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1.
J Transl Med ; 21(1): 8, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36617569

RESUMO

BACKGROUND: Astronauts undergo significant microgravity-induced bone loss during space missions, which has become one of the three major medical problems hindering human's long-term space flight. A risk-free and antiresorptive drug is urgently needed to prevent bone loss during space missions. D-mannose is a natural C-2 epimer of D-glucose and is abundant in cranberries. This study aimed to investigate the protective effects and potential mechanisms of D-mannose against bone loss under weightlessness. METHODS: The hind legs of tail-suspended (TS) rats were used to mimic weightlessness on Earth. Rats were administered D-mannose intragastrically. The osteoclastogenic and osteogenic capacity of D-mannose in vitro and in vivo was analyzed by micro-computed tomography, biomechanical assessment, bone histology, serum markers of bone metabolism, cell proliferation assay, quantitative polymerase chain reaction, and western blotting. RNA-seq transcriptomic analysis was performed to detect the underlying mechanisms of D-mannose in bone protection. RESULTS: The TS rats showed lower bone mineral density (BMD) and poorer bone morphological indices. D-mannose could improve BMD in TS rats. D-mannose inhibited osteoclast proliferation and fusion in vitro, without apparent effects on osteoblasts. RNA-seq transcriptomic analysis showed that D-mannose administration significantly inhibited the cell fusion molecule dendritic cell-specific transmembrane protein (DC-STAMP) and two indispensable transcription factors for osteoclast fusion (c-Fos and nuclear factor of activated T cells 1 [NFATc1]). Finally, TS rats tended to experience dysuria-related urinary tract infections (UTIs), which were suppressed by treatment with D-mannose. CONCLUSION: D-mannose protected against bone loss and UTIs in rats under weightlessness. The bone protective effects of D-mannose were mediated by inhibiting osteoclast cell fusion. Our findings provide a potential strategy to protect against bone loss and UTIs during space missions.


Assuntos
Doenças Ósseas Metabólicas , Reabsorção Óssea , Ausência de Peso , Ratos , Humanos , Animais , Ausência de Peso/efeitos adversos , Manose/farmacologia , Manose/metabolismo , Microtomografia por Raio-X , Osteoclastos , Densidade Óssea , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/metabolismo
2.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674719

RESUMO

Bone metastasis resulting from advanced breast cancer causes osteolysis and increases mortality in patients. Kalkitoxin (KT), a lipopeptide toxin derived from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), has an anti-metastatic effect on cancer cells. We verified that KT suppressed cancer cell migration and invasion in vitro and in animal models in the present study. We confirmed that KT suppressed osteoclast-soup-derived MDA-MB-231 cell invasion in vitro and induced osteolysis in a mouse model, possibly enhancing/inhibiting metastasis markers. Furthermore, KT inhibits CXCL5 and CXCR2 expression, suppressing the secondary growth of breast cancer cells on the bone, brain, and lungs. The breast-cancer-induced osteolysis in the mouse model further reveals that KT plays a protective role, judging by micro-computed tomography and immunohistochemistry. We report for the first time the novel suppressive effects of KT on cancer cell migration and invasion in vitro and on MDA-MB-231-induced bone loss in vivo. These results suggest that KT may be a potential therapeutic drug for the treatment of breast cancer metastasis.


Assuntos
Osteólise , Animais , Camundongos , Osteólise/metabolismo , Microtomografia por Raio-X , Osteoclastos/metabolismo , Lipídeos/farmacologia , Movimento Celular , Linhagem Celular Tumoral , Metástase Neoplásica
3.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674918

RESUMO

Excessive differentiation of osteoclasts contributes to the disruption of bone homeostasis in inflammatory bone diseases. Methyltransferase-like 3 (METTL3), the core methyltransferase that installs an N6-methyladenosine (m6A) modification on RNA, has been reported to participate in bone pathophysiology. However, whether METTL3-mediated m6A affects osteoclast differentiation in inflammatory conditions remains unelucidated. In this study, we observed that the total m6A content and METTL3 expression decreased during LPS-induced osteoclastogenesis. After knocking down METTL3, we found reduced levels of the number of osteoclasts, osteoclast-related gene expression and bone resorption area. A METTL3 deficiency increased osteoclast apoptosis and pro-apoptotic protein expression. RNA sequencing analysis showed that differentially expressed genes in METTL3-deficient cells were mainly associated with the mitochondrial function. The expression of the mitochondrial function-related genes, ATP production and mitochondrial membrane potential decreased after METTL3 knockdown. Moreover, the most obviously upregulated gene in RNA-Seq was Nos2, which encoded the iNOS protein to induce nitric oxide (NO) synthesis. METTL3 knockdown increased the levels of Nos2 mRNA, iNOS protein and NO content. NOS inhibitor L-NAME rescued the inhibited mitochondrial function and osteoclast formation while suppressing osteoclast apoptosis in METTL3-silenced cells. Mechanistically, a METTL3 deficiency promoted the stability and expression of Nos2 mRNA, and similar results were observed after m6A-binding protein YTHDF1 knockdown. Further in vivo evidence revealed that METTL3 knockdown attenuated the inflammatory osteolysis of the murine calvaria and suppressed osteoclast formation. In conclusion, these data suggested that METTL3 knockdown exacerbated iNOS/NO-mediated mitochondrial dysfunction by promoting a Nos2 mRNA stability in a YTHDF1-dependent manner and further inhibited osteoclast differentiation and increased osteoclast apoptosis in inflammatory conditions.


Assuntos
Reabsorção Óssea , Osteoclastos , Camundongos , Animais , Osteoclastos/metabolismo , Óxido Nítrico/metabolismo , Reabsorção Óssea/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , RNA Mensageiro/genética
4.
J Mech Behav Biomed Mater ; 138: 105662, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36630755

RESUMO

Metastatic bone disease occurs in 70-80% of advanced breast cancer patients and bone tissue is accepted to have attractive physical properties that facilitate cancer cell attraction, adhesion, and invasion. Bone cells also facilitate tumour invasion by biochemical signalling and through resorption of the bone matrix (osteolysis), which releases factors that further stimulate tumour cell activity. The evolving mechanical environment during tumour invasion might play an important role in these processes, as the activity of both bone and cancer cells is regulated by mechanical cues. In particular bone loss and altered mineralisation have been reported, yet how these alter the mechanical environment local to bone and tumour cells is unknown. The objective of this study is to quantify changes in the mechanical environment within bone tissue, during bone metastasis and osteolytic resorption, using finite element analysis (FEA) models reconstructed from high-resolution µCT images of metastatic mouse bone. In particular, we quantify time-dependent changes in mechanical stimuli, local to and distant from an invading tumour mass, to investigate putative mechanobiological cues for osteolysis during bone metastasis. We report here that in early metastasis (3 weeks after tumour inoculation), there was a decrease in strain distribution within the proximal femur trabecular and distal cortical bone tissue. These changes in the mechanical environment preceded extensive osteolytic destruction, but coincided with the onset of early osteolysis, cortical thickening and mineralisation of proximal and distal femur bone. We propose that early changes in the mechanical environment within bone tissue may activate resorption by osteoclast cells and thereby contribute to the extensive osteolytic bone loss at later stage (6 weeks) bone metastasis.


Assuntos
Neoplasias Ósseas , Reabsorção Óssea , Osteólise , Camundongos , Animais , Osteólise/diagnóstico por imagem , Osteólise/patologia , Análise de Elementos Finitos , Osso e Ossos/patologia , Neoplasias Ósseas/patologia , Osteoclastos , Reabsorção Óssea/diagnóstico por imagem
5.
J Mech Behav Biomed Mater ; 138: 105666, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36634439

RESUMO

Here, we tested the hypothesis that tensile and compressive stresses generated in the alveolar bone proper regulate site-specific cellular and functional changes in osteoclasts and osteoblasts. Thirty-two 13-week-old male mice were randomly divided into four groups: two experimental groups with vertical loading obliquely from the palatal side to the buccal side of the maxillary molar (0.9 N) 30 min per day for 8 or 15 days and unloaded controls (n = 8). Calcein and alizarin were administered 8 and 2 days before euthanization, respectively, to detect the time of bone formation. Undecalcified sections parallel to the occlusal plane were prepared on the palatal root and the surrounding alveolar bone in the middle of the root length. The alveolar perimeter was divided into 12 equal regions for site analysis, and the bone histomorphometric parameters were obtained for each region. Data from in vivo microfocus computed tomography were used to construct animal-specific finite element models. 2D stress distribution images were overlain on histology images obtained from the same location. Significant differences in the total perimeter between groups and between loading and unloading in each region were statistically analyzed (α = 0.05). Osteoclast counts and the alizarin label ratio were significantly higher in the loaded group than in the unloaded group in regions where the maximum von Mises and principal tensile stresses were the highest along the perimeter. The label ratio of calcein was significantly lower in the 8-day loaded group than in the unloaded group, indicating that the calcein-labeled surface was resorbed by osteoclasts that appeared during the loading period. The effect of loading was mitigated by an increase in the maximum principal compressive stress. We conclude that bone resorption and bone formation are functions of site-specific tension and compression in the alveolar bone proper, confirming our hypothesis. This finding is critical for the advancement of diagnosis and treatment planning in clinical dentistry.


Assuntos
Antraquinonas , Osteoclastos , Animais , Masculino , Camundongos , Análise de Elementos Finitos , Fluoresceínas , Maxila/fisiologia , Estresse Mecânico
6.
Mediators Inflamm ; 2023: 9330439, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36643585

RESUMO

In this study, we examined the effect of the GP130-targeting molecule, LMT-28, on lipopolysaccharide- (LPS-) induced bone resorption around implants in diabetic models using in vitro and rat animal experiments. First, LMT-28 was added to osteoblasts stimulated by LPS and advanced glycation end products (AGEs), and nuclear factor-κB receptor-activating factor ligand (RANKL) and associated pathways were evaluated. Then, LMT-28 was administered by gavage at 0.23 mg/kg once every 5 days for 2 weeks to type 2 diabetic rats with peri-implantitis induced by LPS injection and silk ligature. The expression of IL-6 and RANKL was evaluated by immunohistochemistry, and the bone resorption around implants was evaluated by microcomputed tomography. The results showed that LMT-28 downregulated the expression of RANKL through the JAK2/STAT3 signaling pathway in osteoblasts stimulated by LPS and AGEs, reduced bone resorption around implants with peri-implantitis, decreased the expression of IL-6 and RANKL, and decreased osteoclast activity in type 2 diabetic rats. This study confirmed the ability of LMT-28 to reduce LPS-induced bone resorption around implants in diabetic rats.


Assuntos
Reabsorção Óssea , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Peri-Implantite , Animais , Ratos , Reabsorção Óssea/metabolismo , Receptor gp130 de Citocina , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Lipopolissacarídeos , Osteoclastos/metabolismo , Peri-Implantite/metabolismo , Ligante RANK/metabolismo , Transdução de Sinais , Microtomografia por Raio-X
7.
J Immunol Res ; 2023: 8571649, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36644540

RESUMO

Osteoclast (OC) abnormalities lead to many osteolytic diseases, such as osteoporosis, inflammatory bone erosion, and tumor-induced osteolysis. Exploring effective strategies to remediate OCs dysregulation is essential. FTY720, also known as fingolimod, has been approved for the treatment of multiple sclerosis and has anti-inflammatory and immunosuppressive effects. Here, we found that FTY720 inhibited osteoclastogenesis and OC function by inhibiting nuclear factor kappa-B (NF-κB) signaling. Interestingly, we also found that FTY720 inhibited osteoclastogenesis by upregulating histone deacetylase 4 (HDAC4) expression levels and downregulating activating transcription factor 4 (ATF4) expression levels. In vivo, FTY720 treatment prevented lipopolysaccharide- (LPS-) induced calvarial osteolysis and significantly reduced the number of tartrate-resistant acid phosphatase- (TRAP-) positive OCs. Taken together, these results demonstrate that FTY720 can inhibit osteoclastogenesis and ameliorate inflammation-induced bone loss. Which may provide evidence of a new therapeutic target for skeletal diseases caused by OC abnormalities.


Assuntos
Reabsorção Óssea , Osteólise , Animais , Camundongos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Histona Desacetilases/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoclastos , Osteogênese , Osteólise/tratamento farmacológico , Osteólise/induzido quimicamente , Ligante RANK/metabolismo , Proteínas Repressoras/metabolismo
8.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675029

RESUMO

Osteoprotegerin (OPG) is a new member of the tumor necrosis factor (TNF) receptor superfamily, which can inhibit the differentiation and activity of osteoclasts by binding to nuclear factor kappa B receptor activator (RANK) competitively with nuclear factor kappa B receptor activator ligand (RANKL). The previous experiments found that OPG can induce apoptosis of mature osteoclasts in vitro, which can inhibit the activity of mature osteoclasts, thereby exerting its role in protecting bone tissue. In addition, pyroptosis is a new type of cell death that is different from apoptosis. It is unclear whether OPG can induce mature osteoclast pyroptosis and thereby play its role in protecting bone tissue. In this study, the results showed that compared with the control group, the survival rate of osteoclasts in the OPG group was significantly reduced, and the contents of IL-1ß, IL-18, and LDH in the supernatant both increased. Many osteoclast plasma membranes were observed to rupture in bright fields, and OPG induced loss of their morphology. Flow cytometry was used to analyze the pyroptosis rate; OPG significantly increased the osteoclast pyroptosis rate. To further reveal the mechanism of OPG-induced osteoclast pyroptosis, we examined the expression level of pyroptosis-related genes and proteins, and the results found that OPG increased the expression of NLRP3, ASC, caspase-1, and GSDMD-N compared with the control group. In summary, OPG can induce osteoclast pyroptosis, and its mechanism is related to the expression levels of ASC, NLRP3, caspase 1 and GSDMD, which were included in the classical pathway of pyroptosis.


Assuntos
Osteoclastos , Osteoprotegerina , Osteoclastos/metabolismo , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas de Membrana/genética , NF-kappa B/metabolismo , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteoblastos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Ligante RANK/metabolismo
9.
BMC Oral Health ; 23(1): 11, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36624436

RESUMO

BACKGROUND: To investigate if 5-LO selective inhibitor (MK-886) could be used for systemic treatment of experimentally induced apical periodontitis in a mouse model. METHODS: Twenty-four C57BL/6 mice were used. After coronal opening, a solution containing Escherichia coli LPS (1.0 µg/µL) was inoculated into the root canals of the lower and upper right first molars (n = 72 teeth). After 30 days apical periodontitis was established, and the animals were treated with MK-886 (5 mg/kg), a 5-LO inhibitor, for 7 and 14 days. The tissues were removed for histopathological and histometric analyses, evaluation of osteoclast number and gene expression for receptor activator of nuclear factor kappa-B (Tnfrsf11a), receptor activator of nuclear factor kappa-B ligand (Tnfsf11), osteoprotegerin (Tnfrsf11b), tartrate-resistant acid phosphatase (Acp5), matrix metalloproteinase-9 (Mmp9), cathepsin K (Ctsk) and calcitonin receptor (Calcr). Statistical data analysis was performed using Kruskal Wallis followed by Dunn's tests (α = 0.05). RESULTS: Administration of MK-886 for 7 days exerted no effect on apical periodontitis progression compared to LPS inoculation without treatment (p = 0.3549), while treatment for 14 days exacerbated bone loss (p < 0.0001). Administration of MK-886 enhanced osteoclastogenesis signaling and osteoclast formation within 7 days (p = 0.0005), but exerted no effect at 14 days (p > 0.9999). After 7 days of treatment, MK-886 induced mRNA expression for Acp5 (p = 0.0001), Calcr (p = 0.0003), Mmp9 (p = 0.0005) and Ctsk (p = 0.0008), however no effect in those gene expression was observed after 14 days (p > 0.05). CONCLUSION: Systemic treatment with MK-886 exacerbated LPS-induced apical periodontitis in a mouse model.


Assuntos
Metaloproteinase 9 da Matriz , Periodontite Periapical , Camundongos , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Periodontite Periapical/metabolismo , Osteoclastos
10.
Cell Death Dis ; 14(1): 17, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635269

RESUMO

Bone remodeling is a continuous process between bone-forming osteoblasts and bone-resorbing osteoclasts, with any imbalance resulting in metabolic bone disease, including osteopenia. The HERC1 gene encodes an E3 ubiquitin ligase that affects cellular processes by regulating the ubiquitination of target proteins, such as C-RAF. Of interest, an association exists between biallelic pathogenic sequence variants in the HERC1 gene and the neurodevelopmental disorder MDFPMR syndrome (macrocephaly, dysmorphic facies, and psychomotor retardation). Most pathogenic variants cause loss of HERC1 function, and the affected individuals present with features related to altered bone homeostasis. Herc1-knockout mice offer an excellent model in which to study the role of HERC1 in bone remodeling and to understand its role in disease. In this study, we show that HERC1 regulates osteoblastogenesis and osteoclastogenesis, proving that its depletion increases gene expression of osteoblastic makers during the osteogenic differentiation of mesenchymal stem cells. During this process, HERC1 deficiency increases the levels of C-RAF and of phosphorylated ERK and p38. The Herc1-knockout adult mice developed imbalanced bone homeostasis that presented as osteopenia in both sexes of the adult mice. By contrast, only young female knockout mice had osteopenia and increased number of osteoclasts, with the changes associated with reductions in testosterone and dihydrotestosterone levels. Finally, osteocytes isolated from knockout mice showed a higher expression of osteocytic genes and an increase in the Rankl/Opg ratio, indicating a relevant cell-autonomous role of HERC1 when regulating the transcriptional program of bone formation. Overall, these findings present HERC1 as a modulator of bone homeostasis and highlight potential therapeutic targets for individuals affected by pathological HERC1 variants.


Assuntos
Doenças Ósseas Metabólicas , Reabsorção Óssea , Masculino , Feminino , Animais , Camundongos , Osteogênese/genética , Osteoclastos/metabolismo , Remodelação Óssea/genética , Osteoblastos/metabolismo , Doenças Ósseas Metabólicas/metabolismo , Diferenciação Celular/genética , Camundongos Knockout , Ligante RANK/metabolismo , Reabsorção Óssea/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
11.
Arch Osteoporos ; 18(1): 17, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598583

RESUMO

INTRODUCTION: Hemophilia is a rare X-linked recessive inherited bleeding disorder caused by mutations of the genes encoding coagulation factor VIII (FVIII) or IX (FIX). Patients with hemophilia (PWH) often have a high risk of osteoporosis and fractures that is usually ignored. Herein, we review the underlying mechanisms of osteoporosis and the increased risk of fractures and their treatment in patients with FVIII or FIX deficiency. METHODS: The PubMed, Web of Science, Embase, and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on the mechanisms or treatment of osteoporosis in PWH. RESULTS: The pathogenic mechanisms of osteoporosis in PWH are multifactorial and remain unclear. The available evidence shows that FVIII and FIX deficiency may directly affect bone metabolism by interfering with the RANK/RANKL/OPG pathway. Other potential mechanisms of osteoporosis in PWH include thrombin deficiency and the unloading and immobilization of bone, which will affect osteoblast and osteoclast activity by changing the cytokine profiles. The treatment of osteoporosis in PWH includes antiresorptive, anabolic, and dual-action drugs; weight-bearing exercise; fall prevention; and prophylactic coagulation factor replacement therapy. However, clinical studies of the efficacy of anti-osteoporotic agents in osteoporosis of PWH are urgently needed. CONCLUSION: This review summarizes recent progress in research on the pathogenesis of osteoporosis in PWH and provides insights into potential treatment for osteoporosis in PWH.


Assuntos
Hemofilia A , Hemofilia B , Osteoporose , Humanos , Hemofilia A/terapia , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Hemofilia B/genética , Fator IX/genética , Fator IX/metabolismo , Fator IX/uso terapêutico , Osteoporose/terapia , Osteoporose/tratamento farmacológico , Osteoclastos/metabolismo , Osteoclastos/patologia
12.
J Orthop Surg Res ; 18(1): 3, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36593458

RESUMO

The expression of GPR84 in bone marrow-derived monocytes/macrophages (BMMs) can inhibit osteoclast formation; however, its role in bone metastasis of colorectal cancer (CRC) is still unknown. To investigate the effects of GPR84 on bone metastasis of CRC, the murine CRC cell line MC-38 was injected into tibial bone marrow. We found that the expression of GPR84 in BMMs was gradually downregulated during bone metastasis of CRC, and the activation of GPR84 significantly prevented osteoclastogenesis in the tumor microenvironment. Mechanistically, the MAPK pathway mediated the effects of GPR84 on osteoclast formation. Moreover, we found that IL-11 at least partly inhibited the expression of GPR84 in the tumor microenvironment through the inactivation of STAT1. Additionally, activation of GPR84 could prevent osteolysis during bone metastasis of CRC. Our results suggest that CRC cells downregulate the expression of GPR84 in BMMs to promote osteoclastogenesis in an IL-11-dependent manner. Thus, GPR84 could be a potential therapeutic target to attenuate bone destruction induced by CRC metastasis.


Assuntos
Neoplasias Ósseas , Neoplasias Colorretais , Osteólise , Receptores Acoplados a Proteínas G , Animais , Camundongos , Neoplasias Ósseas/metabolismo , Diferenciação Celular , Neoplasias Colorretais/metabolismo , Interleucina-11/metabolismo , Interleucina-11/farmacologia , Interleucina-11/uso terapêutico , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo , Osteogênese , Osteólise/tratamento farmacológico , Ligante RANK/metabolismo , Receptores Acoplados a Proteínas G/genética , Microambiente Tumoral
13.
Int J Mol Sci ; 24(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36614201

RESUMO

Once prostate cancer cells metastasize to bone, they perceive approximately 2 kPa compression. We hypothesize that 2 kPa compression stimulates the epithelial-to-mesenchymal transition (EMT) of prostate cancer cells and alters their production of paracrine signals to affect osteoclast and osteoblast behavior. Human DU145 prostate cancer cells were subjected to 2 kPa compression for 2 days. Compression decreased expression of 2 epithelial genes, 5 out of 13 mesenchymal genes, and increased 2 mesenchymal genes by DU145 cells, as quantified by qPCR. Conditioned medium (CM) of DU145 cells was added to human monocytes that were stimulated to differentiate into osteoclasts for 21 days. CM from compressed DU145 cells decreased osteoclast resorptive activity by 38% but did not affect osteoclast size and number compared to CM from non-compressed cells. CM was also added to human adipose stromal cells, grown in osteogenic medium. CM of compressed DU145 cells increased bone nodule production (Alizarin Red) by osteoblasts from four out of six donors. Compression did not affect IL6 or TNF-α production by PC DU145 cells. Our data suggest that compression affects EMT-related gene expression in DU145 cells, and alters their production of paracrine signals to decrease osteoclast resorptive activity while increasing mineralization by osteoblasts is donor dependent. This observation gives further insight in the altered behavior of PC cells upon mechanical stimuli, which could provide novel leads for therapies, preventing bone metastases.


Assuntos
Reabsorção Óssea , Neoplasias da Próstata , Masculino , Humanos , Osteoclastos/metabolismo , Osteoblastos/metabolismo , Osso e Ossos/metabolismo , Reabsorção Óssea/metabolismo , Neoplasias da Próstata/metabolismo , Diferenciação Celular
14.
Bull Math Biol ; 85(2): 12, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607440

RESUMO

Pre-metastatic niche is a location where cancer cells, separating from a primary tumor, find "fertile soil" for growth and proliferation, ensuring successful metastasis. Exosomal miRNAs of breast cancer are known to enter the bone and degrade it, which facilitates cancer cells invasion into the bone interior and ensures its successful colonization. In this paper, we use a mathematical model to first describe, in health, the continuous remodeling of the bone by bone-forming osteoblasts, bone-resorbing osteoclasts and the RANKL-OPG-RANK signaling system, which keeps the balance between bone formation and bone resorption. We next demonstrate how breast cancer exosomal miRNAs disrupt this balance, either by increasing or by decreasing the ratio of osteoclasts/osteoblasts, which results in abnormal high bone resorption or abnormal high bone forming, respectively, and in bone weakening in both cases. Finally we consider the case of abnormally high resorption and evaluate the effect of drugs, which may increase bone density to normal level, thus protecting the bone from invasion by cancer cells.


Assuntos
Reabsorção Óssea , Neoplasias da Mama , MicroRNAs , Humanos , Feminino , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Mama/patologia , Osteoprotegerina , Modelos Biológicos , Conceitos Matemáticos , Osteoclastos , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osteoblastos
15.
Oxid Med Cell Longev ; 2023: 2975193, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36686380

RESUMO

Excessive bone resorption due to increased inflammatory factors is a common feature of inflammatory lytic bone diseases. This group of diseases is effectively treated with drugs. In recent years, many studies have reported that traditional Chinese medicine herbs have substantial effects on inflammation, osteoclast differentiation and maturation, and bone destruction. Herein, we investigated the effects of osthole (OST) on lipopolysaccharide- (LPS-) induced macrophage polarization, inflammatory responses, and osteolysis. In vitro, we used immunofluorescence and quantitative real-time polymerase chain reaction assays to confirm whether bone marrow-derived macrophages showed an increased expression of inflammatory factors, such as interleukin-6, iNOS, CCR7, and CD86, in the presence of LPS. However, we found that such expression was suppressed and that the M2 macrophage expression increased in the presence of OST. OST reduced LPS- and RANKL-induced intracellular reactive oxygen species production in the bone marrow-derived macrophages. Further, it potently suppressed osteoclast differentiation and osteoclast-specific gene expression by suppressing the P38/MAPK and NF-κB pathways. Consistent with the in vitro observations, OST greatly ameliorated LPS-induced bone resorption and modulated the ratio of macrophages at the site of osteolysis. Taken together, OST has great potential for use in the management of osteolytic diseases.


Assuntos
Reabsorção Óssea , Osteólise , Animais , Camundongos , Osteólise/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Macrófagos/metabolismo , Osteoclastos/metabolismo , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Crânio/metabolismo , NF-kappa B/metabolismo , Ligante RANK/metabolismo , Diferenciação Celular , Osteogênese , Camundongos Endogâmicos C57BL
16.
Elife ; 122023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36656634

RESUMO

The past decade has seen significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone integrity in disease. Recent breakthroughs have arisen mainly from identifying disease-causing mutations and modeling human bone disease in rodents, in essence, highlighting the integrative nature of skeletal physiology. It has become increasingly clear that bone cells, osteoblasts, osteoclasts, and osteocytes, communicate and regulate the fate of each other through RANK/RANKL/OPG, liver X receptors (LXRs), EphirinB2-EphB4 signaling, sphingolipids, and other membrane-associated proteins, such as semaphorins. Mounting evidence also showed that critical developmental pathways, namely, bone morphogenetic protein (BMP), NOTCH, and WNT, interact each other and play an important role in postnatal bone remodeling. The skeleton communicates not only with closely situated organs, such as bone marrow, muscle, and fat, but also with remote vital organs, such as the kidney, liver, and brain. The metabolic effect of bone-derived osteocalcin highlights a possible role of skeleton in energy homeostasis. Furthermore, studies using genetically modified rodent models disrupting the reciprocal relationship with tropic pituitary hormone and effector hormone have unraveled an independent role of pituitary hormone in skeletal remodeling beyond the role of regulating target endocrine glands. The cytokine-mediated skeletal actions and the evidence of local production of certain pituitary hormones by bone marrow-derived cells displays a unique endocrine-immune-skeletal connection. Here, we discuss recently elucidated mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, crosstalk between bone and vital organs, as well as opportunities for treating diseases of the skeleton.


Assuntos
Osso e Ossos , Osteoblastos , Humanos , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteócitos/metabolismo , Hormônios Hipofisários/metabolismo
17.
J Tradit Chin Med ; 43(1): 198-204, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36640013

RESUMO

OBJECTIVE: To organize the fragmented information available in the literature to describe and summarize the extracts used by natural medicines in the treatment of bone loss, and to provide evidence and support for the potential use of natural medicines in the treatment of osteoporosis. METHODS: A literature survey for relevant information regarding the osteogenesis of Dongkuiguo (), Machixian (). etc., was conducted using PubMed, ScienceDirect, MEDLINE, Springer LINK and Google Scholar electronic databases from the years 2000-2020. RESULTS: Dongkuiguo (), Machixian (). etc., both inhibit the activity of osteoclasts and reduce bone resorption by regulation of signaling pathways through interacting with signaling molecules. CONCLUSIONS: In this review, the current knowledge of the novel medicines with osteogenesis properties were summarized and their potential in the treatment of bone loss were demonstrated, but the lack of research on the regulation of the signaling pathway's mechanism of action, and the corresponding theoretical basis for the application of natural medicines in clinical osteoporosis, made it difficult to be widely applied and promoted in clinical practice. Further experiments with some of the medicines and the mechanisms is needed to realize their potential as osteoporosis treatments.


Assuntos
Reabsorção Óssea , Osteoporose , Humanos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoclastos/metabolismo , Osteogênese , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Transdução de Sinais
18.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 58(1): 86-91, 2023 Jan 09.
Artigo em Chinês | MEDLINE | ID: mdl-36642458

RESUMO

Tunneling nanotube (TNT) is a newly discovered communication mode between animal cells in recent years, which have important physiological and pathological significance. However, the role of TNT in bone biology is still unclear. At present, there are many reports about tunneling nanotubes in bone marrow mesenchymal stem cells, osteoclast precursor cells, osteoblasts and immune cells. This review describes the research advances of TNT and its research progress in bone biology. It looks forward to the research direction of TNT in oral and maxillofacial bone development and bone biology, to provide new strategies for the maintenance of bone homeostasis and the treatment of bone diseases.


Assuntos
Osso e Ossos , Nanotubos , Animais , Osteoclastos , Biologia , Comunicação Celular/fisiologia
19.
PLoS One ; 18(1): e0280601, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662733

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Green-lipped mussel (GLM) has chondro-modulatory and anti-inflammatory properties, but the mechanism underlying the effect of GLM on RA is unclear. To investigate the roles of GLM on the pathogenesis of RA, we examined the effects of GLM in collagen-induced arthritis (CIA) mice and osteoclast differentiation. GLM was orally administrated CIA mice at 3 weeks after chicken type II collagen (CII) immunizations. GLM reduced arthritis severity and the histologic score of CIA mice compared to vehicle. The expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-17) was decreased in the ankle joints of GLM-treated CIA mice. The expression of CD4+ IL-17+ cells decreased in ex vivo splenocytes and the spleens of GLM-treated CIA mice. Moreover, GLM inhibited TRAP+ multinucleated cells among mouse bone marrow-derived monocytes/macrophages (BMM), and the expression of osteoclast-related genes in mouse BMMs and human monocytes in vitro. These results suggest that GLM has potential as a therapeutic agent that can improve disease by controlling pathologic immune cells and osteoclastogenesis.


Assuntos
Artrite Experimental , Artrite Reumatoide , Bivalves , Camundongos , Humanos , Animais , Osteogênese , Interleucina-17/metabolismo , Artrite Reumatoide/tratamento farmacológico , Osteoclastos/metabolismo , Citocinas/metabolismo , Artrite Experimental/tratamento farmacológico , Bivalves/metabolismo
20.
Chem Biol Interact ; 370: 110311, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36563736

RESUMO

Osteoarthritis (OA) is a common degenerative disease characterized by articular cartilage destruction, subchondral bone remodeling, ectopic osteophyte formation and synovitis. It is now recognized that the integrity of the underlying subchondral bone is crucial for the maintenance of the overlying articular cartilage. Therapeutic agents that can prevent subchondral bone loss are demonstrate potential in the prevention and treatment of OA. Diosmetin (DIOS; 3',5,7 -trihydroxy-4'-methoxy flavone), a natural flavonoid, has been shown to exert anti-oxidative, anti-inflammatory, anti-apoptotic and anticancer properties. In this study, we found that diosmetin suppressed the DMM-induced subchondral bone loss and reduced subsequent cartilage degradation in vivo. Cellular-based assays showed that diosmetin inhibited RANKL-induced osteoclast formation and bone resorption,but did not affect IL-1ß-induced chondrocyte hypertrophy. Biochemical analyses demonstrated that the anti-osteoclastic effect of diosmetin was at least in part due to the suppression of RANKL-induced activation of the ERK, p38, and JNK MAPK signaling pathways. Collectively, our results show that diosmetin have potential as a therapeutic agent the treatment of abnormal subchondral bone loss and cartilage degradation associated with the onset of OA.


Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Flavonoides/metabolismo , Osteoclastos , Cartilagem Articular/metabolismo , Modelos Animais de Doenças , Anti-Inflamatórios/farmacologia
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