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1.
Curr Osteoporos Rep ; 22(3): 301-307, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38625510

RESUMO

PURPOSE OF REVIEW: This review summarizes evidence on osteocyte support of extramedullary and bone marrow adipocyte development and discusses the role of endogenous osteocyte activities of nuclear receptors peroxisome proliferator-activated receptor gamma (PPARG) and alpha (PPARA) in this support. RECENT FINDINGS: PPARG and PPARA proteins, key regulators of glucose and fatty acid metabolism, are highly expressed in osteocytes. They play significant roles in the regulation of osteocyte secretome and osteocyte bioenergetics; both activities contributing to the levels of systemic energy metabolism in part through an effect on metabolic function of extramedullary and bone marrow adipocytes. The PPARs-controlled osteocyte endocrine/paracrine activities, including sclerostin expression, directly regulate adipocyte function, while the PPARs-controlled osteocyte fuel utilization and oxidative phosphorylation contribute to the skeletal demands for glucose and fatty acids, whose availability is under the control of adipocytes. Bone is an inherent element of systemic energy metabolism with PPAR nuclear receptors regulating osteocyte-adipocyte metabolic axes.


Assuntos
Adipócitos , Tecido Adiposo , Medula Óssea , Metabolismo Energético , Osteócitos , PPAR gama , Osteócitos/metabolismo , Osteócitos/fisiologia , Humanos , PPAR gama/metabolismo , Medula Óssea/metabolismo , Tecido Adiposo/metabolismo , Adipócitos/metabolismo , Metabolismo Energético/fisiologia , PPAR alfa/metabolismo , Animais
2.
Curr Osteoporos Rep ; 20(5): 229-239, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35960475

RESUMO

PURPOSE OF THE REVIEW: Diabetes mellitus is a chronic metabolic disorder commonly encountered in orthopedic patients. Both type 1 and type 2 diabetes mellitus increase fracture risk and impair fracture healing. This review examines complex etiology of impaired fracture healing in diabetes. RECENT FINDINGS: Recent findings point to several mechanisms leading to orthopedic complications in diabetes. Hyperglycemia and chronic inflammation lead to increased formation of advanced glycation end products and generation of reactive oxygen species, which in turn contribute to the disruption in osteoblast and osteoclast balance leading to decreased bone formation and heightening the risk of nonunion or delayed union as well as impaired fracture healing. The mechanisms attributing to this imbalance is secondary to an increase in pro-inflammatory mediators leading to premature resorption of callus cartilage and impaired bone formation due to compromised osteoblast differentiation and their apoptosis. Other mechanisms include disruption in the bone's microenvironment supporting different stages of healing process including hematoma and callus formation, and their resolution during bone remodeling phase. Complications of diabetes including peripheral neuropathy and peripheral vascular disease also contribute to the impairment of fracture healing. Certain diabetic drugs may have adverse effects on fracture healing. The pathophysiology of impaired fracture healing in diabetic patients is complex. This review provides an update of the most recent findings on how key mediators of bone healing are affected in diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Consolidação da Fratura , Diabetes Mellitus Tipo 2/complicações , Consolidação da Fratura/fisiologia , Produtos Finais de Glicação Avançada , Humanos , Mediadores da Inflamação , Espécies Reativas de Oxigênio
3.
Physiol Genomics ; 53(12): 518-533, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34714176

RESUMO

Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiological interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-wk-old male rats. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. In addition, the number of small in size adipocytes increased, whereas the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short-chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Furthermore, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders.


Assuntos
Bactérias/genética , Bactérias/metabolismo , Desenvolvimento Ósseo/fisiologia , Células da Medula Óssea/metabolismo , Microbioma Gastrointestinal/genética , Vida Livre de Germes , Interações entre Hospedeiro e Microrganismos/genética , Osteogênese/fisiologia , Adipócitos/metabolismo , Animais , Densidade Óssea/fisiologia , Proliferação de Células/fisiologia , Condrócitos/metabolismo , Coprofagia , Disbiose , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Masculino , RNA Ribossômico 16S/genética , Ratos , Ratos Sprague-Dawley
4.
Curr Osteoporos Rep ; 16(2): 123-129, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29460176

RESUMO

PURPOSE OF REVIEW: The goal of this review is to summarize recent findings on marrow adipose tissue (MAT) function and to discuss the possibility of targeting MAT for therapeutic purposes. RECENT FINDINGS: MAT is characterized with high heterogeneity which may suggest both that marrow adipocytes originate from multiple different progenitors and/or their phenotype is determined by skeletal location and environmental cues. Close relationship to osteoblasts and heterogeneity suggests that MAT consists of cells representing spectrum of phenotypes ranging from lipid-filled adipocytes to pre-osteoblasts. We propose a term of adiposteoblast for describing phenotypic spectrum of MAT. Manipulating with MAT activity in diseases where impairment in energy metabolism correlates with bone functional deficit, such as aging and diabetes, may be beneficial for both. Paracrine activities of MAT might be considered for treatment of bone diseases. MAT has unrecognized potential, either beneficial or detrimental, to regulate bone homeostasis in physiological and pathological conditions. More research is required to harness this potential for therapeutic purposes.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Doenças Ósseas/terapia , Medula Óssea/metabolismo , Metabolismo Energético , Osteoblastos/metabolismo , Comunicação Parácrina , Tecido Adiposo/citologia , Doenças Ósseas/metabolismo , Células da Medula Óssea , Humanos
5.
Diabetologia ; 60(7): 1163-1169, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28434032

RESUMO

Skeletal fragility often accompanies diabetes and does not appear to correlate with low bone mass or trauma severity in individuals with diabetes. Instead (and in contrast to those with osteoporotic bone disease), bone remodelling and bone turnover are compromised in both type 1 and type 2 diabetes, contributing to defective bone material quality. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Ann Schwartz (DOI: 10.1007/s00125-017-4283-6 ). This review presents basic science evidence that, alongside other organs, bone is affected in diabetes via impairments in glucose metabolism, toxic effects of glucose oxidative derivatives (advance glycation end-products [AGEs]), and via impairments in bone microvascular function and muscle endocrine function. The cellular and molecular basis for the effects of diabetes on bone are discussed, as is the impact of diabetes on the stem cell niche and fracture healing. Furthermore, the safety of clinically approved glucose-lowering therapies and the possibility of developing a single therapy that would be beneficial for both insulin sensitisation and diabetes bone syndrome are outlined.


Assuntos
Osso e Ossos/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Animais , Biomarcadores/metabolismo , Velocidade do Fluxo Sanguíneo , Glicemia/análise , Densidade Óssea , Osso e Ossos/fisiologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Homeostase , Humanos , Insulina/química , Metformina/uso terapêutico , Camundongos , Microcirculação , Músculos/metabolismo , Osteoporose/tratamento farmacológico , Nicho de Células-Tronco/efeitos dos fármacos , Compostos de Sulfonilureia/uso terapêutico
6.
J Biol Chem ; 291(47): 24475-24486, 2016 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-27687725

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ) and runt-related transcription factor 2 (RUNX2) are key regulators of mesenchymal stem cell (MSC) differentiation toward adipocytes and osteoblasts, respectively. Post-translational modifications of these factors determine their activities. Dephosphorylation of PPARγ at Ser-112 is required for its adipocytic activity, whereas phosphorylation of RUNX2 at serine 319 (Ser-319) promotes its osteoblastic activity. Here we show that protein phosphatase 5 (PP5) reciprocally regulates each receptor by targeting each serine. Mice deficient in PP5 phosphatase have increased osteoblast numbers and high bone formation, which results in high bone mass in the appendicular and axial skeleton. This is associated with a substantial decrease in lipid-containing marrow adipocytes. Indeed, in the absence of PP5 the MSC lineage allocation is skewed toward osteoblasts and away from lipid accumulating adipocytes, although an increase in beige adipocyte gene expression is observed. In the presence of rosiglitazone, PP5 translocates to the nucleus, binds to PPARγ and RUNX2, and dephosphorylates both factors, resulting in activation of PPARγ adipocytic and suppression of RUNX2 osteoblastic activities. Moreover, shRNA knockdown of PP5 results in cells refractory to rosiglitazone treatment. Lastly, mice deficient in PP5 are resistant to the negative effects of rosiglitazone on bone, which in wild type animals causes a 50% decrease in trabecular bone mass. In conclusion, PP5 is a unique phosphatase reciprocally regulating PPARγ and RUNX2 activities in marrow MSC.


Assuntos
Peso Corporal/efeitos dos fármacos , Osso e Ossos/metabolismo , Núcleo Celular/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Glicoproteínas/metabolismo , PPAR gama/metabolismo , Tiazolidinedionas/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Animais , Peso Corporal/genética , Núcleo Celular/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Glicoproteínas/genética , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , PPAR gama/genética , Rosiglitazona
7.
Physiol Genomics ; 48(6): 409-19, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27113531

RESUMO

Through linkage analysis of the Dahl salt-sensitive (S) rat and the spontaneously hypertensive rat (SHR), a blood pressure (BP) quantitative trait locus (QTL) was previously located on rat chromosome 9. Subsequent substitution mapping studies of this QTL revealed multiple BP QTLs within the originally identified logarithm of odds plot by linkage analysis. The focus of this study was on a 14.39 Mb region, the distal portion of which remained unmapped in our previous studies. High-resolution substitution mapping for a BP QTL in the setting of a high-salt diet indicated that an SHR-derived congenic segment of 787.9 kb containing the gene secreted phosphoprotein-2 (Spp2) lowered BP and urinary protein excretion. A nonsynonymous G/T polymorphism in the Spp2 gene was detected between the S and S.SHR congenic rats. A survey of 45 strains showed that the T allele was rare, being detected only in some substrains of SHR and WKY. Protein modeling prediction through SWISSPROT indicated that the predicted protein product of this variant was significantly altered. Importantly, in addition to improved cardiovascular and renal function, high salt-fed congenic animals carrying the SHR T variant of Spp2 had significantly lower bone mass and altered bone microarchitecture. Total bone volume and volume of trabecular bone, cortical thickness, and degree of mineralization of cortical bone were all significantly reduced in congenic rats. Our study points to opposing effects of a congenic segment containing the prioritized candidate gene Spp2 on BP and bone mass.


Assuntos
Pressão Sanguínea/genética , Osso e Ossos/metabolismo , Cromossomos Humanos Par 9/genética , Fosfoproteínas/genética , Locos de Características Quantitativas/genética , Alelos , Animais , Animais Congênicos/genética , Mapeamento Cromossômico/métodos , Ligação Genética/genética , Humanos , Hipertensão/genética , Masculino , Ratos , Ratos Endogâmicos Dahl , Ratos Endogâmicos SHR/genética , Ratos Endogâmicos WKY , Cloreto de Sódio na Dieta/administração & dosagem
9.
Arch Biochem Biophys ; 561: 124-9, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24956594

RESUMO

Environmental and behavioral changes which occurred over the last century led simultaneously to a remarkable increase in human lifespan and to the development of health problems associated with functional impairment of organs either regulating or dependent on balanced energy metabolism. Diseases such as diabetes, obesity and osteoporosis are prevalent in our society and pose major challenges with respect to the overall health and economy. Therefore, better understanding of regulatory axes between bone and fat may provide the basis for development of strategies which will treat these diseases simultaneously and improve health and life quality of elderly.


Assuntos
Tecido Adiposo/fisiologia , Remodelação Óssea/fisiologia , Osso e Ossos/fisiologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Tecido Adiposo/citologia , Animais , Osso e Ossos/citologia , Humanos , Modelos Biológicos
10.
JBMR Plus ; 8(6): ziae053, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38715931

RESUMO

Diabetes predisposes to spine degenerative diseases often requiring surgical intervention. However, the statistics on the prevalence of spinal fusion success and clinical indications leading to the revision surgery in diabetes are conflicting. The purpose of the presented retrospective observational study was to determine the link between diabetes and lumbar spinal fusion complications using a database of patients (n = 552, 45% male, age 54 ± 13.7 years) residing in the same community and receiving care at the same health care facility. Outcome measures included clinical indications and calculated risk ratio (RR) for revision surgery in diabetes. Paravertebral tissue recovered from a non-union site of diabetic and nondiabetic patients was analyzed for microstructure of newly formed bone. Diabetes increased the RR for revision surgery due to non-union complications (2.80; 95% CI, 1.12-7.02) and degenerative processes in adjacent spine segments (2.26; 95% CI, 1.45-3.53). In diabetes, a risk of revision surgery exceeded the RR for primary spinal fusion surgery by 44% (2.36 [95% CI, 1.58-3.52] vs 1.64 [95% CI, 1.16-2.31]), which was already 2-fold higher than diabetes prevalence in the studied community. Micro-CT of bony fragments found in the paravertebral tissue harvested during revision surgery revealed structural differences suggesting that newly formed bone in diabetic patients may be of compromised quality, as compared with that in nondiabetic patients. In conclusion, diabetes significantly increases the risk of unsuccessful lumbar spine fusion outcome requiring revision surgery. Diabetes predisposes to the degeneration of adjacent spine segments and pseudoarthrosis at the fusion sites, and affects the structure of newly formed bone needed to stabilize fusion.

11.
Mol Metab ; : 102000, 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39074536

RESUMO

OBJECTIVE: The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels, which were previously correlated with metabolic status of extramedullary fat depots. METHODS: In vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp1CrePparγflfl male and female mice (γOTKO) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Pparγ. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress. RESULTS: Circulating sclerostin levels of γOTKO male and female mice were not different from control mice. Male γOTKO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with "beiging" of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOTKO males suggested profound changes in cellular metabolism, fuel transport, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, and accumulation of reactive oxygen species (ROS). CONCLUSIONS: PPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure via osteocyte metabolism.

12.
bioRxiv ; 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38645043

RESUMO

Objective: The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels. Methods: In vivo and in vitro models of osteocyte-specific PPARG deletion, i.e. Dmp 1 Cre Pparγ flfl male and female mice (γOT KO ) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited Pparγ . As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress. Results: Circulating sclerostin levels of γOT KO male and female mice were not different from control mice. Male γOT KO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with "beiging" of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOT KO males suggested profound changes in cellular metabolism, fuel transport and usage, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, shifts in fuel utilization, and accumulation of reactive oxygen species (ROS). Conclusions: PPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure via osteocyte metabolism. Highlights: Osteocytes function as a body energostat via their bioenergeticsPPARG protein acts as a "molecular break" of osteocyte mitochondrial activityPPARG deficiency activates TCA cycle, oxidative stress and ROS accumulationPPARG controls osteocyte insulin signaling and fuel utilization.

13.
J Bone Miner Metab ; 31(1): 44-52, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22945906

RESUMO

Smoking has long been associated with osteoporosis, decreased bone mineral density, increased risk of bone fracture, and increased health costs. Nicotine, the main component of cigarette smoke, has major negative effects on bone metabolism and skeletal remodeling in vivo. Although osteoblasts and osteoblast-like cells have been used extensively to study the impact of nicotine, few studies have been performed on human mesenchymal stem cells (hMSCs). In this context, we examined the impact of nicotine on (a) hMSCs proliferation, (b) osteoblastic differentiation, (c) alkaline phosphatase (ALP) activity, and (d) expression of canonical genes during differentiation of hMSCs. MSCs isolated from human bone marrow were treated with different concentrations (0, 0.1, 1 and 10 µM) of nicotine for 7 days. Nicotine caused a dose-dependent decrease in cell proliferation, decreased heme oxygenase-1 (HO-1) expression (p < 0.05) and attenuated osteogenesis (p < 0.05) in hMSCs (45 % reduction at day 14). In addition, nicotine caused a dose-dependent decrease in alizarin red staining for calcium and staining for ALP. Induction of HO-1 by peroxisome proliferator-activated receptor delta agonist (GW0742) prevented the effect of nicotine. Nicotine caused a dose-dependent reduction in the expression of BMP-2, a well-known marker for bone formation; however, this was prevented by GW0742 treatment. Therefore, induction of HO-1 prevents the deleterious effects of nicotine on osteogenesis in hMSC. This offers insight into both how nicotine affects bone remodeling and a therapeutic approach to prevent fracture and osteoporosis in smokers.


Assuntos
Células da Medula Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Heme Oxigenase-1/biossíntese , Células-Tronco Mesenquimais/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , PPAR delta/agonistas , Fumar/efeitos adversos , Tiazóis/farmacologia , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Células da Medula Óssea/patologia , Proteína Morfogenética Óssea 2/biossíntese , Remodelação Óssea/efeitos dos fármacos , Cálcio/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/patologia , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Osteoblastos/patologia , Osteoporose/metabolismo , Osteoporose/prevenção & controle , PPAR delta/metabolismo , Fumar/metabolismo
14.
Proc Natl Acad Sci U S A ; 107(23): 10508-13, 2010 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-20498072

RESUMO

Nocturnin (NOC) is a circadian-regulated protein related to the yeast family of transcription factors involved in the cellular response to nutrient status. In mammals, NOC functions as a deadenylase but lacks a transcriptional activation domain. It is highly expressed in bone-marrow stromal cells (BMSCs), hepatocytes, and adipocytes. In BMSCs exposed to the PPAR-gamma (peroxisome proliferator-activated receptor-gamma) agonist rosiglitazone, Noc expression was enhanced 30-fold. Previously, we reported that Noc(-/-) mice had low body temperature, were protected from diet-induced obesity, and most importantly exhibited absence of Pparg circadian rhythmicity on a high-fat diet. Consistent with its role in influencing BMSCs allocation, Noc(-/-) mice have reduced bone marrow adiposity and high bone mass. In that same vein, NOC overexpression enhances adipogenesis in 3T3-L1 cells but negatively regulates osteogenesis in MC3T3-E1 cells. NOC and a mutated form, which lacks deadenylase activity, bind to PPAR-gamma and markedly enhance PPAR-gamma transcriptional activity. Both WT and mutant NOC facilitate nuclear translocation of PPAR-gamma. Importantly, NOC-mediated nuclear translocation of PPAR-gamma is blocked by a short peptide fragment of NOC that inhibits its physical interaction with PPAR-gamma. The inhibitory effect of this NOC-peptide was partially reversed by rosiglitazone, suggesting that effect of NOC on PPAR-gamma nuclear translocation may be independent of ligand-mediated PPAR-gamma activation. In sum, Noc plays a unique role in the regulation of mesenchymal stem-cell lineage allocation by modulating PPAR-gamma activity through nuclear translocation. These data illustrate a unique mechanism whereby a nutrient-responsive gene influences BMSCs differentiation, adipogenesis, and ultimately body composition.


Assuntos
Adipogenia , Proteínas Nucleares/metabolismo , PPAR gama/metabolismo , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Composição Corporal , Linhagem Celular , Linhagem da Célula , Ritmo Circadiano , Humanos , Camundongos , Camundongos Knockout , Proteínas Nucleares/deficiência , Osteoblastos/citologia , Osteoblastos/metabolismo , Fatores de Transcrição/deficiência
15.
Clin Rev Bone Miner Metab ; 11(1): 49-58, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23543908

RESUMO

Osteoporosis and diabetic disease have reached epidemic proportion and create significant public health concerns. The prevalence of these diseases is alarming, and indicates that in the US, 50% of elderly individuals are osteoporotic and almost 20% of population has either diabetic or prediabetic conditions (Centers for Disease Control and Prevention; http://www.cdc.gov). Osteoporosis and diabetes share many features including genetic predispositions and molecular mechanisms. The linkage between these two chronic diseases, which stems from overlapping molecular controls involved in bone homeostasis and energy metabolism, creates a possibility that certain anti-diabetic therapies may affect bone. This concurs with recent findings indicating that bone status is closely linked to regulation of energy metabolism and insulin sensitivity. Indeed, bone and energy homeostasis are under the control of the same regulatory factors, including insulin, peroxisome proliferator activated receptor gamma (PPARγ), gastrointestinal hormones such as glucose inhibitory protein (GIP) and glucagon inhibitory peptide (GLP), and bone derived hormone osteocalcin. These factors and related mechanisms control glucose homeostasis and fatty acids metabolism in fat tissue, pancreas and intestine, which are pharmacological targets for anti-diabetic therapies. The same factors contribute to the bone quality by their effect on bone cell differentiation and bone remodeling process. This implies that bone should be considered as a vital target for therapies which modulate energy metabolism. This review is summarizing available data on the skeletal effects of clinically approved anti-diabetic therapies.

16.
Front Endocrinol (Lausanne) ; 14: 1145467, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37181042

RESUMO

Introduction: The view that bone and energy metabolism are integrated by common regulatory mechanisms is broadly accepted and supported by multiple strands of evidence. This includes the well-characterized role of the PPARγ nuclear receptor, which is a common denominator in energy metabolism and bone metabolism. Little is known, however, about the role of PPARα nuclear receptor, a major regulator of lipid metabolism in other organs, in bone. Methods: A side-by-side comparative study of 5-15 mo old mice with global PPARα deficiency (αKO) and mice with osteocyte-specific PPARα deficiency (αOTKO) in order to parse out the various activities of PPARα in the skeleton that are of local and systemic significance. This study included transcriptome analysis of PPARα-deficient osteocytes, and analyses of bone mass and bone microarchitecture, systemic energy metabolism with indirect calorimetry, and differentiation potential of hematopoietic and mesenchymal bone cell progenitors. These analyses were paired with in vitro studies of either intact or silenced for PPARα MLO-A5 cells to determine PPARα role in osteocyte bioenergetics. Results: In osteocytes, PPARα controls large number of transcripts coding for signaling and secreted proteins which may regulate bone microenvironment and peripheral fat metabolism. In addition, PPARα in osteocytes controls their bioenergetics and mitochondrial response to stress, which constitutes up to 40% of total PPARα contribution to the global energy metabolism. Similarly to αKO mice, the metabolic phenotype of αOTKO mice (both males and females) is age-dependent. In younger mice, osteocyte metabolism contributes positively to global energetics, however, with aging the high-energy phenotype reverts to a low-energy phenotype and obesity develops, suggesting a longitudinal negative effect of impaired lipid metabolism and mitochondrial dysfunction in osteocytes deficient in PPARα. However, bone phenotype was not affected in αOTKO mice except in the form of an increased volume of marrow adipose tissue in males. In contrast, global PPARα deficiency in αKO mice led to enlarged bone diameter with a proportional increase in number of trabeculae and enlarged marrow cavities; it also altered differentiation of hematopoietic and mesenchymal marrow cells toward osteoclast, osteoblast and adipocyte lineages, respectively. Discussion: PPARα role in bone is multileveled and complex. In osteocytes, PPARα controls the bioenergetics of these cells, which significantly contributes to systemic energy metabolism and their endocrine/paracrine function in controlling marrow adiposity and peripheral fat metabolism.


Assuntos
Osso e Ossos , Metabolismo Energético , Osteócitos , PPAR alfa , Osteócitos/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Metabolismo Energético/genética , Animais , Camundongos , Células Cultivadas , Masculino , Feminino , Transdução de Sinais , Camundongos Knockout , Células-Tronco Hematopoéticas/citologia , Diferenciação Celular/genética , Fatores Etários , Perfilação da Expressão Gênica
17.
Calcif Tissue Int ; 91(2): 139-48, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22752619

RESUMO

Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma activators, and insulin sensitizers represent drugs used to treat hyperglycemia in diabetic patients. Type 2 diabetes mellitus (T2DM) is associated with a twofold increase in fracture risk, and TZDs use increases this risk by an additional twofold. In this study, we analyzed the effect of systemic administration of the TZD rosiglitazone on new bone formation in two in vivo models of bone repair, a model of drilled bone defect regeneration (BDR) and distraction osteogenesis (DO) and a model of extended bone formation. Rosiglitazone significantly inhibited new endosteal bone formation in both models. This effect was correlated with a significant accumulation of fat cells, specifically at sites of bone regeneration. The diminished bone regeneration in the DO model in rosiglitazone-treated animals was associated with a significant decrease in cell proliferation measured by the number of cells expressing proliferating cell nuclear antigen and neovascularization measured by both the number of vascular sinusoids and the number of cells producing proangiogenic vascular endothelial growth factor at the DO site. In summary, rosiglitazone decreased new bone formation in both BDR and DO models of bone repair by mechanisms which include both intrinsic changes in mesenchymal stem cell proliferation and differentiation and changes in the local environment supporting angiogenesis and new bone formation. These studies suggest that bone regeneration may be significantly compromised in T2DM patients on TZD therapy.


Assuntos
Tecido Adiposo , Doenças Ósseas/induzido quimicamente , Regeneração Óssea/efeitos dos fármacos , Coristoma/induzido quimicamente , Osteogênese/efeitos dos fármacos , Tiazolidinedionas/efeitos adversos , Animais , Doenças Ósseas/diagnóstico por imagem , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteogênese/fisiologia , Rosiglitazona , Tiazolidinedionas/farmacologia , Microtomografia por Raio-X
18.
Front Endocrinol (Lausanne) ; 12: 712088, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335478

RESUMO

The 6th International Meeting on Bone Marrow Adiposity (BMA) entitled "Marrow Adiposity: Bone, Aging, and Beyond" (BMA2020) was held virtually on September 9th and 10th, 2020. The mission of this meeting was to facilitate communication and collaboration among scientists from around the world who are interested in different aspects of bone marrow adiposity in health and disease. The BMA2020 meeting brought together 198 attendees from diverse research and clinical backgrounds spanning fields including bone biology, endocrinology, stem cell biology, metabolism, oncology, aging, and hematopoiesis. The congress featured an invited keynote address by Ormond MacDougald and ten invited speakers, in addition to 20 short talks, 35 posters, and several training and networking sessions. This report summarizes and highlights the scientific content of the meeting and the progress of the working groups of the BMA society (http://bma-society.org/).


Assuntos
Adiposidade , Medula Óssea , Medula Óssea/metabolismo , Hematopoese , Humanos , Desnutrição , Neoplasias , Obesidade
19.
Bone ; 147: 115913, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33722775

RESUMO

The peroxisome proliferator activated receptor gamma (PPARG) nuclear receptor regulates energy metabolism and insulin sensitivity. In this study, we present novel evidence for an essential role of PPARG in the regulation of osteocyte function, and support for the emerging concept of the conjunction between regulation of energy metabolism and bone mass. We report that PPARG is essential for sclerostin production, a recently approved target to treat osteoporosis. Our mouse model of osteocyte-specific PPARG deletion (Dmp1CrePparγflfl or γOTKO) is characterized with increased bone mass and reduced bone marrow adiposity, which is consistent with upregulation of WNT signaling and increased bone forming activity of endosteal osteoblasts. An analysis of osteocytes derived from γOTKO and control mice showed an excellent correlation between PPARG and SOST/sclerostin at the transcript and protein levels. The 8 kb sequence upstream of Sost gene transcription start site possesses multiple PPARG binding elements (PPREs) with at least two of them binding PPARG with dynamics reflecting its activation with full agonist rosiglitazone and correlating with increased levels of Sost transcript and sclerostin protein expression (Pearson's r = 0.991, p = 0.001). Older γOTKO female mice are largely protected from TZD-induced bone loss providing proof of concept that PPARG in osteocytes can be pharmacologically targeted. These findings demonstrate that transcriptional activities of PPARG are essential for sclerostin expression in osteocytes and support consideration of targeting PPARG activities with selective modulators to treat osteoporosis.


Assuntos
Osteócitos , PPAR gama , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adiposidade , Animais , Medula Óssea/metabolismo , Feminino , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Osteócitos/metabolismo , PPAR gama/genética
20.
Curr Osteoporos Rep ; 8(4): 178-84, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20809203

RESUMO

Clinical evidence indicates that bone status is affected in patients with type 2 diabetes mellitus (T2DM). Regardless of normal or even high bone mineral density, T2DM patients have increased risk of fractures. One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis. Risk factors for development of TZD-induced secondary osteoporosis are gender (women), age (elderly), and duration of treatment. TZDs exert their antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ) nuclear receptor, which controls glucose and fatty acid metabolism. In bone, PPAR-γ controls differentiation of cells of mesenchymal and hematopoietic lineages. PPAR-γ activation with TZDs leads to unbalanced bone remodeling: bone resorption increases and bone formation decreases. Laboratory research evidence points toward a possible separation of unwanted effects of PPAR-γ on bone from its beneficial antidiabetic effects by using selective PPAR-γ modulators. This review also discusses potential pharmacologic means to protect bone from detrimental effects of clinically used TZDs (pioglitazone and rosiglitazone) by using combinational therapy with approved antiosteoporotic drugs, or by using lower doses of TZDs in combination with other antidiabetic therapy. We also suggest a possible orthopedic complication, not yet supported by clinical studies, of delayed fracture healing in T2DM patients on TZD therapy.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Osteoporose/induzido quimicamente , Tiazolidinedionas/efeitos adversos , Animais , Densidade Óssea/fisiologia , Diferenciação Celular/fisiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Combinação de Medicamentos , Quimioterapia Combinada , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Osteoporose/fisiopatologia , Osteoporose/prevenção & controle , PPAR gama/antagonistas & inibidores , Pioglitazona , Rosiglitazona , Tiazolidinedionas/uso terapêutico
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