RESUMO
BACKGROUND: Glucocorticoids and sclerostin act as inhibitors of the Wnt signaling pathway, thereby hindering bone formation. Given the pathway's intricate association with mesenchymal stem cells, the hypothesis suggests that heightened sclerostin levels may be intricately linked to an augmentation in marrow adiposity induced by glucocorticoids. This study endeavored to delve into the nuanced relationship between circulating sclerostin and bone marrow adipose tissue in postmenopausal women grappling with glucocorticoid-induced osteoporosis (GIO). METHODS: In this cross-sectional study, 103 patients with autoimmune-associated diseases underwent glucocorticoid treatment, boasting an average age of 61.3 years (standard deviation 7.1 years). The investigation encompassed a thorough assessment, incorporating medical history, anthropometric data, biochemical analysis, and dual-energy X-ray absorptiometry measurements of lumbar and femoral bone mineral density (BMD). Osteoporosis criteria were established at a T-score of -2.5 or lower. Additionally, MR spectroscopy quantified the vertebral marrow fat fraction. RESULTS: BMD at the femoral neck, total hip, and lumbar spine showcased an inverse correlation with marrow fat fraction (r = -0.511 to - 0.647, P < 0.001). Serum sclerostin levels exhibited a positive correlation with BMD at various skeletal sites (r = 0.476 to 0.589, P < 0.001). A noteworthy correlation emerged between circulating sclerostin and marrow fat fraction at the lumbar spine (r = -0.731, 95% CI, -0.810 to -0.627, P < 0.001). Multivariate analysis brought to light that vertebral marrow fat fraction significantly contributed to sclerostin serum concentrations (standardized regression coefficient ß = 0.462, P < 0.001). Even after adjusting for age, body mass index, physical activity, renal function, BMD, and the duration and doses of glucocorticoid treatment, serum sclerostin levels maintained a significant correlation with marrow fat fraction. CONCLUSIONS: Circulating sclerostin levels exhibited a noteworthy association with marrow adiposity in postmenopausal women grappling with GIO.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Adiposidade , Densidade Óssea , Medula Óssea , Glucocorticoides , Pós-Menopausa , Humanos , Feminino , Pessoa de Meia-Idade , Glucocorticoides/efeitos adversos , Estudos Transversais , Adiposidade/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Idoso , Marcadores Genéticos , Biomarcadores/sangue , Biomarcadores/análise , Osteoporose Pós-Menopausa/sangue , Absorciometria de FótonRESUMO
PURPOSE OF REVIEW: Obesity is highly prevalent and is associated with bone fragility and fracture. The changing nutrient availability to bone in obesity is an important facet of bone health. The goal of this article is to summarize current knowledge on the effects of carbohydrate and dietary fat availability on bone, particularly in the context of other tissues. RECENT FINDINGS: The skeleton is a primary site for fatty acid and glucose uptake. The trafficking of carbohydrates and fats into tissues changes with weight loss and periods of weight gain. Exercise acutely influences nutrient uptake into bone and may affect nutrient partitioning to bone. Bone cells secrete hormones that signal to the brain and other tissues information about its energetic state, which may alter whole-body nutrient trafficking. There is a critical need for studies to address the changes that metabolic perturbations have on nutrient availability in bone.
Assuntos
Densidade Óssea , Obesidade , Humanos , Obesidade/metabolismo , Gorduras na Dieta/metabolismo , Metabolismo Energético , Nutrientes , Ingestão de EnergiaRESUMO
Sclerostin is a Wnt signaling pathway inhibitor that negatively regulates bone formation. Bone-marrow-derived stromal cell (BMSC) differentiation is influenced by the Wnt pathway, leading to the hypothesis that higher levels of sclerostin might be associated with an increase in bone marrow adiposity (BMA). The main purpose of this study was to determine whether a relationship exists between circulating sclerostin and BMA in post-menopausal women with and without fragility fractures. The relationships between circulating sclerostin and body composition parameters were then examined. The outcomes measures included vertebral and hip proton density fat fraction (PDFF) using the water fat imaging (WFI) MRI method; DXA scans; and laboratory measurements, including serum sclerostin. In 199 participants, no significant correlations were found between serum sclerostin and PDFF. In both groups, serum sclerostin was correlated positively with bone mineral density (R = 0.27 to 0.56) and negatively with renal function (R = -0.22 to -0.29). Serum sclerostin correlated negatively with visceral adiposity in both groups (R = -0.24 to -0.32). Serum sclerostin correlated negatively with total body fat (R = -0.47) and appendicular lean mass (R = -0.26) in the fracture group, but not in the controls. No evidence of a relationship between serum sclerostin and BMA was found. However, serum sclerostin was negatively correlated with body composition components, such as visceral adiposity, total body fat and appendicular lean mass.
Assuntos
Adiposidade , Medula Óssea , Humanos , Feminino , Adiposidade/fisiologia , Pós-Menopausa/fisiologia , Densidade Óssea/fisiologia , Absorciometria de Fóton/métodos , ObesidadeRESUMO
OBJECTIVE: To determine changes of subchondral bone composition, micro-structure, bone marrow adiposity and micro-vascular perfusion in end-stage osteonecrosis of the femoral head (ONFH) compared to osteoarthritis (OA) using a combined in vivo and ex vivo approach. DESIGN: Male patients up to 70 years old referred for total hip replacement surgery for end-stage ONFH were included (n = 14). Fifteen patients with OA were controls. Pre-operative MRI was used to assess bone perfusion (dynamic contrast-enhanced (DCE) sequences) and marrow fat content (chemical shift imaging). Three distinct zones of femoral head subchondral bone - necrotic, sclerotic, distant - were compared between groups. After surgery, plugs were sampled in these zones and Raman spectroscopy was applied to characterize bone mineral and organic components (old and newly-formed), and contrast-enhanced micro-computed tomography (CE-µCT) to determine bone micro-structural parameters and volume of bone marrow adipocytes, using conventional 2D histology as a reference. RESULTS: In the necrotic zone of ONFH patients compared to OA patients: 1) the subchondral plate did not exhibit significant changes in composition nor structure; 2) the volume fraction of subchondral trabecular bone was significantly lower; 3) type-B carbonate substitution was less pronounced, 4) collagen maturity was more pronounced; and 5) bone marrow adipocytes were significantly depleted. The sclerotic zone from the ONFH group showed greater trabecular thickness, and higher DCE-MRI AUC and Ktrans. Volume fraction of subchondral bone, trabecular number, and Kep were significantly lower in the distant zone of the ONFH group. CONCLUSIONS: This study demonstrated alterations of subchondral bone microstructure, composition, perfusion and/or adipose content in all zones of the femoral head.
Assuntos
Artroplastia de Quadril , Necrose da Cabeça do Fêmur , Osteoartrite , Fêmur/patologia , Cabeça do Fêmur/diagnóstico por imagem , Cabeça do Fêmur/patologia , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Humanos , Masculino , Osteoartrite/patologia , Microtomografia por Raio-X/métodosRESUMO
We examined serum IGF-1 in premenopausal IOP, finding relationships that were opposite to those expected: higher IGF-1 was associated with lower bone formation and higher body fat, and lower BMD response to teriparatide. These paradoxical relationships between serum IGF-1, bone, and fat may contribute to the mechanism of idiopathic osteoporosis in premenopausal women. INTRODUCTION: Premenopausal women with idiopathic osteoporosis (IOP) have marked deficits in bone microarchitecture but variable bone remodeling. We previously reported that those with low tissue-level bone formation rate (BFR) are less responsive to teriparatide and have higher serum IGF-1, a hormone anabolic for osteoblasts and other tissues. The IGF-1 data were unexpected because IGF-1 is low in other forms of low turnover osteoporosis-leading us to hypothesize that IGF-1 relationships are paradoxical in IOP. This study aimed to determine whether IOP women with low BFR have higher IGF-1 and paradoxical IGF-1 relationships in skeletal and non-skeletal tissues, and whether IGF-1 and the related measures predict teriparatide response. METHODS: This research is an ancillary study to a 24 month clinical trial of teriparatide for IOP. Baseline assessments were related to trial outcomes: BMD, bone remodeling. SUBJECTS: Premenopausal women with IOP(n = 34); bone remodeling status was defined by baseline cancellous BFR/BS on bone biopsy. MEASURES: Serum IGF-1 parameters, compartmental adiposity (DXA, CT, MRI), serum hormones, and cardiovascular-risk-markers related to fat distribution. RESULTS: As seen in other populations, lower BFR was associated with higher body fat and poorer teriparatide response. However, in contrast to observations in other populations, low BFR, higher body fat, and poorer teriparatide response were all related to higher IGF-1: IGF-1 Z-score was inversely related to BFR at all bone surfaces (r = - 0.39 to - 0.46; p < 0.05), directly related to central fat (p = 0.05) and leptin (p = 0.03). IGF-1 inversely related to 24 month hip BMD %change (r = - 0.46; p = 0.01). CONCLUSIONS: Paradoxical IGF-1 relationships suggest that abnormal or atypical regulation of bone and fat may contribute to osteoporosis mechanisms in premenopausal IOP.
Assuntos
Conservadores da Densidade Óssea , Osteoporose , Tecido Adiposo , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , Fator de Crescimento Insulin-Like I , Osteogênese , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Teriparatida/uso terapêuticoRESUMO
Twenty men with spinal cord injury (SCI) were randomized into two 16-week intervention groups receiving testosterone treatment (TT) or TT combined with resistance training (TT + RT). TT + RT appears to hold the potential to reverse or slow down bone loss following SCI if provided over a longer period. INTRODUCTION: Persons with SCI experience bone loss below the level of injury. The combined effects of resistance training and TT on bone quality following SCI remain unknown. METHODS: Men with SCI were randomized into 16-week treatments receiving TT or TT + RT. Magnetic resonance imaging (MRI) of the right lower extremity before participation and post-intervention was used to visualize the proximal, middle, and distal femoral shaft, the quadriceps tendon, and the intermuscular fascia of the quadriceps. For the TT + RT group, MRI microarchitecture techniques were utilized to elucidate trabecular changes around the knee. Individual mixed models were used to estimate effect sizes. RESULTS: Twenty participants completed the pilot trial. A small effect for yellow marrow in the distal femur was indicated as increases following TT and decreases following TT + RT were observed. Another small effect was observed as the TT + RT group displayed greater increases in intermuscular fascia length than the TT arm. Distal femur trabecular changes for the TT + RT group were generally small in effect (decreased trabecular thickness variability, spacing, and spacing variability; increased network area). Medium effects were generally observed in the proximal tibia (increased plate width, trabecular thickness, and network area; decreased trabecular spacing and spacing variability). CONCLUSIONS: This pilot suggests longer TT + RT interventions may be a viable rehabilitation technique to combat bone loss following SCI. CLINICAL TRIAL REGISTRATION: Registered with clinicaltrials.gov : NCT01652040 (07/27/2012).
Assuntos
Treinamento Resistido , Traumatismos da Medula Espinal , Densidade Óssea , Osso e Ossos , Humanos , Masculino , Traumatismos da Medula Espinal/tratamento farmacológico , Testosterona , TíbiaRESUMO
Intensive methotrexate (MTX) treatment for childhood malignancies decreases osteogenesis but increases adipogenesis from the bone marrow stromal cells (BMSCs), resulting in bone loss and bone marrow adiposity. However, the underlying mechanisms are unclear. While microRNAs (miRNAs) have emerged as bone homeostasis regulators and miR-542-3p was recently shown to regulate osteogenesis in a bone loss context, the role of miR-542-3p in regulating osteogenesis and adipogenesis balance is not clear. Herein, in a rat MTX treatment-induced bone loss model, miR-542-3p was found significantly downregulated during the period of bone loss and marrow adiposity. Following target prediction, network construction, and functional annotation/ enrichment analyses, luciferase assays confirmed sFRP-1 and Smurf2 as the direct targets of miR-542-3p. miRNA-542-3p overexpression suppressed sFRP-1 and Smurf2 expression post-transcriptionally. Using in vitro models, miR-542-3p treatment stimulated osteogenesis but attenuated adipogenesis following MTX treatment. Subsequent signalling analyses revealed that miR-542-3p influences Wnt/ß-catenin and TGF-ß signalling pathways in osteoblastic cells. Our findings suggest that MTX treatment-induced bone loss and marrow adiposity could be molecularly linked to miR-542-3p pathways. Our results also indicate that miR-542-3p might be a therapeutic target for preserving bone and attenuating marrow fat formation during/after MTX chemotherapy.
Assuntos
Adipogenia/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Metotrexato/farmacologia , MicroRNAs/metabolismo , Osteogênese/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Osso e Ossos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/genética , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
Bone marrow adipose tissue (BMAT) has recently been found to induce osteoclastogenesis by secreting RANKL. Although Type 1 diabetes mellitus (T1DM) has been reported to be associated with increased BMAT and bone loss, little is known about the relationship between BMAT and osteoclasts in T1DM. We studied the role of BMAT in the alterations of osteoclast activities in early-stage T1DM, by using a streptozotocin-induced T1DM mouse model. Our results showed that osteoclast activity was enhanced in the long bones of T1DM mice, accompanied by increased protein expression of RANKL. However, RANKL mRNA levels in bone tissues of T1DM mice remained unchanged. Meanwhile, we found that BMAT was significantly increased in the long bones of T1DM mice, and both mRNA and protein levels of RANKL were elevated in the diabetic BMAT. More importantly, RANKL protein was mainly expressed on the cell membranes of the increased adipocytes, most of which were located next to the metaphyseal region. These results suggest that the enhanced bone resorption in early-stage diabetic mice is induced by RANKL derived from BMAT rather than the bone tissue itself.
Assuntos
Adipócitos/patologia , Reabsorção Óssea/patologia , Diabetes Mellitus Tipo 1/patologia , Ligante RANK/metabolismo , Adipócitos/metabolismo , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligante RANK/análiseRESUMO
Leptin, a hormone primarily produced by adipocytes, contributes to the regulation of bone health by modulating bone density, growth and adiposity. Upon leptin binding, multiple sites of the long form of the leptin receptor (LepRb) are phosphorylated to trigger activation of downstream signaling pathways. To address the role of LepRb-signaling pathways in bone health, we compared the effects of three LepRb mutations on bone density, adiposity, and growth in male and female mice. The ∆65 mutation, which lacks the known tyrosine phosphorylation sites, caused obesity and the most dramatic bone phenotype marked by excessive bone adiposity, osteoporosis, and decreased growth, consistent with the phenotype of db/db and ob/ob mice that fully lack leptin receptor signaling. Mutation of LepRb Tyr 1138 , which results in an inability to recruit and phosphorylate signal transducer and activator of transcription 3, also caused obesity, but bone loss and adiposity were more dominant in male mice and no growth defect was observed. In contrast, mutation of LepRb Tyr 985 , which blocks SHP2/SOCS3 recruitment to LepRb and contributes to leptin hypersensitivity, promoted increased femur bone density only in male mice, while marrow adiposity and bone growth were not affected. Additional analyses of vertebral trabecular bone volume indicate that only the Tyr 1138 mutant mice exhibit bone loss in vertebrae. Together, our findings suggest that the phosphorylation status of specific sites of the LepRb contribute to the sex- and location-dependent bone responses to leptin. Unraveling the mechanisms by which leptin responses are sex- and location-dependent can contribute to the development of uniquely targeted osteoporosis therapies.
Assuntos
Adiposidade/fisiologia , Densidade Óssea/fisiologia , Leptina/metabolismo , Receptores para Leptina/metabolismo , Caracteres Sexuais , Transdução de Sinais/fisiologia , Adipócitos Brancos/metabolismo , Animais , Osso Esponjoso/metabolismo , Feminino , Fêmur/metabolismo , Leptina/genética , Masculino , Camundongos , Camundongos Mutantes , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Receptores para Leptina/genética , Coluna Vertebral/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismoRESUMO
Global gene deletion studies have established that Runt-related transcription factor-2 (Runx2) is essential during skeletogenesis for osteoblastic differentiation in both intramembranous and endochondral ossification processes. However, the postnatal significance of Runx2 in vivo is poorly understood because a global Runx2 deletion causes perinatal lethality. In this study, we generated tamoxifen-induced Runx2 global deficient mice by crossing Runx2flox mice with ROSA26-CreERT2 mice (Rosa26-CreERT2; Runx2flox/flox). Four-week-old mice were intraperitoneally treated with tamoxifen for five consecutive days, sacrificed, and analyzed six weeks after tamoxifen administration. Deletion of Runx2 led to low bone mass, which is associated with decreased bone formation and bone resorption as well as excessive bone marrow adiposity. Collectively, postnatal Runx2 absolutely plays an important role in maintaining the homeostasis of bone tissues not only in bone mass, but also in the bone marrow environment.
Assuntos
Adipócitos/citologia , Densidade Óssea , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/fisiologia , Deleção de Genes , Adiposidade , Envelhecimento , Animais , Células da Medula Óssea/citologia , Cruzamentos Genéticos , Modelos Animais de Doenças , Feminino , Genótipo , Masculino , Camundongos , Camundongos Transgênicos , Osteoporose , Fenótipo , Tamoxifeno/farmacologia , Tíbia , Microtomografia por Raio-XRESUMO
PURPOSE OF REVIEW: The goal of this review is to explore clinical associations between peripheral neuropathy and diabetic bone disease and to discuss how nerve dysfunction may contribute to dysregulation of bone metabolism, reduced bone quality, and fracture risk. RECENT FINDINGS: Diabetic neuropathy can decrease peripheral sensation (sensory neuropathy), impair motor coordination (motor neuropathy), and increase postural hypotension (autonomic neuropathy). Together, this can impair overall balance and increase the risk for falls and fractures. In addition, the peripheral nervous system has the potential to regulate bone metabolism directly through the action of local neurotransmitters on bone cells and indirectly through neuroregulation of the skeletal vascular supply. This review critically evaluates existing evidence for diabetic peripheral neuropathy as a risk factor or direct actor on bone disease. In addition, we address therapeutic and experimental considerations to guide patient care and future research evaluating the emerging relationship between diabetic neuropathy and bone health.
Assuntos
Doenças Ósseas/etiologia , Neuropatias Diabéticas/complicações , Doenças do Sistema Nervoso Periférico/complicações , Densidade Óssea , Doenças Ósseas/fisiopatologia , Remodelação Óssea , Neuropatias Diabéticas/fisiopatologia , Humanos , Doenças do Sistema Nervoso Periférico/fisiopatologia , Equilíbrio Postural , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. RECENT FINDINGS: Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.
Assuntos
Adipócitos/metabolismo , Doenças Ósseas Metabólicas/metabolismo , Células da Medula Óssea/metabolismo , Osso e Ossos/metabolismo , Senescência Celular , Insulina/metabolismo , Adipogenia , Tecido Adiposo/metabolismo , Animais , Medula Óssea/metabolismo , Diferenciação Celular , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Células-Tronco Mesenquimais/metabolismo , Obesidade/metabolismo , Hormônio Paratireóideo/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor de Insulina/metabolismoRESUMO
Oleoyl serine (OS), an endogenous fatty acyl amide (FAA) found in bone, has been shown to have an anti-osteoporotic effect. OS, being an amide, can be hydrolyzed in the body by amidases. Hindering its amide bond by introducing adjacent substituents has been demonstrated as a successful method for prolonging its skeletal activity. Here, we tested the therapeutic efficacy of two methylated OS derivatives, oleoyl α-methyl serine (HU-671) and 2-methyl-oleoyl serine (HU-681), in an ovariectomized mouse model for osteoporosis by utilizing combined micro-computed tomography, histomorphometry, and cell culture analyses. Our findings indicate that daily treatment for 6 weeks with OS or HU-671 completely rescues bone loss, whereas HU-681 has only a partial effect. The increased bone density was primarily due to enhanced trabecular thickness and number. Moreover, the most effective dose of HU-671 was 0.5 mg/kg/day, an order of magnitude lower than with OS. The reversal of bone loss resulted from increased bone formation and decreased bone resorption, as well as reversal of bone marrow adiposity. These results were further confirmed by determining the serum levels of osteocalcin and type 1 collagen C-terminal crosslinks, as well as demonstrating the enhanced antiadipogenic effect of HU-671. Taken together, these data suggest that methylation interferes with OS's metabolism, thus enhancing its effects by extending its availability to its target cells.
Assuntos
Adiposidade/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Ácidos Oleicos/química , Osteoporose/etiologia , Osteoporose/metabolismo , Serina/análogos & derivados , Serina/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Medula Óssea/diagnóstico por imagem , Modelos Animais de Doenças , Feminino , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoporose/diagnóstico , Ovariectomia/efeitos adversos , Serina/química , Microtomografia por Raio-XRESUMO
Although bone marrow and bone toxicities have been reported in breast cancer survivors, preventative strategies are yet to be developed. Clinical studies suggest consumption of long chain omega-3 polyunsaturated fatty acids (LCn3PUFA) can attenuate age-related bone loss, and recent animal studies also revealed benefits of LCn3PUFA in alleviating bone marrow and bone toxicities associated with methotrexate chemotherapy. Using a female rat model for one of the most commonly used anthracycline-containing breast cancer chemotherapy regimens (adriamycin + cyclophosphamide) (AC) chemotherapy, this study investigated potential effects of daily LCn3PUFA consumption in preserving bone marrow and bone microenvironment during chemotherapy. AC treatment for four cycles significantly reduced bone marrow cellularity and increased marrow adipocyte contents. It increased trabecular bone separation but no obvious changes in bone volume or bone cell densities. LCn3PUFA supplementation (375 mg/100 g/day) attenuated AC-induced bone marrow cell depletion and marrow adiposity. It also partially attenuated AC-induced increases in trabecular bone separation and the cell sizes and nuclear numbers of osteoclasts formed ex vivo from bone marrow cells isolated from AC-treated rats. This study suggests that LCn3PUFA supplementation may have beneficial effects in preventing bone marrow damage and partially protecting the bone during AC cancer chemotherapy.
Assuntos
Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Ciclofosfamida/efeitos adversos , Suplementos Nutricionais , Doxorrubicina/efeitos adversos , Ácidos Graxos Ômega-3/farmacologia , Animais , Antineoplásicos/efeitos adversos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Microambiente Celular/efeitos dos fármacos , Feminino , Osteoclastos/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Fatores Sexuais , Microtomografia por Raio-XRESUMO
PURPOSE: Anthracyclines (including doxorubicin) are still the backbone of commonly used breast cancer chemotherapy regimens. Despite increasing use of doxorubicin and cyclophosphamide (AC) combinations for treating breast cancer, their potential to cause adverse skeletal effects remains unclear. METHODS: This study examined the effects of treatments with the AC regimen on bone and bone marrow in adult female rats. RESULTS: AC treatment for four cycles (weekly intravenous injection of 2 mg/kg doxorubicin and 20 mg/kg cyclophosphamide) resulted in a reduced volume of trabecular bone at the metaphysis, which was associated with reduced serum levels of 25-hydroxy vitamin D3 and alkaline phosphatase. Reductions in densities of osteocytes and bone lining cells were also observed. In addition, bone marrow was severely damaged, including a severe reduction in bone marrow cellularity and an increase in marrow adipocyte content. Accompanying these changes, there were increases in mRNA expression of adipogenesis regulatory genes (PPARγ and FABP4) and an inflammatory cytokine (TNFα) in metaphysis bone and bone marrow. CONCLUSIONS: This study indicates that AC chemotherapy may induce some bone loss, due to reduced bone formation, and bone marrow damage, due to increased marrow adiposity. Preventive strategies for preserving the bone and bone marrow microenvironment during anthracycline chemotherapy warrant further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Medula Óssea/efeitos dos fármacos , Ciclofosfamida/toxicidade , Doxorrubicina/toxicidade , Fêmur/efeitos dos fármacos , Tíbia/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Fosfatase Alcalina/sangue , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Medula Óssea/metabolismo , Medula Óssea/patologia , Calcifediol/sangue , Células Cultivadas , Microambiente Celular , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Fêmur/metabolismo , Fêmur/patologia , Injeções Intravenosas , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteócitos/efeitos dos fármacos , Osteócitos/metabolismo , Osteócitos/patologia , PPAR gama/genética , PPAR gama/metabolismo , Ratos Sprague-Dawley , Tíbia/metabolismo , Tíbia/patologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Several studies have demonstrated the relationship between bone marrow adiposity (BMAT) and bone mass. 1H magnetic resonance spectroscopy is a noninvasive technique able to assess both BMAT quantity and quality. The aim of our study was to perform quantitative and qualitative analyses of BMAT and to investigate its association with bone mineral density (BMD) in healthy nonobese volunteers. Fifty-one healthy volunteers, 21 men and 30 women, underwent 1.5 T 1H magnetic resonance spectroscopy of the lumbar spine. BMD was determined by dual-energy X-ray absorptiometry of the lumbar spine. Correlation analysis was performed to evaluate association among lipids fractions, BMD, and age. The female and male volunteers had similar body mass index and BMD (p > 0.05). Our data demonstrated an inverse correlation of BMD and BMAT with age, with a stronger correlation of saturated lipids (r = 0.701; p < 0.0001) compared with unsaturated lipids (UL) (r = 0.278; p = 0.004). Importantly, female subjects had the highest amount of UL (confidence interval: 0.685%-1.722%; p < 0.001). Our study reports that men and women with similar BMD and body mass index have striking differences in bone marrow lipids composition, namely women have higher UL than men. In addition, we believe that our study brings new insights to the complex network involving BMAT and other factors that influence bone integrity.
Assuntos
Tecido Adiposo/diagnóstico por imagem , Medula Óssea/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Absorciometria de Fóton , Tecido Adiposo/metabolismo , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Densidade Óssea , Medula Óssea/metabolismo , Gorduras/metabolismo , Gorduras Insaturadas/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espectroscopia de Prótons por Ressonância Magnética , Fatores Sexuais , Adulto JovemRESUMO
UNLABELLED: Increased neuropeptide Y (NPY) expression occurred in the glucocorticoid-induced osteoporotic skeleton. NPY knockout mice exhibited a minor response to the glucocorticoid-mediated exacerbation of bone accretion and fatty marrow pathogenesis. NPY deletion restored SITR1 signaling and enhanced PPARγ ubiquitination of bone tissue, an alternative strategy for ameliorating glucocorticoid-induced skeletal deterioration. INTRODUCTION: Glucocorticoid excess is observed to worsen the pathogenesis of osteoporosis and fatty marrow. This study was undertaken to investigate the contribution of neuropeptide Y (NPY) to glucocorticoid-induced bone loss and marrow adiposity. METHODS: NPY knockout and wild-type mice were administered methylprednisolone for four consecutive weeks. Bone mineral density, microarchitecture, and calcein-labeled mineral acquisition were quantified by µCT, dual energy X-ray absorptiometry, and histomorphometry. Expression of osteogenic and adipogenic markers and acetylation states of PPARγ were detected by RT-quantitative PCR, immunoprecipitation, and immunoblotting. RESULTS: High NPY levels were associated with glucocorticoid-induced trabecular bone deterioration and marrow fat accumulation. Mice lacking NPY had high bone mass concomitant with spacious trabecular and cortical bone microstructure. NPY deletion shielded skeletal tissues from the glucocorticoid-induced impediment of bone mass, trabecular morphometric characteristics, mineral accretion activity, and fatty marrow development. Ex vivo, NPY deficiency sustained osteogenic differentiation capacity and curtailed the glucocorticoid-mediated escalation of adipocyte formation reactions of primary bone-marrow mesenchymal cells. NPY deletion appeared to modulate Y1 and Y2 receptors, sirtuin 1, ERK, and p38 signaling pathways, an effect that facilitated hypoacetylation and ubiquitination of adipogenic transcription factor PPARγ in the skeletal tissues exposed to glucocorticoid stress. CONCLUSIONS: NPY mediates the glucocorticoid-induced disturbance of mineral accretion and marrow adipogenesis through post-translational modification of PPARγ. This study brings a new molecular insight into the disintegration of adipogenic and osteogenic activities within glucocorticoid-mediated osteoporotic skeletons. Control of NPY is an alternative strategy to ameliorate glucocorticoid-induced bone destruction and fatty marrow.
Assuntos
Adiposidade , Medula Óssea/patologia , Neuropeptídeo Y/fisiologia , Osteogênese , Osteoporose/fisiopatologia , Animais , Glucocorticoides/efeitos adversos , Masculino , Camundongos , Camundongos Knockout , Neuropeptídeo Y/genética , Osteoporose/induzido quimicamenteRESUMO
The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5-fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation.
Assuntos
Adiposidade/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Células da Medula Óssea/metabolismo , Medula Óssea/metabolismo , Osteoclastos/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Medula Óssea/patologia , Células da Medula Óssea/patologia , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacologia , Epirubicina/efeitos adversos , Epirubicina/farmacologia , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Osteoclastos/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Objective Teriparatide could induce osteoblast differentiation of mesenchymal stem cells while inhibiting adipocyte differentiation. However, there are significant differences between ex vivo and in vivo models. We aimed to evaluate the impact of teriparatide on marrow and abdominal fat accumulation in postmenopausal osteopenic women. Methods Postmenopausal osteopenic women were randomly assigned to receive teriparatide or placebo for 12 months. Subcutaneous (SAT) and visceral adipose tissue (VAT), marrow fat fraction (MFF), bone density (BMD) and bone biomarkers were measured at baseline, 6 and 12 months. Results At 12 months, mean percentage changes in BMD from baseline were 3.51%, 2.21% and 1.80% at lumbar spine, total hip and femoral neck for the teriparatide group, respectively. Relative to baseline conditions, teriparatide reduced MFF (-3.54% at 6 months; -5.87% at 12 months, all p < 0.01). A significant difference in MFF, but not BMD, was first detected at 6 months (p = 0.012) between groups. MFF was negatively associated with SAT (r = -0.479) and positively associated with VAT (r = 0.531) and VAT/SAT (r = 0.415, all p < 0.05). Teriparatide treatment did not alter abdominal fat composition. Conclusion Teriparatide effectively lowers marrow adiposity but not abdominal fat accumulation in postmenopausal osteopenic women.
Assuntos
Adiposidade/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Medula Óssea/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/uso terapêutico , Gordura Abdominal/efeitos dos fármacos , Gordura Abdominal/fisiopatologia , Absorciometria de Fóton , Idoso , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Medula Óssea/química , Feminino , Colo do Fêmur , Humanos , Vértebras Lombares , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/diagnóstico por imagem , PlacebosRESUMO
Hyperlipidemia-induced osteoporosis is marked by increased bone marrow adiposity, and treatment with statins for hyperlipidemia often leads to new-onset osteoporosis. Endosome-associated trafficking regulator 1 (ENTR1) has been found to interact with different proteins in pathophysiology, but its exact role in adipogenesis is not yet understood. This research aimed to explore the role of ENTR1 in adipogenesis and to discover a new small molecule that targets ENTR1 for evaluating its effectiveness in treating hyperlipidemia-induced osteoporosis. We found that ENTR1 expression increased during the adipogenesis of bone marrow mesenchymal cells (BMSCs). ENTR1 gain- and loss-of-function assays significantly enhanced lipid droplets formation. Mechanistically, ENTR1 binds peroxisome proliferator-activated receptor γ (PPARγ) and enhances its expression, thereby elevating adipogenic markers including C/EBPα and LDLR. Therapeutically, AN698/40746067 attenuated adipogenesis by targeting ENTR1 to suppress PPARγ. In vivo, AN698/40746067 reduced bone marrow adiposity and bone loss, as well as prevented lipogenesis-related obesity, inflammation, steatohepatitis, and abnormal serum lipid levels during hyperlipidemia. Together, these findings suggest that ENTR1 facilitates adipogenesis by PPARγ involved in BMSCs' differentiation, and targeted inhibition of ENTR1 by AN698/40746067 may offer a promising therapy for addressing lipogenesis-related challenges and alleviating osteoporosis following hyperlipidemia.