RESUMO
Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Denosumab/efeitos adversos , Difosfonatos/efeitos adversos , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Doenças Periodontais/epidemiologia , Comitês Consultivos , Antibacterianos/uso terapêutico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Conservadores da Densidade Óssea/administração & dosagem , Desbridamento , Denosumab/administração & dosagem , Difosfonatos/administração & dosagem , Relação Dose-Resposta a Droga , Fraturas Ósseas/prevenção & controle , Humanos , Higiene Bucal/métodos , Doenças Periodontais/terapia , Guias de Prática Clínica como Assunto , Fatores de Risco , Teriparatida/uso terapêuticoRESUMO
Inflammatory bowel diseases are commonly complicated by weight and bone loss. We hypothesized that IL-15, a pro-inflammatory cytokine expressed in colitis and an osteoclastogenic factor, could play a central role in systemic and skeletal complications of inflammatory bowel diseases. We evaluated the effects of an IL-15 antagonist, CRB-15, in mice with chronic colitis induced by oral 2% dextran sulfate sodium for 1 week, followed by another 1% for 2 weeks. During the last 2 weeks, mice were treated daily with CRB-15 or an IgG2a control antibody. Intestinal inflammation, disease severity, and bone parameters were evaluated at days 14 and 21. CRB-15 improved survival, early weight loss, and colitis clinical score, although colon damage and inflammation were prevented in only half the survivors. CRB-15 also delayed loss of femur bone mineral density and trabecular microarchitecture. Bone loss was characterized by decreased bone formation, but increased bone marrow osteoclast progenitors and osteoclast numbers on bone surfaces. CRB-15 prevented the suppression of osteoblastic markers of bone formation, and reduced osteoclast progenitors at day 14, but not later. However, by day 21, CRB-15 decreased tumor necrosis factor α and increased IL-10 expression in bone, paralleling a reduction of osteoclasts. These results delineate the role of IL-15 on the systemic and skeletal manifestations of chronic colitis and provide a proof-of-concept for future therapeutic developments.
Assuntos
Colite/prevenção & controle , Interleucina-15/antagonistas & inibidores , Osteoporose/prevenção & controle , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Doença Crônica , Colite/induzido quimicamente , Colite/complicações , Colite/fisiopatologia , Citocinas/metabolismo , Sulfato de Dextrana , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Fêmur/patologia , Fêmur/fisiopatologia , Mediadores da Inflamação/metabolismo , Interleucina-15/farmacologia , Interleucina-15/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteoporose/etiologia , Osteoporose/patologia , Osteoporose/fisiopatologia , Proteínas Recombinantes de Fusão/farmacologia , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
Vitamin D deficiency is associated with osteoporosis and is thought to increase the risk of cancer and CVD. Despite these numerous potential health effects, data on vitamin D status at the population level and within key subgroups are limited. The aims of the present study were to examine patterns of 25-hydroxyvitamin D (25(OH)D) levels worldwide and to assess differences by age, sex and region. In a systematic literature review using the Medline and EMBASE databases, we identified 195 studies conducted in forty-four countries involving more than 168 000 participants. Mean population-level 25(OH)D values varied considerably across the studies (range 4·9-136·2 nmol/l), with 37·3 % of the studies reporting mean values below 50 nmol/l. The highest 25(OH)D values were observed in North America. Although age-related differences were observed in the Asia/Pacific and Middle East/Africa regions, they were not observed elsewhere and sex-related differences were not observed in any region. Substantial heterogeneity between the studies precluded drawing conclusions on overall vitamin D status at the population level. Exploratory analyses, however, suggested that newborns and institutionalised elderly from several regions worldwide appeared to be at a generally higher risk of exhibiting lower 25(OH)D values. Substantial details on worldwide patterns of vitamin D status at the population level and within key subgroups are needed to inform public health policy development to reduce risk for potential health consequences of an inadequate vitamin D status.
Assuntos
Saúde Global , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Fatores Etários , Humanos , Fatores de Risco , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicaçõesRESUMO
CONTEXT: The risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context. OBJECTIVE: This review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes. METHODS: A group of experts from the International Osteoporosis Foundation and European Calcified Tissue Society reviewed the literature focusing on biochemical markers, diabetes, diabetes treatments, and bone in adults. RESULTS: Although bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers (BTMs) in diabetics similarly to nondiabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with bone mineral density and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, glycated hemoglobin A1c (HbA1c) and advanced glycation end products, inflammatory markers, and adipokines, as well as insulin-like growth factor-1 and calciotropic hormones. CONCLUSION: Several biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while BTMs could be used to monitor the effects of antiosteoporosis therapy.
RESUMO
CONTEXT: The risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context. This review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes. METHODS: Literature review by a group of experts from the International Osteoporosis Foundation (IOF) and European Calcified Tissue Society (ECTS) focusing on biochemical markers, diabetes, diabetes treatments and bone in adults. RESULTS: Although bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers in diabetics similarly to non-diabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with BMD and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, HbA1c and advanced glycation end products (AGEs), inflammatory markers and adipokines, as well as IGF-1 and calciotropic hormones. CONCLUSION: Several biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while bone turnover markers could be used to monitor the effects of anti-osteoporosis therapy.
RESUMO
PTH stimulates osteoblastic cells to form new bone and to produce osteoblast-osteoclast coupling factors such as RANKL. Whether osteoclasts or their activity are needed for PTH anabolism remains uncertain. We treated ovariectomized huRANKL knock-in mice with a human RANKL inhibitor denosumab (DMAb), alendronate (Aln), or vehicle for 4 weeks, followed by co-treatment with intermittent PTH for 4 weeks. Loss of bone mass and microarchitecture was prevented by Aln and further significantly improved by DMAb. PTH improved bone mass, microstructure, and strength, and was additive to Aln but not to DMAb. Aln inhibited biochemical and histomorphometrical indices of bone turnover,--i.e. osteocalcin and bone formation rate (BFR) on cancellous bone surfaces-, and Dmab inhibited them further. However Aln increased whereas Dmab suppressed osteoclast number and surfaces. PTH significantly increased osteocalcin and bone formation indices, in the absence or presence of either antiresorptive, although BFR remained lower in presence of Dmab. To further evaluate PTH effects in the complete absence of osteoclasts, high dose PTH was administered to RANK(-/-) mice. PTH increased osteocalcin similarly in RANK(-/-) and WT mice. It also increased BMD in RANK(-/-) mice, although less than in WT. These results further indicate that osteoclasts are not strictly required for PTH anabolism, which presumably still occurs via stimulation of modeling-based bone formation. However the magnitude of PTH anabolic effects on the skeleton, in particular its additive effects with antiresorptives, depends on the extent of the remodeling space, as determined by the number and activity of osteoclasts on bone surfaces.
Assuntos
Alendronato/farmacologia , Anticorpos Monoclonais/farmacologia , Osso e Ossos/metabolismo , Técnicas de Introdução de Genes , Osteoclastos/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Ligante RANK/farmacologia , Receptor Ativador de Fator Nuclear kappa-B/genética , Alendronato/administração & dosagem , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Biomarcadores/metabolismo , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Denosumab , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Ovariectomia , Hormônio Paratireóideo/administração & dosagem , Ligante RANK/administração & dosagem , Receptor Ativador de Fator Nuclear kappa-B/antagonistas & inibidores , Receptor Ativador de Fator Nuclear kappa-B/deficiência , Receptor Ativador de Fator Nuclear kappa-B/metabolismoRESUMO
OBJECTIVE: T cell production of RANKL, interferon-γ (IFNγ), and other cytokines in inflammatory processes such as rheumatoid arthritis or secondary to conditions such as estrogen deficiency stimulates osteoclast activity, which leads to bone resorption and bone loss. The purpose of this study was to characterize the effects of interleukin-15 (IL-15), a master T cell growth factor whose role in bone remodeling remains unknown. METHODS: We used mice lacking the IL-15 receptor (IL-15Rα(-/-) ) to investigate the effects of IL-15 on osteoclast development, T cell and dendritic cell activation in vitro and in vivo, bone mass, and microarchitecture in intact and ovariectomized (OVX) mice. RESULTS: In wild-type (WT) animals, IL-15 and RANKL provided a costimulatory signal for osteoclast development. Spleens from IL-15Rα(-/-) mice contained few c-Kit+ osteoclast precursors, and the expression of NF-ATc1 and the osteoclastogenic response to RANKL were impaired. In addition, dendritic cell-dependent and T cell-dependent mechanisms of osteoclast activation, including RANKL and IFNγ production, were impaired in IL-15Rα(-/-) mice. In turn, IL-15Rα(-/-) T cells failed to stimulate WT osteoclasts, whereas WT T cells failed to stimulate IL-15Rα(-/-) osteoclasts. Compared with WT mice, both intact and OVX IL-15Rα(-/-) mice had significantly greater bone mineral density and microarchitecture, including a higher trabecular bone volume fraction and cortical thickness. The numbers of osteoclasts on the bone surface as well as markers of bone turnover were significantly decreased in IL-15Rα(-/-) mice. CONCLUSION: In the absence of IL-15 signaling, several converging mechanisms of osteoclastogenesis are inhibited, both directly and indirectly, through T cells, which leads to a high bone mass phenotype. Targeting the IL-15 pathway may represent a novel therapeutic approach to treating primary and secondary osteoporosis.
Assuntos
Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Osteoclastos/metabolismo , Ligante RANK/metabolismo , Receptores de Interleucina-15/metabolismo , Linfócitos T/metabolismo , Animais , Western Blotting , Densidade Óssea , Diferenciação Celular , Células Cultivadas , Feminino , Camundongos , Camundongos Knockout , Ligante RANK/genética , Receptores de Interleucina-15/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Baço/metabolismoRESUMO
Long bones from mammals host blood cell formation and contain multiple cell types, including adipocytes. Physiological functions of bone marrow adipocytes are poorly documented. Herein, we used adipocyte-deficient PPARγ-whole body null mice to investigate the consequence of total adipocyte deficiency on bone homeostasis in mice. We first highlighted the dual bone phenotype of PPARγ null mice: one the one hand, the increased bone formation and subsequent trabecularization extending in the long bone diaphysis, due to the well-known impact of PPARγ deficiency on osteoblasts formation and activity; on the other hand, an increased osteoclastogenesis in the cortical bone. We then further explored the cause of this unexpected increased osteoclastogenesis using two independent models of lipoatrophy, which recapitulated this phenotype. This demonstrates that hyperosteoclastogenesis is not intrinsically linked to PPARγ deficiency, but is a consequence of the total lipodystrophy. We further showed that adiponectin, a cytokine produced by adipocytes and mesenchymal stromal cells is a potent inhibitor of osteoclastogenesis in vitro and in vivo. Moreover, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon inhibited mature osteoclast activity both in mouse and human cells by blocking podosome formation through AMPK activation. Finally, we demonstrated that AdipoRon treatment blocks bone erosion in vivo in a murine model of inflammatory bone loss, providing potential new approaches to treat osteoporosis.
RESUMO
UNLABELLED: Skeletal anabolism with PTH is achieved through daily injections that result in brief exposure to the peptide. We hypothesized that similar anabolic effects could be achieved with less frequent but more sustained exposures to PTH. A PTH-Fc fusion protein with a longer half-life than PTH(1-34) increased cortical and cancellous BMD and bone strength with once- or twice-weekly injections. INTRODUCTION: The anabolic effects of PTH are currently achieved with, and thought to require, daily injections that result in brief exposure to the peptide. We hypothesized that less frequent but more sustained exposures to PTH could also be anabolic for bone, provided that serum levels of PTH were not constant. MATERIALS AND METHODS: PTH(1-34) was fused to the Fc fragment of human IgG1 to increase the half-life of PTH. Skeletal anabolism was examined in mice and rats treated once or twice per week with this PTH-Fc fusion protein. RESULTS: PTH-Fc and PTH(1-34) had similar effects on PTH/PTHrP receptor activation, internalization, and signaling in vitro. However, PTH-Fc had a 33-fold longer mean residence time in the circulation of rats compared with that of PTH(1-34). Subcutaneous injection of PTH-Fc once or twice per week resulted in significant increases in bone volume, density, and strength in osteopenic ovariectomized mice and rats. These anabolic effects occurred in association with hypercalcemia and were significantly greater than those achievable with high concentrations of daily PTH(1-34). PTH-Fc also significantly improved cortical bone volume and density under conditions where daily PTH(1-34) did not. Antiresorptive co-therapy with estrogen further enhanced the ability of PTH-Fc to increase bone mass and strength in ovariectomized rats. CONCLUSIONS: These results challenge the notion that brief daily exposure to PTH is essential for its anabolic effects on cortical and cancellous bone. PTH-derived molecules with a sustained circulating half-life may represent a powerful and previously undefined anabolic regimen for cortical and cancellous bone.
Assuntos
Anabolizantes/administração & dosagem , Anabolizantes/farmacologia , Osso e Ossos/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Hormônio Paratireóideo/administração & dosagem , Hormônio Paratireóideo/farmacologia , Proteínas Recombinantes/farmacologia , Envelhecimento/fisiologia , Anabolizantes/farmacocinética , Animais , Arrestinas/metabolismo , Osso e Ossos/metabolismo , Linhagem Celular , Cricetinae , Relação Dose-Resposta a Droga , Estrogênios/farmacologia , Meia-Vida , Humanos , Masculino , Camundongos , Ovariectomia , Hormônio Paratireóideo/farmacocinética , Transporte Proteico , Ratos , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Fatores de Tempo , beta-ArrestinasRESUMO
The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. However, in both T1DM and T2DM, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly so when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia, oxidative stress and the accumulation of advanced glycation endproducts that compromise collagen properties, increase marrow adiposity, release inflammatory factors and adipokines from visceral fat, and potentially alter the function of osteocytes. Additional factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus.
Assuntos
Remodelação Óssea/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fraturas Ósseas/metabolismo , Acidentes por Quedas/prevenção & controle , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Remodelação Óssea/efeitos dos fármacos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fraturas Ósseas/etiologia , Humanos , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêuticoRESUMO
Intermittent administration of parathyroid hormone (PTH) induces bone remodeling and renewed bone modeling, resulting in net bone gain. beta-blockers improve trabecular bone architecture in young ovariectomized mice by preventing the inhibition of bone formation and stimulation of bone resorption induced by the adrenergic system. To test the hypothesis that PTH and beta-blockers may exert synergistic effects on the skeleton, 15-week-old ovariectomized mice were either given oral propranolol (PRO) or left untreated for 8 weeks, adding daily hPTH(1-34) (80 microg/kg/day) or vehicle (VEH) during the last 4 weeks. The skeletal response was evaluated using pDXA, microCT, histomorphometry and biochemical markers. PRO significantly attenuated loss of bone mineral density (BMD) at whole body (WB) (-0.1% in PRO vs. -2.4% in VEH, P < 0.05), but not at spine or femur 4 weeks after OVX. Thereafter, PTH increased BMD at all sites in both PRO- and VEH-treated mice (+6.7% to +14%, P < 0.05 to P < 0.0001 vs. VEH). Over 8 weeks, sequential-combined treatment of PRO and PTH significantly improved BMD over PTH alone at WB (+9.1% vs. +4.4% over baseline, respectively, P < 0.005) and spine (+9% vs. -1.7%, respectively, P < 0.05). These effects were paralleled by a decrease in TRACP5b with PRO (P < 0.05 vs. VEH) and an increase in osteocalcin with PTH, irrespective of PRO (P < 0.0001 vs. VEH). Trabecular bone microarchitecture, such as BV/TV, trabecular number and ConnD, was significantly improved by sequential-combined treatment of PRO and PTH compared to PTH alone. At midshaft femur, both PRO and PTH significantly increased cross-sectional area (CSA), but the effects of the two drugs on CSA and cortical thickness were not additive. Dynamic histomorphometry indicated that bone formation was increased by PTH at both cortical and trabecular surfaces, whereas PRO increased osteoblast number and surface on trabecular surfaces. The combined treatment further improved the extent of mineralization and BFR over PTH alone (P < 0.05) at endocortical surfaces and recapitulated the effects of PTH and PRO alone on trabecular surfaces. These results indicate that beta-adrenergic blockade may partially improve the bone remodeling balance induced by estrogen deficiency. In turn, PRO exerted synergistic effects with intermittent PTH on bone mass and cancellous bone architecture. As such, combined therapy of beta-blockers and PTH may be of interest in the treatment of postmenopausal osteoporosis.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Ovariectomia , Hormônio Paratireóideo/farmacologia , Propranolol/farmacologia , Animais , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Fêmur/citologia , Fêmur/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Fatores de TempoRESUMO
UNLABELLED: Cytoplasmic arrestins regulate PTH signaling in vitro. We show that female beta-arrestin2(-/-) mice have decreased bone mass and altered bone architecture. The effects of intermittent PTH administration on bone microarchitecture differed in beta-arrestin2(-/-) and wildtype mice. These data indicate that arrestin-mediated regulation of intracellular signaling contributes to the differential effects of PTH at endosteal and periosteal bone surfaces. INTRODUCTION: The effects of PTH differ at endosteal and periosteal surfaces, suggesting that PTH activity in these compartments may depend on some yet unidentified mechanism(s) of regulation. The action of PTH in bone is mediated primarily by intracellular cAMP, and the cytoplasmic molecule beta-arrestin2 plays a central role in this signaling regulation. Thus, we hypothesized that arrestins would modulate the effects of PTH on bone in vivo. MATERIALS AND METHODS: We used pDXA, muCT, histomorphometry, and serum markers of bone turnover to assess the skeletal response to intermittent PTH (0, 20, 40, or 80 mug/kg/day) in adult female mice null for beta-arrestin2 (beta-arr2(-/-)) and wildtype (WT) littermates (7-11/group). RESULTS AND CONCLUSIONS: beta-arr2(-/-) mice had significantly lower total body BMD, trabecular bone volume fraction (BV/TV), and femoral cross-sectional area compared with WT. In WT females, PTH increased total body BMD, trabecular bone parameters, and cortical thickness, with a trend toward decreased midfemoral medullary area. In beta-arr2(-/-) mice, PTH not only improved total body BMD, trabecular bone architecture, and cortical thickness, but also dose-dependently increased femoral cross-sectional area and medullary area. Histomorphometry showed that PTH-stimulated periosteal bone formation was 2-fold higher in beta-arr2(-/-) compared with WT. Osteocalcin levels were significantly lower in beta-arr2(-/-) mice, but increased dose-dependently with PTH in both beta-arr2(-/-) and WT. In contrast, whereas the resorption marker TRACP5B increased dose-dependently in WT, 20-80 mug/kg/day of PTH was equipotent with regard to stimulation of TRACP5B in beta-arr2(-/-). In summary, beta-arrestin2 plays an important role in bone mass acquisition and remodeling. In estrogen-replete female mice, the ability of intermittent PTH to stimulate periosteal bone apposition and endosteal resorption is inhibited by arrestins. We therefore infer that arrestin-mediated regulation of intracellular signaling contributes to the differential effects of PTH on cancellous and cortical bone.
Assuntos
Arrestinas/fisiologia , Osso e Ossos/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Animais , Arrestinas/genética , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Feminino , Fêmur/citologia , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Camundongos , Camundongos Knockout , Hormônio Paratireóideo/metabolismo , Transdução de Sinais , beta-Arrestina 2 , beta-ArrestinasRESUMO
High-fat diet-induced obesity (DIO) in rodents is associated with hyperleptinemia and resistance to leptin, but the response to agents acting downstream of leptin receptors remains unknown. We assessed the response of mice with DIO to treatment with MTII, an alpha-melanocyte-stimulating hormone analog. MTII delivered four times daily by intraperitoneal injection to C57BL/6J mice produced a dose-responsive effect on food intake, body weight, leptin, corticosterone, insulin, and free fatty acids. In DIO mice, administration of MTII 100 microg q.i.d. i.p. markedly suppressed feeding during the first 4 days of treatment, with food intake returning to control levels at day 5. Progressive weight loss also occurred over the first 4 days, after which weight plateaued at a level below control. After 8 days of treatment, MTII-treated DIO mice had major suppression of both leptin and insulin levels. Central administration of MTII for 4 days (10 nmol/day) in DIO mice significantly suppressed food intake, induced weight loss, and increased energy expenditure. These results indicate that 1) MTII administration to DIO mice causes suppression of food intake and body weight loss, and decreased food intake is primarily responsible for weight loss; 2) peripheral MTII improves insulin resistance in DIO mice; 3) "tachyphylaxis" to the effect of chronic MTII treatment on food intake occurs; and 4) at least some of the effects of MTII are exerted centrally. In conclusion, treatment with a melanocortin agonist is a promising therapeutic approach to DIO and associated insulin resistance.
Assuntos
Obesidade/tratamento farmacológico , Oligopeptídeos/farmacologia , Receptores da Corticotropina/agonistas , Animais , Glicemia , Peso Corporal/efeitos dos fármacos , Corticosterona/sangue , Dieta , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Intraventriculares , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Melanocortina , alfa-MSH/análogos & derivadosRESUMO
The human PTH receptor type 2 (PTH2R) is activated by PTH and tuberoinfundibular peptide of 39 residues (TIP39), resulting in cAMP and intracellular Ca signaling. We now report that, despite these similarities, PTH and TIP39 elicit distinct responses from PTH2R. First, TIP39 induced beta-arrestin and protein kinase Cbeta mobilization and receptor internalization, whereas PTH did not. However, PTH stimulated trafficking of these molecules for a chimeric PTH2R containing the N terminus and third extracellular loop of PTH receptor type 1 (PTH1R). Second, whereas PTH-stimulated cAMP activity was brief and rapidly resensitized, the response to TIP39 was sustained and partly desensitized for a prolonged period. PTH2R desensitization was mediated by beta-arrestin interaction with the C terminus (amino acids 426-457) of PTH2R, whereas beta-arrestin mobilization had a minor influence on PTH2R internalization in response to TIP39, as shown with C terminus deletion mutants and/or dominant negative forms of beta-arrestin and dynamin. These data contrast with PTH1R, at which these dominant negative mutants markedly inhibited receptor internalization. Collectively, these results further highlight how specific interactions within the ligand-receptor bimolecular complex mediate distinct postactivation responses of class II G protein- coupled receptors and provide novel insights into the physiological regulation of PTH2R activity.
Assuntos
Hormônio Paratireóideo/metabolismo , Receptor Tipo 2 de Hormônio Paratireóideo/metabolismo , Sequência de Aminoácidos , Animais , Arrestinas/metabolismo , Cálcio/metabolismo , Linhagem Celular , Clonagem Molecular , AMP Cíclico/metabolismo , Dinaminas/metabolismo , Endocitose , Genes Dominantes , Proteínas de Fluorescência Verde/metabolismo , Humanos , Cinética , Ligantes , Dados de Sequência Molecular , Mutação , Peptídeos/química , Plasmídeos/metabolismo , Ligação Proteica , Proteína Quinase C/metabolismo , Proteína Quinase C beta , Estrutura Terciária de Proteína , Ratos , Receptor Tipo 2 de Hormônio Paratireóideo/química , Proteínas Recombinantes de Fusão/química , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Temperatura , Fatores de Tempo , beta-ArrestinasRESUMO
This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.
Assuntos
Mandíbula , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções Bacterianas/imunologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico por imagem , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/imunologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Tomografia Computadorizada de Feixe Cônico , Consenso , Denosumab , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Mandíbula/diagnóstico por imagem , Mandíbula/imunologia , Monócitos/imunologia , Monócitos/patologia , Osteoporose/diagnóstico , Osteoporose/diagnóstico por imagem , Osteoporose/tratamento farmacológico , Osteoporose/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Fatores de Risco , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Leptin deficiency causes obesity in rodents and humans, but circulating levels of leptin are paradoxically elevated in obesity. The mechanisms underlying this leptin resistance are unknown, but may involve reduced leptin transport across the blood-brain barrier via short isoforms of the leptin receptor (Ob-R). Here, we first quantified short Ob-R mRNA expression in isolated rat cerebral microvessels constituting the blood-brain barrier and found that Ob-Ra and Ob-Rc mRNA were abundantly expressed in similar amounts. Second, brain uptake of leptin was reduced in mice lacking Ob-R. Third, brain uptake of leptin in New Zealand Obese mice, a strain that responds to central, but not peripheral, leptin, was reduced, suggesting that their obesity is at least partly due to deficient leptin transport into the brain. Fourth, brain uptake of leptin was significantly reduced in diet-induced obese mice. Neither New Zealand Obese mice nor diet-induced obese mice exhibited significant decreases in Ob-R mRNA expression in isolated cerebral microvessels. These data support the ideas that short isoforms of Ob-R are involved in brain uptake of leptin and that impaired blood-brain barrier function contributes to the pathogenesis of obesity. However, the mechanisms by which obesity-related deficits in brain uptake of leptin occur remain to be defined.
Assuntos
Química Encefálica/fisiologia , Proteínas de Transporte/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Receptores de Superfície Celular , Animais , Barreira Hematoencefálica/fisiologia , Peso Corporal/genética , Capilares/metabolismo , Proteínas de Transporte/genética , Circulação Cerebrovascular/fisiologia , Gorduras na Dieta , Isomerismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar , Receptores para Leptina , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
As they age, mice deficient for the ß2-adrenergic receptor (Adrb2(-/-) ) maintain greater trabecular bone microarchitecture, as a result of lower bone resorption and increased bone formation. The role of ß1-adrenergic receptor signaling and its interaction with ß2-adrenergic receptor on bone mass regulation, however, remains poorly understood. We first investigated the skeletal response to mechanical stimulation in mice deficient for ß1-adrenergic receptors and/or ß2-adrenergic receptors. Upon axial compression loading of the tibia, bone density, cancellous and cortical microarchitecture, as well as histomorphometric bone forming indices, were increased in both Adrb2(-/-) and wild-type (WT) mice, but not in Adrb1(-/-) nor in Adrb1b2(-/-) mice. Moreover, in the unstimulated femur and vertebra, bone mass and microarchitecture were increased in Adrb2(-/-) mice, whereas in Adrb1(-/-) and Adrb1b2(-/-) double knockout mice, femur bone mineral density (BMD), cancellous bone volume/total volume (BV/TV), cortical size, and cortical thickness were lower compared to WT. Bone histomorphometry and biochemical markers showed markedly decreased bone formation in Adrb1b2(-/-) mice during growth, which paralleled a significant decline in circulating insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGF-BP3). Finally, administration of the ß-adrenergic agonist isoproterenol increased bone resorption and receptor activator of NF-κB ligand (RANKL) and decreased bone mass and microarchitecture in WT but not in Adrb1b2(-/-) mice. Altogether, these results demonstrate that ß1- and ß2-adrenergic signaling exert opposite effects on bone, with ß1 exerting a predominant anabolic stimulus in response to mechanical stimulation and during growth, whereas ß2-adrenergic receptor signaling mainly regulates bone resorption during aging.
Assuntos
Osso e Ossos/patologia , Deleção de Genes , Receptores Adrenérgicos beta 1/deficiência , Receptores Adrenérgicos beta 2/deficiência , Estresse Mecânico , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Fêmur/patologia , Fêmur/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Isoproterenol/farmacologia , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Fenótipo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismoRESUMO
OBJECTIVE: The aim of this study was to determine the skeletal effect of quercetin-6-C-ß-D-glucopyranoside (QCG) isolated from the extract of Ulmus wallichiana and compare this effect with quercetin (Q) in a rat model of postmenopausal bone loss. METHODS: Murine bone marrow cells were used to study the effect of QCG or Q on osteoclast differentiation. QCG or Q (1.0 and 5.0 mg kg(-1) d(-1) doses) was administered orally to ovarietomized (OVx) rats for 12 weeks. Sham-operated + vehicle and OVx + vehicle groups served as positive and negative controls, respectively. Bone mineral density, bone microarchitecture, biomechanical strength, bone turnover markers, and uterotrophic effect were studied. One-way analysis of variance was used to test significance of effects. RESULTS: QCG at 1.0 nM significantly inhibited differentiation of multinucleated osteoclasts and expression of osteoclastogenic genes from bone marrow cells, whereas Q at 10.0 µM had comparable results. OVx rats treated with QCG exhibited significantly higher bone mass and better microarchitecture in trabecular and cortical bones compared with OVx + vehicle. QCG treatment of OVx rats had better functional impact than did Q-treated OVx rats, evident from increased bone biomechanical strength. Serum osteocalcin and urinary fragments of type 1 collagen were significantly lower in QCG-treated OVx rats compared with OVx + vehicle group. The protective effect of QCG under ovariectomy-induced bone loss setting was found to be significantly better than Q. Uterine histomorphometry parameters of OVx rats did not change with QCG treatment. CONCLUSIONS: QCG improves bone biomechanical quality more effectively than Q through positive modifications of bone mineral density and bone microarchitecture without a hyperplastic effect on the uterus.
Assuntos
Osteoclastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Quercetina/análogos & derivados , Quercetina/farmacologia , Ulmus/química , Animais , Densidade Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/ultraestrutura , Células Cultivadas , Colágeno Tipo I/urina , Modelos Animais de Doenças , Feminino , Glucosídeos/isolamento & purificação , Humanos , Osteocalcina/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Extratos Vegetais/química , Quercetina/isolamento & purificação , Quercetina/fisiologia , Ratos , Útero/citologia , Útero/efeitos dos fármacosRESUMO
Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro-computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-ßA, and TGFß2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients.
Assuntos
Densidade Óssea/fisiologia , Distrofia Muscular Animal/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Animais , Anticorpos Bloqueadores/farmacologia , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Criança , Citocinas/sangue , Citocinas/genética , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Camundongos , Distrofia Muscular de Duchenne/sangue , Técnicas de Cultura de Órgãos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese/efeitos dos fármacos , Fenótipo , Radiografia , Regulação para Cima/efeitos dos fármacosRESUMO
8,8''-Biapigeninyl (BA), a condensation product of two apigenin molecules, is found abundantly in the nuts of Cupressus sempervirens. We investigated the effects of BA on murine bone cells in vitro and in ovariectomized (OVx) mice. BA at 10(-10)M and 10(-8)M, inhibited osteoclastogenesis of bone marrow cells (BMCs) and displayed concentration dependence. BA at 10(-8) M and 10(-6) M inhibited differentiation of 3T3-L1 and BMCs to mature adipocytes. BA (10(-10)M) stimulated osteoblast proliferation, differentiation and mineralization. In stimulating osteoblast function, BA was found to be 10(4)-fold more potent than apigenin. The effect of BA in osteoblasts appeared to be mediated via estrogen receptors (ER) as antiestrogen, ICI-182780 abolished BA-stimulated osteoblast differentiation. In OVx mice BA treatment (at 1.0-, 5.0- and 10.0 mg kg(-1) day(-1) doses) given orally for 30 days dose-dependently inhibited mRNA levels of osteoclastic genes including tartrate-resistant acid phosphatase, receptor activator of nuclear factor (RANK), tumor necrosis factor alpha, interleukin-6 and the ratio of RANK ligand/osteoprotegerin ratio in bones compared with OVx mice treated with vehicle. In addition, BA treatment to OVx mice dose-dependently stimulated production of osteoprogenitor cells in the bone marrow and increased mRNA levels of osteogenic genes core binding factor alpha-1, type I collagen and bone morphogenic protein-2 in bones compared with OVx+vehicle group. Microcomputed tomography revealed that BA treatment to OVx mice improved parameters of trabecular and cortical architecture. BA exhibited no uterine estrogenicity. From these data, we conclude that BA exerts osteoprotective effect in OVx mice by multiple beneficial effects on bone cells.