695-705, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25359628

RESUMO

T cells are known to potentiate the bone anabolic activity of intermittent parathyroid hormone (iPTH) treatment. One of the involved mechanisms is increased T cell secretion of Wnt10b, a potent osteogenic Wnt ligand that activates Wnt signaling in stromal cells (SCs). However, additional mechanisms might play a role, including direct interactions between surface receptors expressed by T cells and SCs. Here we show that iPTH failed to promote SC proliferation and differentiation into osteoblasts (OBs) and activate Wnt signaling in SCs of mice with a global or T cell-specific deletion of the T cell costimulatory molecule CD40 ligand (CD40L). Attesting to the relevance of T cell-expressed CD40L, iPTH induced a blunted increase in bone formation and failed to increase trabecular bone volume in CD40L(-/-) mice and mice with a T cell-specific deletion of CD40L. CD40L null mice exhibited a blunted increase in T cell production of Wnt10b and abrogated CD40 signaling in SCs in response to iPTH treatment. Therefore, expression of the T cell surface receptor CD40L enables iPTH to exert its bone anabolic activity by activating CD40 signaling in SCs and maximally stimulating T cell production of Wnt10b.


Assuntos
Anabolizantes/farmacologia , Osso e Ossos/efeitos dos fármacos , Ligante de CD40/imunologia , Hormônio Paratireóideo/farmacologia , Linfócitos T/imunologia , Anabolizantes/administração & dosagem , Animais , Ligante de CD40/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hormônio Paratireóideo/administração & dosagem
14.
J Bone Miner Res ; 29(1): 43-54, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24357520

RESUMO

Both blunted osteocytic production of the Wnt inhibitor sclerostin (Scl) and increased T-cell production of the Wnt ligand Wnt10b contribute to the bone anabolic activity of intermittent parathyroid hormone (iPTH) treatment. However, the relative contribution of these mechanisms is unknown. In this study, we modeled the repressive effects of iPTH on Scl production in mice by treatment with a neutralizing anti-Scl antibody (Scl-Ab) to determine the contribution of T-cell-produced Wnt10b to the Scl-independent modalities of action of iPTH. We report that combined treatment with Scl-Ab and iPTH was more potent than either iPTH or Scl-Ab alone in increasing stromal cell production of OPG, osteoblastogenesis, osteoblast life span, bone turnover, bone mineral density, and trabecular bone volume and structure in mice with T cells capable of producing Wnt10b. In T-cell-null mice and mice lacking T-cell production of Wnt10b, combined treatment increased bone turnover significantly more than iPTH or Scl-Ab alone. However, in these mice, combined treatment with Scl-Ab and iPTH was equally effective as Scl-Ab alone in increasing the osteoblastic pool, bone volume, density, and structure. These findings demonstrate that the Scl-independent activity of iPTH on osteoblasts and bone mass is mediated by T-cell-produced Wnt10b. The data provide a proof of concept of a more potent therapeutic effect of combined treatment with iPTH and Scl-Ab than either alone.


Assuntos
Glicoproteínas/antagonistas & inibidores , Hormônio Paratireóideo/administração & dosagem , Proteínas Wnt/biossíntese , Proteínas Adaptadoras de Transdução de Sinal , Animais , Anticorpos/farmacologia , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Feminino , Glicoproteínas/biossíntese , Glicoproteínas/imunologia , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Linfócitos T/metabolismo
15.
Menopause ; 19(8): 856-63, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22781783

RESUMO

OBJECTIVE: Formononetin (Formo) prevents ovariectomy (Ovx)-induced bone loss in rats. However, there are no reports on the curative effects of Formo. The objective of this study was to investigate the ability of Formo in restoring trabecular microarchitecture and promoting new bone formation in osteopenic rats. METHODS: Adult Sprague-Dawley rats were ovariectomized and left for 90 days for osteopenia to develop. After 90 days, Formo (10.0 mg kg d) was given orally for the next 12 weeks to Ovx rats in a therapeutic protocol. Sham-operated, Ovx + vehicle, and Ovx + parathyroid hormone (PTH) groups served as controls. Trabecular microarchitecture, osteoid formation, bone turnover/resorption markers, and bone osteoprotegerin-to-receptor activator for nuclear κB ligand ratio were studied. One-way analysis of variance was used to test significance of effects. RESULTS: Formo treatment significantly restored the lost trabecular microarchitecture in the femurs and tibia of osteopenic Ovx rats and promoted new bone formation. Formo was devoid of any uterine estrogenicity. Serum levels of type I collagen N-terminal propeptide, which is a reliable marker of bone formation, were increased in Ovx rats treated with Formo compared with Ovx + vehicle group, and the levels were comparable with those in the sham group. Formo prevented the Ovx-induced increase in bone turnover markers, including serum osteocalcin and urinary type I collagen degradation product. Furthermore, Formo-treated Ovx rats had an increased bone osteoprotegerin-to-receptor activator for nuclear κB ligand ratio compared with the Ovx + vehicle group. CONCLUSIONS: Daily oral administration of Formo for 12 weeks has a substantial anabolic effect, thus raising the possibility of its use in postmenopausal osteoporosis.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Isoflavonas/administração & dosagem , Ovariectomia , Fitoestrógenos/administração & dosagem , Animais , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/patologia , Remodelação Óssea/efeitos dos fármacos , Feminino , Fêmur/patologia , Osteogênese/efeitos dos fármacos , Osteoprotegerina/genética , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Ligante RANK/genética , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Tíbia/patologia
16.
PLoS One ; 6(6): e21216, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21731677

RESUMO

Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent CD4⁺ CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17ß-stradiol (E2) and have osteoprotective role. This study explores the effect of daidzein (Daid) on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx). After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4⁺ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4⁺CD28null T cells, however, treatment with Daid increased the percentage of CD4⁺CD28⁺ T cells. Co-culture of CD4⁺CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP) expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4⁺CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220⁺ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency.


Assuntos
Linfócitos B/citologia , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/citologia , Isoflavonas/farmacologia , Linfopoese/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Contagem de Linfócitos , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Osteoclastos/citologia , Ovariectomia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Radiografia , Espécies Reativas de Oxigênio/metabolismo , Baço/efeitos dos fármacos , Baço/patologia , Timo/efeitos dos fármacos , Timo/patologia , Fator de Necrose Tumoral alfa/sangue , Nucleolina
17.
Mol Endocrinol ; 25(6): 922-32, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21493670

RESUMO

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expression. This induction in PGC-1α concomitantly enhances mitochondrial mass and expression of several PGC-1α target genes involved in mitochondrial function. Using FXR-rich or FXR-nonexpressing cell lines and tissues, we found that this effect of GW4064 is not mediated directly by FXR but occurs via activation of estrogen receptor-related receptor α (ERRα). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1α mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1α expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differences revealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERRα-FXR-PGC-1α and small heterodimer partner offers new insights into the biological functions of ERRα and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.


Assuntos
Isoxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores de Estrogênio/metabolismo , Transativadores/genética , Transcrição Gênica/efeitos dos fármacos , Animais , Sítios de Ligação , Linhagem Celular , Genes Reporter , Humanos , Isoxazóis/química , Fígado/metabolismo , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Knockout , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Regiões Promotoras Genéticas , Ratos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Estrogênio/química , Receptores de Estrogênio/genética , Termodinâmica , Transativadores/metabolismo , Fatores de Transcrição , Receptor ERRalfa Relacionado ao Estrogênio
18.
Menopause ; 17(2): 393-402, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20009959

RESUMO

OBJECTIVE: This study aimed to determine the skeletal effects of total ethanolic extract (TEE) and its butanolic fraction (BF) from the stem-bark of Ulmus wallichiana, which is rich in C-glycosylated flavonoids, in growing rats (for peak bone [PB] achievement) and in ovariectomized (OVx) rats (for menopausal bone loss). METHODS: TEE (750 mg kg(-1) d(-1)) and BF (50 mg kg(-1) d(-1)) were given orally for 10 weeks to weaning female Sprague-Dawley rats and for 12 weeks to adult OVx rats of the same strain, respectively. In studies with OVx rats, sham operated + vehicle, OVx + 17beta-estradiol, and OVx + vehicle groups served as various controls. Bone mineral density (BMD), biomechanical strength, bone histology, formations of osteoprogenitor cells, osteoid formation, and bone turnover/resorption markers were studied. Bioactive marker compounds in TEE and BF were analyzed by high-performance liquid chromatography. One-way analysis of variance was used to test significance of effects. RESULTS: In growing rats, both TEE and BF increased BMD, bone strength, and bone formation rate, suggesting higher PB achievement. OVx rats treated with either TEE or BF exhibited increased BMD at various anatomical positions and improved bone strength and trabecular architecture compared with the OVx + vehicle group. Serum osteocalcin and urinary type 1 collagen degradation product levels in OVx rats treated with either TEE or BF were significantly lower than those of the OVx + vehicle group. Neither TEE nor BF exhibited uterine estrogenicity. Analysis of marker compounds revealed significant enrichment of two bioactive markers in BF over TEE. CONCLUSIONS: Derived from U wallichiana, BF at much a lower dose than TEE was effective in PB achievement and prevention of OVx-induced bone loss.


Assuntos
Densidade Óssea/efeitos dos fármacos , Flavonoides/farmacologia , Glicosídeos/farmacologia , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Fitoterapia , Ulmus/química , Animais , Biomarcadores , Cromatografia Líquida de Alta Pressão , Feminino , Flavonoides/isolamento & purificação , Glicosídeos/isolamento & purificação , Humanos , Osteoblastos/efeitos dos fármacos , Ovariectomia , Casca de Planta/química , Preparações de Plantas/química , Preparações de Plantas/uso terapêutico , Caules de Planta/química , Ratos , Ratos Sprague-Dawley , Suporte de Carga
19.
J Cell Biochem ; 108(2): 388-99, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19598169

RESUMO

Following a lead obtained from stem-bark extract of Butea monosperma, two structurally related methoxyisoflavones; cajanin and isoformononetin were studied for their effects in osteoblasts. Cajanin had strong mitogenic as well as differentiation-promoting effects on osteoblasts that involved subsequent activation of MEK-Erk and Akt pathways. On the other hand, isoformononetin exhibited potent anti-apoptotic effect in addition to promoting osteoblast differentiation that involved parallel activation of MEK-Erk and Akt pathways. Unlike genistein or daidzein, none of these two compounds appear to act via estrogen receptors in osteoblast. Once daily oral (by gavage) treatment for 30 consecutive days was given to recently weaned female Sprague-Dawley rats with each of these compounds at 10.0 mg kg(-1) day(-1) dose. Cajanin increased bone mineral density (BMD) at all skeletal sites studied, bone biomechanical strength, mineral apposition rate (MAR) and bone formation rate (BFR), compared with control. BMD levels at various anatomic positions were also increased with isoformononetin compared with control however, its effect was less potent than cajanin. Isoformononetin had no effect on the parameters of bone biomechanical strength although it enhanced MAR and BFR compared with control. Isoformononetin had very mild uterotrophic effect, whereas cajanin was devoid of any such effect. Our data suggest that cajanin is more potent than isoformononetin in accelerating peak bone mass achievement. To the best of our knowledge, this work represents the first attempt to elucidate structure-activity relationship between the two methoxylated isoflavones regarding their effects in osteoblasts and bone formation.


Assuntos
Dietilestilbestrol/análogos & derivados , Genisteína/análogos & derivados , Isoflavonas/farmacologia , Sistema de Sinalização das MAP Quinases , Osteogênese , Fitoestrógenos/farmacologia , Envelhecimento , Análise de Variância , Animais , Apoptose , Densidade Óssea , Células da Medula Óssea/metabolismo , Osso e Ossos/metabolismo , Calcificação Fisiológica , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Dietilestilbestrol/administração & dosagem , Dietilestilbestrol/síntese química , Dietilestilbestrol/farmacologia , Inibidores Enzimáticos/metabolismo , Antagonistas de Estrogênios/metabolismo , Moduladores de Receptor Estrogênico/metabolismo , Estrogênios/metabolismo , Feminino , Isoflavonas/administração & dosagem , Isoflavonas/síntese química , Osteoblastos/metabolismo , Fitoestrógenos/administração & dosagem , Fitoestrógenos/síntese química , Ratos , Ratos Sprague-Dawley , Útero/citologia , Útero/metabolismo
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