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1.
Life Sci ; 244: 117336, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972206

RESUMO

AIMS: Postmenopausal osteoporosis and other osteolytic bone diseases are often caused by the elevation in osteoclastogenesis and/or increased osteoclastic bone resorption, leading to excessive bone loss. Hederagenin (Hed) is a pentacyclic triterpenoid saponin extracted from various natural medicinal plants and exhibits numerous biological activities and may offer benefits against bone-related conditions. We evaluated the effects of Hed on osteoclast formation and bone resorption in vitro and the in vivo therapeutic benefits in the mouse model of ovariectomy (OVX)-induced bone loss. MAIN METHODS: In vitro, osteoclast formation were determined by TRAcp staining; bone resorption were examined using Hydroxyapatite resorption assay and Podosomal actin belt formation assay; Related molecular mechanisms were determined by western blot assay. Construction of OVX mice by bilateral oophorectomy to simulate bone loss in vivo. KEY FINDINGS: In vitro cellular assays showed that Hed inhibited RANKL-induced osteoclast formation and osteoclast bone (hydroxyapatite) resorption as well as marker gene expression from BMM culture. Mechanistically, Hed attenuated RANKL-induced intracellular reactive oxygen species (ROS) production, and MAPK signaling pathway (ERK and p38) activation which curbed the downstream induction of c-Fos and NFATc1. Consistent with the in vitro findings, Hed administration effectively protected OVX mice from bone loss by reducing osteoclast number and activity on bone surface. SIGNIFICANCE: Our data provided promising evidence for the potential use of Hederagenin in the treatment of osteoclast-mediated osteolytic bone diseases such as postmenopausal osteoporosis.


Assuntos
Reabsorção Óssea/prevenção & controle , Ácido Oleanólico/análogos & derivados , Osteogênese/efeitos dos fármacos , Ovariectomia/efeitos adversos , Substâncias Protetoras/farmacologia , Ligante RANK/metabolismo , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oleanólico/farmacologia , Ligante RANK/genética , Transdução de Sinais
2.
Cell Prolif ; 53(2): e12752, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31889368

RESUMO

OBJECTIVES: Insulin-like growth factor-binding protein 7 (IGFBP7) is a low-affinity insulin growth factor (IGF) binder that may play an important role in bone metabolism. We previously reported that IGFBP7 enhanced osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) via the Wnt/ß-catenin signalling pathway. In this study, we tried to reveal its function in osteoclast differentiation and osteoporosis. METHODS: We used both in vitro and in vivo studies to investigate the effects of IGFBP7 on RANKL-induced osteoclastogenesis and osteoporosis, together with the underlying molecular mechanisms of these processes. RESULTS: We show that IGFBP7 inhibited receptor activation of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis, F-actin ring formation and bone resorption, which was confirmed by using recombinant IGFBP7 protein, lentivirus and siRNA. The NF-κB signalling pathway was inhibited during this process. Moreover, in a mouse ovariectomy-induced osteoporosis model, IGFBP7 treatment attenuated osteoporotic bone loss by inhibiting osteoclast activity. CONCLUSIONS: Taken together, these findings show that IGFBP7 suppressed osteoclastogenesis in vitro and in vivo and suggest that IGFBP7 is a negative regulator of osteoclastogenesis and plays a protective role in osteoporosis. These novel insights into IGFBP7 may facilitate the development of potential treatment strategies for oestrogen deficiency-induced osteoporosis and other osteoclast-related disorders.


Assuntos
Reabsorção Óssea/metabolismo , Estrogênios/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Osteoclastos/metabolismo , Osteogênese/fisiologia , Ligante RANK/metabolismo , Animais , Células da Medula Óssea/metabolismo , Diferenciação Celular/fisiologia , Feminino , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteoporose/metabolismo
3.
Int J Mol Sci ; 20(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618828

RESUMO

Exercise therapy inhibits joint destruction by suppressing pro-inflammatory cytokines. The efficacy of pharmacotherapy for rheumatoid arthritis differs depending on the phase of the disease, but that of exercise therapy for each phase is unknown. We assessed the differences in the efficacy of treadmill running on rheumatoid arthritis at various phases, using rat rheumatoid arthritis models. Rats with collagen-induced arthritis were used as rheumatoid arthritis models, and the phase after immunization was divided as pre-arthritis and established phases. Histologically, the groups with forced treadmill running in the established phase had significantly inhibited joint destruction compared with the other groups. The group with forced treadmill running in only the established phase had significantly better bone morphometry and reduced expression of connexin 43 and tumor necrosis factor α in the synovial membranes compared with the no treadmill group. Furthermore, few cells were positive for cathepsin K immunostaining in the groups with forced treadmill running in the established phase. Our results suggest that the efficacy of exercise therapy may differ depending on rheumatoid arthritis disease activity. Active exercise during phases of decreased disease activity may effectively inhibit arthritis and joint destruction.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Cartilagem Articular/patologia , Condicionamento Físico Animal , Animais , Artrite Experimental , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/metabolismo , Biomarcadores , Peso Corporal , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/metabolismo , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/metabolismo , Conexina 43/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Ratos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/metabolismo
4.
Orthopade ; 48(11): 911-916, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31531702

RESUMO

Inflammatory rheumatic diseases are often associated with secondary osteoporosis, as many inflammatory messengers can interfere with bone metabolism and adversely affect it. In addition to a decrease in densitometric bone density, remodeling occurs in the trabecular bone, which can lead to a disturbed microarchitecture and increase the risk of fracture.Central to this is the close integration of bone metabolism and the immune system. Proinflammatory cytokines play an important role not only in the inflammatory process, but also as mediators of bone resorption because they stimulate osteoclastogenesis and induce further signal transduction cascades with negative influence on the bone. The understanding gained in recent years of the underlying immunological processes has led to the development of new and targeted treatment approaches.


Assuntos
Reabsorção Óssea/imunologia , Citocinas/fisiologia , Osteoporose , Doenças Reumáticas/imunologia , Remodelação Óssea , Reabsorção Óssea/metabolismo , Humanos , Mediadores da Inflamação/fisiologia , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Doenças Reumáticas/metabolismo
5.
Molecules ; 24(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540026

RESUMO

Osteogenesis is an orchestrated process regulated by osteoclastogenesis and osteoblastogenesis. Excessive osteoclastogenesis causes bone diseases, such as osteoporosis. Although a few drugs are effective in osteoporosis treatment, these drugs lead to side effects, including cellulitis, flatulence, and hypocalcemia. In this study, we reported a 2-(N-Phenylmethylsulfonamido)-N-(2-(phenylthio)phenyl)propanamide (PSTP) compound, PSTP-3,5-Me, as a potential therapeutic agent for osteoporosis. Mouse bone marrow-derived macrophages (BMMs) were differentiated into osteoclasts by receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in the presence of PSTP-3,5-Me. PSTP-3,5-Me inhibited osteoclast differentiation by reduced tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and suppressed the expression of osteoclast marker genes, such as cathepsin K (Ctsk) and TRAP (Acp5). We investigated signaling pathways mediated by RANKL and its receptor, RANK, and found that PSTP-3,5-Me inhibits nucleus translocation of nuclear factor of activated T cell cytoplasmic-1 (NFATc1). Moreover, PSTP-3,5-Me inhibited F-actin ring formation and mineral resorption. Overall, our data suggests that PSTP-3,5-Me attenuates osteoclast differentiation by blocking the activation of NFATc1.


Assuntos
Antígenos de Diferenciação/biossíntese , Células da Medula Óssea/metabolismo , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoclastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células da Medula Óssea/patologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Feminino , Camundongos , Osteoclastos/patologia , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/patologia , Sulfonamidas/farmacologia
6.
Nutrients ; 11(9)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546863

RESUMO

Ovotransferrin, a member of the transferrin family, is the second main protein found in egg white. Ovotransferrin was reported to have antimicrobial, antioxidant, and immunomodulating activities. The aim of this work was to characterize the cellular and molecular functions of egg white ovotransferrin on osteoclasts differentiation and function. Osteoclasts were prepared from mouse macrophage RAW 264.7 cells stimulated with receptor activator of nuclear factor κB ligand (RANKL). Ovotransferrin inhibited osteoclasts differentiation and the calcium-phosphate resorptive ability via the suppression of RANKL-induced nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Ovotransferrin induced apoptosis of matured osteoclasts, accompanied by increased expression of Bcl-2-like protein 11 (Bim) and Bcl-2-assoicated death promoter (Bad), but decreased expression of B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-xl). We established a novel role of egg white ovotransferrin as an inhibitor of osteoclastogenesis, which may be used for the prevention of osteoporosis.


Assuntos
Reabsorção Óssea/metabolismo , Conalbumina/farmacologia , Clara de Ovo/química , Osteoclastos/efeitos dos fármacos , Ligante RANK/metabolismo , Animais , Apoptose , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Osteoclastos/fisiologia , Ligante RANK/genética , Células RAW 264.7
7.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514440

RESUMO

Bone is a peculiar tissue subjected to a continuous process of self-renewal essential to assure the integrity of the skeleton and to explicate the endocrine functions. The study of bone diseases characterized by increased or reduced bone mass due to osteoclast alterations has been essential to understand the great role played by osteocalcin in the endocrine functions of the skeleton. The ability of osteoclasts to regulate the decarboxylation of osteocalcin and to control glucose metabolism, male fertility, and cognitive functions was demonstrated by the use of animal models. In this review we described how diseases characterized by defective and increased bone resorption activity, as osteopetrosis and osteoporosis, were essential to understand the involvement of bone tissue in whole body physiology. To translate this knowledge into humans, recently published reports on patients were described, but further studies should be performed to confirm this complex hormonal regulation in humans.


Assuntos
Densidade Óssea , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Sistema Endócrino/metabolismo , Osteocalcina/metabolismo , Animais , Fertilidade , Glucose/metabolismo , Humanos
8.
Mediators Inflamm ; 2019: 8767529, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31427888

RESUMO

Chronic apical periodontitis is characterized by alveolar bone absorption in the apical region and is the result of the participation of various inflammatory mediators. Studies have shown that the Bruton tyrosine kinase- (Btk-) phospholipase Cγ2 (PLCγ2) signaling pathway plays an important role in bone absorption, but it is unknown whether it plays a role in apical periodontitis bone destruction. Therefore, this study verified the role of Btk and PLCγ2 in bone resorption of apical periodontitis by in vivo and in vitro experiments. In the in vivo experiment, a mice model of apical periodontitis was established; apical bone resorption was confirmed by the numbers of osteoclasts and HE staining. Btk, PLCγ2, and nuclear factor of activated T-cells 1 (NFATc-1) were detected by immunohistochemical staining. In the in vitro experiment, lipopolysaccharides (LPS) were used to stimulate osteoclast precursor cell RAW264.7 to establish an inflammatory microenvironment and detect osteoclast differentiation. By silencing Btk, the expression of Btk, PLCγ2, and NFATc-1 was detected by real-time qPCR and Western blot, and osteoclastogenesis was detected by enzyme histochemical staining to further confirm the role of Btk in bone resorption. It was found that the expression of Btk, PLCγ2, and NFATc-1 changed significantly with the progression of inflammation and bone destruction, indicating that Btk and PLCγ2 may be involved in the progression of inflammation in apical periodontitis and bone absorption. In vitro experiments confirmed that the differentiation of osteoclasts and the expression of PLCγ2 and NFATc-1 were significantly inhibited after silencing Btk expression, but osteoclast precursor cells could be differentiated due to the proinflammatory factor lipopolysaccharide. This study demonstrates that Btk and PLCγ2 are key factors involved in the apical inflammatory response and bone destruction.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Periodontite Periapical/metabolismo , Fosfolipase C gama/metabolismo , Animais , Reabsorção Óssea/metabolismo , Diferenciação Celular/fisiologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo , Osteoclastos/fisiologia , Células RAW 264.7 , Transdução de Sinais/fisiologia
9.
Biol Cell ; 111(11): 271-283, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31461543

RESUMO

BACKGROUND INFORMATION: Osteoclast resorption is dependent on a podosome-rich structure called sealing zone. It tightly attaches the osteoclast to the bone creating a favourable acidic microenvironment for bone degradation. This adhesion structure needs to be stabilised by microtubules whose acetylation is maintained by down-regulation of deacetylase HDAC6 and/or of microtubule destabilising kinase GSK3ß activities. We already established that Dock5 is a guanine nucleotide exchange factor for Rac1. As a consequence, Dock5 inhibition results in a decrease of the GTPase activity associated with impaired podosome assembly into sealing zones and resorbing activity in osteoclasts. More, administration of C21, a chemical compound that directly inhibits the exchange activity of Dock5, disrupts osteoclast podosome organisation and protects mice against bone degradation in models recapitulating major osteolytic diseases. RESULTS: In this report, we show that Dock5 knockout osteoclasts also present a reduced acetylated tubulin level leading to a decreased length and duration of microtubule growth phases, whereas their growth speed remains unaffected. Dock5 does not act by direct interaction with the polymerised tubulin. Using specific Rac inhibitors, we showed that Dock5 regulates microtubule dynamic instability through Rac-dependent and -independent pathways. The latter involves GSK3ß inhibitory serine 9 phosphorylation downstream of Akt activation but not HDAC6 activity. CONCLUSION: We showed that Dock5 is a new regulator of microtubule dynamic instability in osteoclast. SIGNIFICANCE: Dock5 dual role in the regulation of the actin cytoskeleton and microtubule, which both need to be intact for bone resorption, reinforces the fact that it is an interesting therapeutic target for osteolytic pathologies.


Assuntos
Reabsorção Óssea/metabolismo , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Microtúbulos/metabolismo , Osteoclastos/metabolismo , Tubulina (Proteína)/metabolismo , Animais , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/antagonistas & inibidores , Osteoclastos/citologia , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
10.
South Med J ; 112(8): 428-432, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31375839

RESUMO

OBJECTIVES: Individuals with intellectual disabilities (IDs) are at increased risk for low bone mass and fragility fractures, and those who are nonambulatory may be at even higher risk. Patients with IDs often are vitamin D deficient, but there is little information concerning how vitamin D treatment of patients with IDs affects markers of bone formation and resorption. METHODS: We performed a retrospective analysis of 23 institutionalized individuals with IDs who were the subject of a performance improvement continuing medical education project designed to reduce risk for fracture by optimizing serum vitamin D levels. Patients were divided into those with normal weight-bearing (NWB) physical activity (15 patients: 14 men, 1 woman) and those with low weight-bearing (LWB) physical activity (8 patients: 7 men, 1 woman). All of the subjects received 50,000 IU of vitamin D3 weekly for 4 to 8 weeks, followed by a maintenance dose of 50,000 IU monthly for 3 to 6 months. Bone turnover markers (type 1 cross-linked C-telopeptide [CTX], type 1 N-terminal propeptide [P1NP], and parathyroid hormone [PTH]) and 25(OH)-vitamin D levels were measured before and after vitamin D supplementation. RESULTS: At baseline, there were no significant differences in the serum levels of 25OH-D, PTH, P1NP, or CTX between the two groups (NWB and LWB). Vitamin D levels were increased to a higher value in LWB subjects than in NWB subjects (61 ± 4.1 vs 48.4 ± 2.2 ng/mL, P < 0.001). Vitamin D treatment suppressed PTH (20.5% ± 14.3% vs 31.4% ± 7.7%, P = not significant) and P1NP (33.0% ± 6.2% vs 29.4% ± 6.9%, P = not significant) similarly in both groups. Although CTX levels declined by 26.4% ± 5.3% (P = 0.0002) in NWB individuals (as anticipated), vitamin D supplementation resulted in an unexpected 25.8% ± 8% increase (P = 0.01) in CTX in LWB individuals, suggesting osteoclast activation. CONCLUSIONS: Although high-dose vitamin D appeared to suppress osteoclast activity in NWB adults with IDs, the increase in serum CTX levels in those with LWB activity implies activation of osteoclasts that could exacerbate their unique low bone mass and increase fracture risk. The results support the use of a lower-dose vitamin D regimen in this patient group with LWB.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/prevenção & controle , Exercício/fisiologia , Deficiência Intelectual/complicações , Deficiência Intelectual/tratamento farmacológico , Vitamina D/farmacologia , Suporte de Carga/fisiologia , Adulto , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vitaminas/farmacologia , Adulto Jovem
11.
Int J Mol Sci ; 20(14)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336616

RESUMO

Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction-oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O2-) and hydrogen peroxide (H2O2), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases.


Assuntos
Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Diferenciação Celular , Osteoclastos/citologia , Osteoclastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Biomarcadores , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/genética , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Cells ; 8(6)2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234425

RESUMO

Osteoclast-mediated bone destruction is amplified in the hypoxic synovial microenvironment of rheumatoid arthritis (RA). This increased bone resorption is driven by the hypoxia-inducible transcription factor HIF. We identified hypoxic induction of the HIF-regulated adenosine A2B receptor in primary human osteoclasts (mRNA, 3.8-fold increase, p < 0.01) and sought to identify the role(s) of purinergic signaling via this receptor in the bone resorption process. Primary human osteoclasts were differentiated from CD14+ monocytes and exposed to hypoxia (2% O2) and A2B receptor inhibitors (MRS1754, PSB603). The hypoxic increase in bone resorption was prevented by the inhibition of the A2B receptor, at least partly by the attenuation of glycolytic and mitochondrial metabolism via inhibition of HIF. A2B receptor inhibition also reduced osteoclastogenesis in hypoxia by inhibiting early cell fusion (day 3-4, p < 0.05). The A2B receptor is only functional in hypoxic or inflammatory environments when the extracellular concentrations of adenosine (1.6-fold increase, p < 0.05) are sufficient to activate the receptor. Inhibition of the A2B receptor under normoxic conditions therefore did not affect any parameter tested. Reciprocal positive regulation of HIF and the A2B receptor in a hypoxic microenvironment thus enhances glycolytic and mitochondrial metabolism in osteoclasts to drive increased bone resorption. A2B receptor inhibition could potentially prevent the pathological osteolysis associated with hypoxic diseases such as rheumatoid arthritis.


Assuntos
Reabsorção Óssea/metabolismo , Microambiente Celular , Osteoclastos/metabolismo , Receptor A2B de Adenosina/metabolismo , Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia
13.
Metabolism ; 97: 81-86, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181216

RESUMO

Burn injury results in a triad of inter-related adaptive responses: a systemic inflammatory response, a stress response, and a consequent hypermetabolic state which supports the former two. Details of what precisely triggers these responses as well as the sequence of events leading up to these responses are not clear. We review the musculoskeletal effects of burn injury to determine the precise contributions of this system in the generation and sustenance of this post-burn triad as well as the possible effects of pharmacologic intervention in the musculoskeletal response to burns on the resulting hypermetabolism. Inflammation-associated bone resorption liberates calcium, which may either prolong or intensify the systemic inflammatory response. Phosphate and magnesium liberated from bone could contribute to sustaining the increased ATP turnover in skeletal muscle that accompanies burn hypermetabolism. Reduced bone formation resulting from both pro-inflammatory cytokines and elevated endogenous glucocorticoid production results in reduced bone mass and therefore reduced osteocalcin production, which may contribute to reduced glucose uptake by skeletal muscle. Moreover, bone resorption liberates muscle catabolic factors such as transforming growth factor ß, which contribute to the muscle wasting of burn hypermetabolism. Pharmacologic intervention with anti-resorptive agents early in the process preserve bone and muscle mass post-burn and future research should address the consequences for the hypermetabolic triad duration and intensity accompanying burn injury.


Assuntos
Osso e Ossos/metabolismo , Queimaduras/metabolismo , Músculo Esquelético/metabolismo , Trifosfato de Adenosina/metabolismo , Reabsorção Óssea/metabolismo , Citocinas/metabolismo , Humanos , Inflamação/metabolismo
14.
J Appl Oral Sci ; 27: e20180641, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31166414

RESUMO

OBJECTIVES: Infection, inflammation and bone resorption are closely related events in apical periodontitis development. Therefore, we sought to investigate the role of cyclooxygenase (COX) in osteoclastogenesis and bone metabolism signaling in periapical bone tissue after bacterial lipopolysaccharide (LPS) inoculation into root canals. METHODOLOGY: Seventy two C57BL/6 mice had the root canals of the first molars inoculated with a solution containing LPS from E. coli (1.0 mg/mL) and received selective (celecoxib) or non-selective (indomethacin) COX-2 inhibitor. After 7, 14, 21 and 28 days the animals were euthanized and the tissues removed for total RNA extraction. Evaluation of gene expression was performed by qRT-PCR. Statistical analysis was performed using analysis of variance (ANOVA) followed by post-tests (α=0.05). RESULTS: LPS induced expression of mRNA for COX-2 (Ptgs2) and PGE2 receptors (Ptger1, Ptger3 and Ptger4), indicating that cyclooxygenase is involved in periapical response to LPS. A signaling that favours bone resorption was observed because Tnfsf11 (RANKL), Vegfa, Ctsk, Mmp9, Cd36, Icam, Vcam1, Nfkb1 and Sox9 were upregulated in response to LPS. Indomethacin and celecoxib differentially modulated expression of osteoclastogenic and other bone metabolism genes: celecoxib downregulated Igf1r, Ctsk, Mmp9, Cd36, Icam1, Nfkb1, Smad3, Sox9, Csf3, Vcam1 and Itga3 whereas indomethacin inhibited Tgfbr1, Igf1r, Ctsk, Mmp9, Sox9, Cd36 and Icam1. CONCLUSIONS: We demonstrated that gene expression for COX-2 and PGE2 receptors was upregulated after LPS inoculation into the root canals. Additionally, early administration of indomethacin and celecoxib (NSAIDs) inhibited osteoclastogenic signaling. The relevance of the cyclooxygenase pathway in apical periodontitis was shown by a wide modulation in the expression of genes involved in both bone catabolism and anabolism.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Cavidade Pulpar/metabolismo , Lipopolissacarídeos/farmacologia , Osteogênese/fisiologia , Tecido Periapical/efeitos dos fármacos , Tecido Periapical/metabolismo , Prostaglandina-Endoperóxido Sintases/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Reabsorção Óssea/metabolismo , Celecoxib/farmacologia , Ciclo-Oxigenase 2/análise , Escherichia coli/metabolismo , Expressão Gênica , Indometacina/farmacologia , Lipopolissacarídeos/análise , Masculino , Camundongos Endogâmicos C57BL , Osteogênese/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/análise , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Receptores de Prostaglandina E/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Regulação para Cima
15.
EBioMedicine ; 44: 452-466, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31151929

RESUMO

BACKGROUND: Cancer-associated bone disease is a serious complication in bone sarcomas and metastatic carcinomas of breast and prostate origin. Monoacylglycerol lipase (MAGL) is an enzyme of the endocannabinoid system, and is responsible for the degradation of the most abundant endocannabinoid in bone, 2-arachidonoyl glycerol (2AG). METHODS: The effects of the verified MAGL inhibitor on bone remodelling were assessed in healthy mice and in mouse models of bone disease caused by prostate and breast cancers and osteosarcoma. FINDINGS: JZL184 reduced osteolytic bone metastasis in mouse models of breast and prostate cancers, and inhibited skeletal tumour growth, metastasis and the formation of ectopic bone in models of osteosarcoma. Additionally, JZL184 suppressed cachexia and prolonged survival in mice injected with metastatic osteosarcoma and osteotropic cancer cells. Functional and histological analysis revealed that the osteoprotective action of JZL184 in cancer models is predominately due to inhibition of tumour growth and metastasis. In the absence of cancer, however, exposure to JZL184 exerts a paradoxical reduction of bone volume via an effect that is mediated by both Cnr1 and Cnr2 cannabinoid receptors. INTERPRETATION: MAGL inhibitors such as JZL184, or its novel analogues, may be of value in the treatment of bone disease caused by primary bone cancer and bone metastasis, however, activation of the skeletal endocannabinoid system may limit their usefulness as osteoprotective agents.


Assuntos
Benzodioxóis/farmacologia , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Piperidinas/farmacologia , Animais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Comunicação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Camundongos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteólise/tratamento farmacológico , Osteólise/etiologia , Osteólise/metabolismo , Osteólise/patologia , Receptores de Canabinoides/metabolismo
16.
Arthritis Rheumatol ; 71(11): 1801-1811, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31162832

RESUMO

OBJECTIVE: The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long-lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown. METHODS: ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATXC tsk ). Arthritic and erosive diseases were studied in human tumor necrosis factor-transgenic (hTNF+/- ) mice and mice with K/BxN serum transfer-induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)-induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro-computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays. RESULTS: OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF+/- mice, as compared to vehicle-treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC-derived ATX was revealed to be instrumental in OC bone resorptive activity and was up-regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone-protective properties. CONCLUSION: Our results identify ATX as a novel OC factor that specifically controls inflammation-induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Reabsorção Óssea/metabolismo , Osteoclastos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/imunologia , Calcâneo/diagnóstico por imagem , Feminino , Fêmur/diagnóstico por imagem , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Ovariectomia , Tálus/diagnóstico por imagem , Fator de Necrose Tumoral alfa/genética , Microtomografia por Raio-X
17.
Int J Mol Sci ; 20(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181716

RESUMO

Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/ß-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.


Assuntos
Reabsorção Óssea/metabolismo , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Cinacalcete/farmacologia , Osteoclastos/efeitos dos fármacos , Insuficiência Renal Crônica/complicações , Proteínas Wnt/metabolismo , Animais , Densidade Óssea , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Células Cultivadas , Cinacalcete/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo
18.
Endocrinology ; 160(7): 1659-1673, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31081900

RESUMO

Excess of glucocorticoids (GCs) is a leading cause of bone fragility, and therapeutic targets are sorely needed. We report that genetic deletion or pharmacological inhibition of proline-rich tyrosine kinase 2 (Pyk2) prevents GC-induced bone loss by overriding GC effects of detachment-induced bone cell apoptosis (anoikis). In wild-type or vehicle-treated mice, GCs either prevented osteoclast apoptosis or promoted osteoblast/osteocyte apoptosis. In contrast, mice lacking Pyk2 [knockout (KO)] or treated with Pyk2 kinase inhibitor PF-431396 (PF) were protected. KO or PF-treated mice were also protected from GC-induced bone resorption, microarchitecture deterioration, and weakening of biomechanical properties. In KO and PF-treated mice, GC increased osteoclasts in bone and circulating tartrate-resistant acid phosphatase form 5b, an index of osteoclast number. However, bone surfaces covered by osteoclasts and circulating C-terminal telopeptides of type I collagen, an index of osteoclast function, were not increased. The mismatch between osteoclast number vs function induced by Pyk2 deficiency/inhibition was due to osteoclast detachment and anoikis. Further, GC prolongation of osteoclast lifespan was absent in KO and PF-treated osteoclasts, demonstrating Pyk2 as an intrinsic osteoclast-survival regulator. Circumventing Pyk2 activation preserves skeletal integrity by preventing GC effects on bone cell survival (proapoptotic for osteoblasts/osteocytes, antiapoptotic for osteoclasts) and GC-induced bone resorption. Thus, Pyk2/anoikis signaling as a therapeutic target for GC-induced osteoporosis.


Assuntos
Anoikis/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Quinase 2 de Adesão Focal/antagonistas & inibidores , Glucocorticoides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Feminino , Quinase 2 de Adesão Focal/genética , Quinase 2 de Adesão Focal/metabolismo , Camundongos , Camundongos Knockout , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo
19.
BMB Rep ; 52(6): 409-414, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31068248

RESUMO

Natural compounds isolated from medicinal herbs and plants have immense significance in maintaining bone health. Hydrolysable tannins have been shown to possess a variety of medicinal properties including antiviral, anticancer, and anti-osteoclastogenic activities. As a part of a study on the discovery of alternative agent against skeletal diseases, we isolated a hydrolysable tannin, 2-O-digalloyl-1,3,4,6-tetra-Ogalloyl- ß-D-glucose (DTOGG), from Galla Rhois and examined the effect on osteoclast formation and function. We found that DTOGG significantly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by downregulating the expression of the key regulator in osteoclastogenesis as well as osteoclast-related genes. Analysis of RANKL/RANK signaling revealed that DTOGG impaired activation of IκBα and p65 in the nuclear factor kappa-lightchain- enhancer of activated B cells (NF-κB) signaling pathway. Furthermore, DTOGG reduced bone resorbing activity of osteoclasts, compared to the vehicle-treated control. These results suggest that DTOGG could be a useful natural compound to manage osteoclast-mediated skeletal diseases. [BMB Reports 2019; 52(6): 409-414].


Assuntos
Ácido Gálico/análogos & derivados , Glucosídeos/farmacologia , NF-kappa B/metabolismo , Osteoclastos/efeitos dos fármacos , Ligante RANK/efeitos dos fármacos , Animais , Produtos Biológicos/química , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ácido Gálico/isolamento & purificação , Ácido Gálico/farmacologia , Glucose/metabolismo , Glucosídeos/isolamento & purificação , Proteínas I-kappa B/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052533

RESUMO

Alterations in the process of mechanotransduction have been implicated in the pathogenesis of several diseases such as genetic diseases, osteoporosis, cardiovascular anomalies, and cancer. Several studies over the past twenty years have demonstrated that polycystins (polycystin-1, PC1; and polycystin-2, PC2) respond to changes of extracellular mechanical cues, and mediate pathogenic mechanotransduction and cyst formation in kidney cells. However, recent reports reveal the emergence of polycystins as key proteins that facilitate the transduction of mechano-induced signals in various clinical entities besides polycystic kidney disease, such as cancer, cardiovascular defects, bone loss, and deformations, as well as inflammatory processes like psoriasis. Herewith, we discuss data from recent studies that establish this role with potential clinical utility.


Assuntos
Reabsorção Óssea/patologia , Cardiomiopatias/patologia , Neoplasias/patologia , Psoríase/patologia , Canais de Cátion TRPP/metabolismo , Animais , Reabsorção Óssea/metabolismo , Cardiomiopatias/metabolismo , Humanos , Mecanotransdução Celular , Neoplasias/metabolismo , Psoríase/metabolismo , Canais de Cátion TRPP/análise
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