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1.
Shanghai Kou Qiang Yi Xue ; 33(1): 85-89, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38583031

RESUMO

PURPOSE: To study the relationship between the expression of prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) and the osteogenic activity and oxygen level of alveolar bone. METHODS: The alveolar bones of 56 patients with chronic periodontitis who received dental treatment from March 2021 to March 2023 were collected as the experimental (periodontitis) group, and the healthy alveolar bones of 53 patients who received dental treatment during the same period were selected as the control group. The osteoblasts were cultured by tissue block culture, and modified Kaplow's alkaline phosphatase (ALP) staining was used to identify the cells. COX-2, PGE2 and osteoclastogenesis inhibitory factor (OPG) receptor activator of nuclear factor-κb ligand (RANKL) and other indicators were determined by ELISA. PGE2, COX-2, OPG, internal oxygen level, ALP, RANKL and their correlation were compared between the two groups. Statistical analysis was performed with SPSS 27.0 software package. RESULTS: PGE2, COX-2 and RANKL in periodontitis group were significantly higher than those in the control group, but OPG, internal oxygen level and ALP were significantly lower than those in the control group (P<0.05). PGE2 and COX2 were highly positively correlated with OPG, internal oxygen level and ALP, but were highly positively correlated with RANKL(P<0.05). CONCLUSIONS: The expression of PGE2 and COX-2 is highly negatively correlated with ALP and oxygen levels. Clinical treatment may consider increasing oxygen levels, increasing oxygen partial pressure, and regulating ALP levels by drugs, so as to change the inflammatory condition of periodontitis or other dental diseases.


Assuntos
Dinoprostona , Periodontite , Humanos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Osteoblastos/metabolismo , Osteogênese , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo
2.
Elife ; 132024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38591777

RESUMO

Bone remodeling is a complex process involving the coordinated actions of osteoblasts and osteoclasts to maintain bone homeostasis. While the influence of osteoblasts on osteoclast differentiation is well established, the reciprocal regulation of osteoblasts by osteoclasts has long remained enigmatic. In the past few years, a fascinating new role for osteoclasts has been unveiled in promoting bone formation and facilitating osteoblast migration to the remodeling sites through a number of different mechanisms, including the release of factors from the bone matrix following bone resorption and direct cell-cell interactions. Additionally, considerable evidence has shown that osteoclasts can secrete coupling factors known as clastokines, emphasizing the crucial role of these cells in maintaining bone homeostasis. Due to their osteoprotective function, clastokines hold great promise as potential therapeutic targets for bone diseases. However, despite long-standing work to uncover new clastokines and their effect in vivo, more substantial efforts are still required to decipher the mechanisms and pathways behind their activity in order to translate them into therapies. This comprehensive review provides insights into our evolving understanding of the osteoclast function, highlights the significance of clastokines in bone remodeling, and explores their potential as treatments for bone diseases suggesting future directions for the field.


Assuntos
Reabsorção Óssea , Osteoclastos , Humanos , Osteoclastos/metabolismo , Osteoblastos/metabolismo , Reabsorção Óssea/metabolismo , Remodelação Óssea , Osteogênese/fisiologia , Diferenciação Celular/fisiologia
3.
J Orthop Surg Res ; 19(1): 179, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468352

RESUMO

BACKGROUND: Cholesterol (CHO) is an essential component of the body. However, high CHO levels in the body can damage bone mass and promote osteoporosis. CHO accumulation can cause osteoblast apoptosis, which has a negative effect on bone formation. The pathogenesis of osteoporosis is a complicate process that includes oxidative stress, endoplasmic reticulum (ER) stress, and inflammation. Geniposide (GEN) is a natural compound with anti-osteoporotic effect. However, the roles of GEN in osteopathogenesis are still unclear. Our previous studies demonstrated that GEN could reduce the accumulation of CHO in osteoblasts and the activation of ER stress in osteoblasts. However, the molecular mechanism of GEN in inhibiting CHO-induced apoptosis in osteoblasts needs to be further investigated. METHODS: MC3T3-E1 cells were treated with osteogenic induction medium (OIM). Ethanol-solubilized cholesterol (100 µM) was used as a stimulator, and 10 µM and 25 µM geniposide was added for treatment. The alterations of protein expression were detected by western blot, and the cell apoptosis was analyzed by a flow cytometer. RESULTS: CHO promoted osteoblast apoptosis by activating ER stress in osteoblasts, while GEN alleviated the activation of ER stress and reduced osteoblast apoptosis by activating the GLP-1R/ABCA1 pathway. Inhibition of ABCA1 or GLP-1R could eliminate the protective activity of GEN against CHO-induced ER stress and osteoblast apoptosis. CONCLUSION: GEN alleviated CHO-induced ER stress and apoptosis in osteoblasts by mediating the GLP-1R/ABCA1 pathway.


Assuntos
Iridoides , Osteoblastos , Osteoporose , Humanos , Osteoblastos/metabolismo , Osteoporose/metabolismo , Apoptose , Estresse do Retículo Endoplasmático , Colesterol/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/farmacologia
4.
Int J Mol Sci ; 25(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474093

RESUMO

The treatment of patients with advanced cancer poses clinical problems due to the complications that arise as the disease progresses. Bone metastases are a common problem that cancer patients may face, and currently, there are no effective drugs to treat these individuals. Prostate, breast, and lung cancers often spread to the bone, causing significant and disabling health conditions. The bone is a highly active and dynamic tissue and is considered a favorable environment for the growth of cancer. The role of osteoblasts and osteoclasts in the process of bone remodeling and the way in which their interactions change during the progression of metastasis is critical to understanding the pathophysiology of this disease. These interactions create a self-perpetuating loop that stimulates the growth of metastatic cells in the bone. The metabolic reprogramming of both cancer cells and cells in the bone microenvironment has serious implications for the development and progression of metastasis. Insight into the process of bone remodeling and the systemic elements that regulate this process, as well as the cellular changes that occur during the progression of bone metastases, is critical to the discovery of a cure for this disease. It is crucial to explore different therapeutic options that focus specifically on malignancy in the bone microenvironment in order to effectively treat this disease. This review will focus on the bone remodeling process and the effects of metabolic disorders as well as systemic factors like hormones and cytokines on the development of bone metastases. We will also examine the various therapeutic alternatives available today and the upcoming advances in novel treatments.


Assuntos
Neoplasias Ósseas , Masculino , Humanos , Neoplasias Ósseas/patologia , Osso e Ossos/metabolismo , Osteoclastos/metabolismo , Osteoblastos/metabolismo , Citocinas/metabolismo , Microambiente Tumoral
5.
Cells ; 13(5)2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38474370

RESUMO

Parathyroid hormone (PTH) plays a pivotal role in maintaining calcium homeostasis, largely by modulating bone remodeling processes. Its effects on bone are notably dependent on the duration and frequency of exposure. Specifically, PTH can initiate both bone formation and resorption, with the outcome being influenced by the manner of PTH administration: continuous or intermittent. In continuous administration, PTH tends to promote bone resorption, possibly by regulating certain genes within bone cells. Conversely, intermittent exposure generally favors bone formation, possibly through transient gene activation. PTH's role extends to various aspects of bone cell activity. It directly influences skeletal stem cells, osteoblastic lineage cells, osteocytes, and T cells, playing a critical role in bone generation. Simultaneously, it indirectly affects osteoclast precursor cells and osteoclasts, and has a direct impact on T cells, contributing to its role in bone resorption. Despite these insights, the intricate mechanisms through which PTH acts within the bone marrow niche are not entirely understood. This article reviews the dual roles of PTH-catabolic and anabolic-on bone cells, highlighting the cellular and molecular pathways involved in these processes. The complex interplay of these factors in bone remodeling underscores the need for further investigation to fully comprehend PTH's multifaceted influence on bone health.


Assuntos
Reabsorção Óssea , Hormônio Paratireóideo , Humanos , Osso e Ossos/metabolismo , Medula Óssea/metabolismo , Reabsorção Óssea/metabolismo , Osteoblastos/metabolismo , Hormônio Paratireóideo/metabolismo
6.
BMC Musculoskelet Disord ; 25(1): 213, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38481217

RESUMO

Osteoporosis is caused by the imbalance of osteoblasts and osteoclasts. The regulatory mechanisms of differentially expressed genes (DEGs) in pathogenesis of osteoporosis are of significant and needed to be further investigated. GSE100609 dataset downloaded from Gene Expression Omnibus (GEO) database was used to identified DEGs in osteoporosis patients. KEGG analysis was conducted to demonstrate signaling pathways related to enriched genes. Osteoporosis patients and the human mesenchymal stem cells (hMSCs) were obtained for in vivo and in vitro resaerch. Lentivirus construction and viral infection was used to knockdown genes. mRNA expression and protein expression were detected via qRT-PCR and western blot assay separately. Alkaline phosphatase (ALP) activity detection, alizarin Red S (ARS) staining, and expression of bone morphogenetic protein 2 (BMP2), osteocalcin (OCN) and Osterix were evaluated to determine osteoblast differentiation capacity. UL-16 binding protein 1 (ULBP1) gene was upregulated in osteoporosis and downregulated in differentiated hMSCs. Knockdown of ULBP1 increased ALP activity, mineralization ability evaluated by ARS staining, expression of BMP2, OCN and Osterix in differentiated hMSCs. Furthermore, rescue experiment demonstrated that suppressed ULBP1 boosted osteoblast differentiation by activating TNF-ß signaling pathway. Knockdown of ULBP1 gene could promoted osteoblast differentiation by activating TNF-ß signaling pathway in differentiated hMSCs. ULBP1 may be a the Achilles' heel of osteoporosis, and suppression of ULBP1 could be a promising treatment for osteoporosis.


Assuntos
Células-Tronco Mesenquimais , Osteoporose , Humanos , Proteínas de Transporte/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Linfotoxina-alfa/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteogênese/genética , Osteoporose/genética , Proteína Smad2/metabolismo
7.
Int J Mol Sci ; 25(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542323

RESUMO

As the global population ages, the number of patients with osteoporosis is rapidly rising. The existing first-line clinical drugs are bone resorption inhibitors that have difficulty restoring the bone mass of elderly patients to the safe range. The range and period of use of existing peptides and monoclonal antibodies are limited, and small-molecule bone formation-promoting drugs are urgently required. We established an I-9 synthesis route with high yield, simple operation, and low cost that was suitable for future large-scale production. I-9 administration promoted bone formation and increased bone mass in mice with low bone mass in an aged C57 mouse model. Our findings revealed a hitherto undescribed pathway involving the BMP2-ERK-ATF4 axis that promotes osteoblast differentiation; I-9 has favorable biosafety in mice. This study systematically investigated the efficacy, safety, and mechanism of I-9 for treating osteoporosis and positions this drug for preclinical research in the future. Thus, this study has promoted the development of small-molecule bone-promoting drugs.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Idoso , Camundongos , Humanos , Animais , Osteogênese , Preparações Farmacêuticas/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Peptídeos/metabolismo , Diferenciação Celular , Osteoblastos/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Proteína Morfogenética Óssea 2/metabolismo
8.
Aging (Albany NY) ; 16(5): 4832-4840, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461437

RESUMO

Osteoporosis is a usual bone disease in aging populations, principally in postmenopausal women. Anti-resorptive and anabolic drugs have been applied to prevent and cure osteoporosis and are associated to a different of adverse effects. Du-Zhong is usually applied in Traditional Chinese Medicine to strengthen bone, regulate bone metabolism, and treat osteoporosis. Chlorogenic acid is a major polyphenol in Du-Zhong. In the current study, chlorogenic acid was found to enhance osteoblast proliferation and differentiation. Chlorogenic acid also inhibits the RANKL-induced osteoclastogenesis. Notably, ovariectomy significantly decreased bone volume and mechanical properties in the ovariectomized (OVX) rats. Administration of chlorogenic acid antagonized OVX-induced bone loss. Taken together, chlorogenic acid seems to be a hopeful molecule for the development of novel anti-osteoporosis treatment.


Assuntos
Osteoclastos , Osteoporose , Humanos , Ratos , Feminino , Animais , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , Ácido Clorogênico/metabolismo , Osteogênese , Osteoporose/metabolismo , Osteoblastos/metabolismo , Diferenciação Celular
9.
Front Biosci (Landmark Ed) ; 29(3): 115, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38538259

RESUMO

BACKGROUND: Postmenopausal osteoporosis (PMOP) is a prevalent disease, which features decreased bone mass, bone weakness and deteriorated bone microstructure in postmenopausal women. Although many factors have been revealed to contribute to the occurrence of PMOP, its mechanism remains undefined. This work aimed to identify significant changes in gene expression during PMOP formation and to examine the most valuable differential genes in postmenopausal osteoporosis versus the control group. METHODS: The GSE68303 dataset that contains 12 ovariectomize (OVX) experimental and 11 sham groups was downloaded and analyzed. The results indicated that interferon regulatory factor 4 (IRF4) might be a hub gene in the development of postmenopausal osteoporosis. Western blot and immunohistochemistry were carried out to evaluate IRF4 levels in thoracic vertebra extracts from OVX and Sham mice. To assess IRF4's impact on osteogenic differentiation in postmenopausal bone marrow mesenchymal stem cells (BM-MSCs), IRF4 overexpression (OV-IRF4) and knockdown (Sh-IRF4) plasmids were constructed. RESULTS: The results showed that comparing with the sham group, bone samples from the OVX group showed higher IRF4 expression. Alkaline phosphatase (ALP) staining revealed that IRF4 overexpression significantly inhibited ALP activity, while IRF4 knockdown promoted ALP activity in BM-MSCs. Simvastatin-treated OVX mice showed increased total bone volume/total tissue volume (BV/TV) and elevated Runx2 expression by immunohistochemical staining compared with the OVX group. CONCLUSIONS: This study demonstrated that IRF4 is associated with OVX induced osteoporosis, it can regulate bone stability by inhibiting the osteogenic differentiation BM-MSCs. This study may help enhance our understanding of the molecular mechanism of PMOP formation, providing new insights into estrogen defiance induced osteoporosis.


Assuntos
Fatores Reguladores de Interferon , Osteogênese , Osteoporose Pós-Menopausa , Animais , Feminino , Humanos , Camundongos , Diferenciação Celular/fisiologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Osteoblastos/metabolismo , Osteogênese/genética , Osteoporose Pós-Menopausa/genética
10.
J Endocrinol ; 261(2)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38492310

RESUMO

Estrogen deficiency is one of the main causes for postmenopausal osteoporosis. Current osteoporotic therapies are of high cost and associated with serious side effects. So there is an urgent need for cost-effective anti-osteoporotic agents. Anti-osteoporotic activity of Litsea glutinosa extract (LGE) is less explored. Moreover, its role in fracture healing and mechanism of action is still unknown. In the present study we explore the osteoprotective potential of LGE in osteoblast cells and fractured and ovariectomized (Ovx) mice models. Alkaline phosphatase (ALP), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and mineralization assays revealed that LGE treatment increased osteoblast cell differentiation, viability and mineralization. LGE treatment at 0.01 µg increased the expression of BMP2, PSMAD, RUNX2 and type 1 col. LGE also mitigated RANKL-induced osteoclastogenesis. Next, drill hole injury Balb/C mice model was treated with LGE for 12 days. Micro-CT analysis and Calcein labeling at the fracture site showed that LGE (20 mg/kg) enhanced new bone formation and bone regeneration, also increased expression of BMP2/SMAD1 signaling genes at fracture site. Ovx mice were treated with LGE for 1 month. µCT analysis indicated that the treatment of LGE at 20 mg/kg dose prevented the alteration in bone microarchitecture and maintained bone mineral density and bone mineral content. Treatment also increased bone strength and restored the bone turnover markers. Furthermore, in bone samples, LGE increased osteogenesis by enhancing the expression of BMP2/SMAD1 signaling components and decreased osteoclast number and surface. We conclude that LGE promotes osteogenesis via modulating the BMP2/SMAD1 signaling pathway. The study advocates the therapeutic potential of LGE in osteoporosis treatment.


Assuntos
Doenças Ósseas Metabólicas , Litsea , Camundongos , Animais , Feminino , Humanos , Consolidação da Fratura , Osteogênese , Doenças Ósseas Metabólicas/metabolismo , Transdução de Sinais , Osteoblastos/metabolismo , Diferenciação Celular , Ovariectomia , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 2/farmacologia
11.
Biochim Biophys Acta Mol Cell Res ; 1871(4): 119712, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38521466

RESUMO

Inflammatory environments can trigger endoplasmic reticulum (ER) stress and lead to pyroptosis in various tissues and cells, including liver, brain, and immune cells. As a key factor of ER stress, DNA damage-inducible transcript 3 (DDIT3)/CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is upregulated in osteoblasts during inflammatory stimulation. DDIT3/CHOP may therefore regulate osteoblast pyroptosis in inflammatory conditions. During this investigation, we found that lipopolysaccharides (LPS)/adenosine 5'-triphosphate (ATP) stimulation in vitro induced osteoblasts to undergo pyroptosis, and the expression of DDIT3/CHOP was increased during this process. The overexpression of DDIT3/CHOP further promoted osteoblast pyroptosis as evidenced by the increased expression of the inflammasome NLR family pyrin domain containing 3 (NLRP3) and ratios of caspase-1 p20/caspase-1 and cleaved gasdermin D (GSDMD)/GSDMD. To explore the specific mechanism of this effect, we found through fluorescence imaging and Western blot analysis that LPS/ATP stimulation promoted PTEN-induced kinase 1 (PINK1)/E3 ubiquitin-protein ligase parkin (Parkin)-mediated mitophagy in osteoblasts, and this alteration was suppressed by the DDIT3/CHOP overexpression, resulting in increased ratio of pyroptosis compared with the control groups. The impact of DDIT3/CHOP on pyroptosis in osteoblasts was reversed by the application of carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a specific mitophagy agonist. Therefore, our data demonstrated that DDIT3/CHOP promotes osteoblast pyroptosis by inhibiting PINK1/Parkin-mediated mitophagy in an inflammatory environment.


Assuntos
Lipopolissacarídeos , Piroptose , Lipopolissacarídeos/farmacologia , Mitofagia , Caspase 1/metabolismo , Caspase 1/farmacologia , Trifosfato de Adenosina/metabolismo , Osteoblastos/metabolismo , Proteínas Quinases , Ubiquitina-Proteína Ligases/farmacologia
12.
Stem Cell Reports ; 19(4): 486-500, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38458190

RESUMO

Maintenance of hematopoietic stem cell (HSC) function in the niche is an orchestrated event. Osteomacs (OM) are key cellular components of the niche. Previously, we documented that osteoblasts, OM, and megakaryocytes interact to promote hematopoiesis. Here, we further characterize OM and identify megakaryocyte-induced mediators that augment the role of OM in the niche. Single-cell mRNA-seq, mass spectrometry, and CyTOF examination of megakaryocyte-stimulated OM suggested that upregulation of CD166 and Embigin on OM augment their hematopoiesis maintenance function. CD166 knockout OM or shRNA-Embigin knockdown OM confirmed that the loss of these molecules significantly reduced the ability of OM to augment the osteoblast-mediated hematopoietic-enhancing activity. Recombinant CD166 and Embigin partially substituted for OM function, characterizing both proteins as critical mediators of OM hematopoietic function. Our data identify Embigin and CD166 as OM-regulated critical components of HSC function in the niche and potential participants in various in vitro manipulations of stem cells.


Assuntos
Células-Tronco Hematopoéticas , Megacariócitos , Animais , Humanos , Camundongos , Megacariócitos/metabolismo , Regulação para Cima , Células-Tronco Hematopoéticas/metabolismo , Hematopoese/fisiologia , Osteoblastos/metabolismo , Nicho de Células-Tronco/fisiologia
13.
Environ Pollut ; 347: 123731, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38458519

RESUMO

Bisphenol A (BPA), an ingredient in consumer products, has been suggested that it can interfere with bone development and maintenance, whereas the molecule mechanism remains unclear. The objective of this study is to investigate the effect of BPA on early bone differentiation and metabolism, and its potential molecule mechanism by employing hFOB1.19 cell as an in vitro model, as well as larval zebrafish as an in vivo model. The in vitro experiments indicated that BPA decreased cell viability, inhibited osteogenic activity (such as ALP, RUNX2), increased ROS production, upregulated transcriptional or protein levels of apoptosis-related molecules (such as Caspase 3, Caspase 9), while suppressed transcriptional or protein levels of pyroptosis-specific markers (TNF-α, TNF-ß, IL-1ß, ASC, Caspase 1, and GSDMD). Moreover, the evidences from in vivo model demonstrated that exposure to BPA distinctly disrupted pharyngeal cartilage, craniofacial bone development, and retarded bone mineralization. The transcriptional level of bone development-related genes (bmp2, dlx2a, runx2, and sp7), apoptosis-related genes (bcl2), and pyroptosis-related genes (cas1, nlrp3) were significantly altered after treating with BPA in zebrafish larvae. In summary, our study, combining in vitro and in vivo models, confirmed that BPA has detrimental effects on osteoblast activity and bone development. These effects may be due to the promotion of apoptosis, the initiation of oxidative stress, and the inhibition of pyroptosis.


Assuntos
Compostos Benzidrílicos , Subunidade alfa 1 de Fator de Ligação ao Core , Fenóis , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Osteoblastos/metabolismo , Estresse Oxidativo
14.
BMC Musculoskelet Disord ; 25(1): 206, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38454404

RESUMO

BACKGROUND: Osteoporosis is a genetic disease caused by the imbalance between osteoblast-led bone formation and osteoclast-induced bone resorption. However, further gene-related pathogenesis remains to be elucidated. METHODS: The aberrant expressed genes in osteoporosis was identified by analyzing the microarray profile GSE100609. Serum samples of patients with osteoporosis and normal group were collected, and the mRNA expression of candidate genes was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The mouse cranial osteoblast MC3T3-E1 cells were treated with dexamethasone (DEX) to mimic osteoporosis in vitro. Alizarin Red staining and alkaline phosphatase (ALP) staining methods were combined to measure matrix mineralization deposition of MC3T3-E1 cells. Meanwhile, the expression of osteogenesis related genes including alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OPN), Osterix, and bone morphogenetic protein 2 (BMP2) were evaluated by qRT-PCR and western blotting methods. Then the effects of candidate genes on regulating impede bone loss caused by ovariectomy (OVX) in mice were studied. RESULTS: Cyclin A1 (CCNA1) was found to be significantly upregulated in serum of osteoporosis patients and the osteoporosis model cells, which was in line with the bioinformatic analysis. The osteogenic differentiation ability of MC3T3-E1 cells was inhibited by DEX treatment, which was manifested by decreased Alizarin Red staining intensity, ALP staining intensity, and expression levels of ALP, OCN, OPN, Osterix, and BMP2. The effects of CCNA1 inhibition on regulating osteogenesis were opposite to that of DEX. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that genes negatively associated with CCNA1 were enriched in the TGF-beta signaling pathway. Inhibitor of TGF-beta signaling pathway partly reversed osteogenesis induced by suppressed CCNA1. Furthermore, suppressed CCNA1 relieved bone mass of OVX mice in vivo. CONCLUSION: Downregulation of CCNA1 could activate TGF-beta signaling pathway and promote bone formation, thus playing a role in treatment of osteoporosis.


Assuntos
Antraquinonas , Osteoporose , Fator de Crescimento Transformador beta , Animais , Feminino , Humanos , Camundongos , Fosfatase Alcalina/metabolismo , Diferenciação Celular , Ciclina A1/metabolismo , Osteoblastos/metabolismo , Osteogênese , Osteoporose/induzido quimicamente , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento Transformadores/efeitos adversos , Fatores de Crescimento Transformadores/metabolismo
15.
Autoimmunity ; 57(1): 2319207, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38404066

RESUMO

Objective: Todetect the abnormal distribution of B-lymphocytes between peripheral and bone marrow (BM) compartments and explore the mechanism of abnormal chemotaxis of B-lymphocytes in lupus subjects. Methods: The proportions of CXC chemokine receptor (CXCR)4+ B cells and CFDA-labeled MRL/lpr-derived B cells were detected by flow cytometry. The levels of CXC chemokine ligand (CXCL)12in peripheral blood (PB)were measured by ELISA. The migrated B cells to osteoblasts (OBs) was measured by transwell migration assay. The relative spatial position of B cells, OBs and CXCL12 was presented by Immunofluorescence assay. Results: Firstly, we found that the percentage of CXCR4+ B cells was lower in PB and higher in the BM from both MRL/lpr mice and patientswith Systemic lupus erythematosus (SLE). Secondly, OBs from MRL/lpr mice produced more CXCL12 than that from C57BL/6 mice. Besides, MRL/lpr-derived OBs demonstrated more potent chemotactic ability toward B-lymphocytes than control OBs by vitro an vivo. Additionally, more B-lymphocytes were found to co-localize with OBs within the periosteal zone of bone in MRL/lpr mice. Lastly, the percentages of CXCR4+B cells were found to be negatively correlated with serum Immunoglobulin (Ig) G concentration, moreover, BM CXCL12 levels were found to be positively correlated with SLE disease activity index Score and negatively correlated with serum Complement3 (C3) concentration. Conclusions: our results indicated that there is a shifted distribution of B-lymphocytes between BM and peripheral compartments in both SLE patients and MRL/lpr mice. Besides, the up-regulated levels of CXCL12 in OBs was indicated to contribute to the enhanced chemotactic migration and anchorage of B-lymphocytes to OBs.


Assuntos
Medula Óssea , Lúpus Eritematoso Sistêmico , Camundongos , Animais , Humanos , Medula Óssea/metabolismo , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos C57BL , Linfócitos B/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Osteoblastos/metabolismo , Quimiocina CXCL12/metabolismo
16.
Int J Mol Sci ; 25(4)2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38396954

RESUMO

Runx2 (runt related transcription factor 2) is an essential transcription factor for osteoblast proliferation and differentiation. Uridine diphosphate (UDP)-N-acetylgalactosamine (GalNAc): polypeptide GalNAc-transferase 3 (Galnt3) prevents proteolytic processing of fibroblast growth factor 23 (Fgf23), which is a hormone that regulates the serum level of phosphorus. Runx2 and Galnt3 were expressed in osteoblasts and osteocytes, and Fgf23 expression was restricted to osteocytes in bone. Overexpression and knock-down of Runx2 upregulated and downregulated, respectively, the expressions of Galnt3 and Fgf23, and Runx2 directly regulated the transcriptional activity of Galnt3 in reporter assays. The expressions of Galnt3 and Fgf23 in osteoblast-specific Runx2 knockout (Runx2fl/flCre) mice were about half those in Runx2fl/fl mice. However, the serum levels of phosphorus and intact Fgf23 in Runx2fl/flCre mice were similar to those in Runx2fl/fl mice. The trabecular bone volume was increased during aging in both male and female Galnt3-/- mice, but the osteoid was reduced. The markers for bone formation and resorption in Galnt3-/- mice were similar to the control in both sexes. Galnt3-/- mice exhibited hyperphosphatemia and hypercalcemia, and the intact Fgf23 was about 40% that of wild-type mice. These findings indicated that Runx2 regulates the expressions of Galnt3 and Fgf23 and that Galnt3 decelerates the mineralization of osteoid by stabilizing Fgf23.


Assuntos
Calcificação Fisiológica , Calcinose , N-Acetilgalactosaminiltransferases , Osteoblastos , Animais , Feminino , Masculino , Camundongos , Calcinose/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Fatores de Crescimento de Fibroblastos/metabolismo , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Osteoblastos/metabolismo , Fósforo
17.
Biomolecules ; 14(2)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38397376

RESUMO

Zebrafish are now widely used to study skeletal development and bone-related diseases. To that end, understanding osteoblast differentiation and function, the expression of essential transcription factors, signaling molecules, and extracellular matrix proteins is crucial. We isolated Sp7-expressing osteoblasts from 4-day-old larvae using a fluorescent reporter. We identified two distinct subpopulations and characterized their specific transcriptome as well as their structural, regulatory, and signaling profile. Based on their differential expression in these subpopulations, we generated mutants for the extracellular matrix protein genes col10a1a and fbln1 to study their functions. The col10a1a-/- mutant larvae display reduced chondrocranium size and decreased bone mineralization, while in adults a reduced vertebral thickness and tissue mineral density, and fusion of the caudal fin vertebrae were observed. In contrast, fbln1-/- mutants showed an increased mineralization of cranial elements and a reduced ceratohyal angle in larvae, while in adults a significantly increased vertebral centra thickness, length, volume, surface area, and tissue mineral density was observed. In addition, absence of the opercle specifically on the right side was observed. Transcriptomic analysis reveals up-regulation of genes involved in collagen biosynthesis and down-regulation of Fgf8 signaling in fbln1-/- mutants. Taken together, our results highlight the importance of bone extracellular matrix protein genes col10a1a and fbln1 in skeletal development and homeostasis.


Assuntos
Colágeno Tipo X , Proteínas da Matriz Extracelular , Osteoblastos , Peixe-Zebra , Animais , Diferenciação Celular , Matriz Extracelular/genética , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Homeostase/genética , Minerais/metabolismo , Osteoblastos/metabolismo , Transcriptoma/genética , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Colágeno Tipo X/genética , Colágeno Tipo X/fisiologia
18.
Med Oncol ; 41(3): 72, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38345752

RESUMO

Inflammation disrupts bone metabolism and leads to bone damage. C-reactive protein (CRP) is a typical inflammation marker. Although CRP measurement has been conducted for many decades, how osteoblastic differentiation influences molecular mechanisms remains largely unknown. The present study attempted to investigate the effects of CRP on primary cultured osteoblast precursor cells (OPCs) while elucidating the underlying molecular mechanisms. OPCs were isolated from suckling Sprague-Dawleyrats. Fewer OPCs were observed after recombinant C-reactive protein treatment. In a series of experiments, CRP inhibited OPC proliferation, osteoblastic differentiation, and the OPC gene expression of the hedgehog (Hh) signaling pathway. The inhibitory effect of CRP on OPC proliferation occurred via blockade of the G1-S transition of the cell cycle. In addition, the regulation effect of proto cilium on osteoblastic differentiation was analyzed using the bioinformatics p. This revealed the primary cilia activation of recombinant CRP effect on OPCs through in vitro experiments. A specific Sonic Hedgehog signaling agonist (SAG) rescued osteoblastic differentiation inhibited by recombinant CRP. Moreover, chloral hydrate, which removes primary cilia, inhibited the Suppressor of Fused (SUFU) formation and blocked Gli2 degradation. This counteracted osteogenesis inhibition caused by CRP. Therefore, these data depict that CRP can inhibit the proliferation and osteoblastic differentiation of OPCs. The underlying mechanism could be associated with primary cilia activation and Hh pathway repression.


Assuntos
Proteína C-Reativa , Proteínas Hedgehog , Humanos , Proteínas Hedgehog/metabolismo , Proteína C-Reativa/farmacologia , Proteína C-Reativa/metabolismo , Cílios/metabolismo , Regulação para Cima , Diferenciação Celular/fisiologia , Transdução de Sinais , Osteoblastos/metabolismo , Inflamação/metabolismo
19.
Bone ; 181: 117038, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38316337

RESUMO

Osteoblast polarity, proliferation, differentiation, and migration are essential for maintaining normal bone structure and function. While the microtubule-associated protein Map1b has been extensively studied in nerve cells, its role in bone cells is less known. We investigated the functional significance of Map1b in mouse bone marrow stromal cells (ST2) and elucidated its relationship and influence on cytoskeletal polarity and Golgi organization. Our results suggest that Map1b, as a microtubule regulatory protein, can also regulate the expression of cyclin PCNA, p-H3(S10) and migration-related protein integrin ß1, thereby affecting the proliferation and migration of osteoblasts. The downstream target gene Rgc32 was screened by RNA sequencing. Furthermore, Map1b, as a downstream mediator, regulates the Wnt5a signaling pathway. This study expands our understanding of the involvement of Map1b in bone biology and highlights its crucial role in governing osteoblast polarity, proliferation, and migration, thereby providing a basis for developing novel therapeutic strategies targeting Map1b in orthopedic medicine and promoting precision treatment modalities. Further investigations on the precise mechanisms underlying Map1b's influence on bone cell function and disease progression are needed.


Assuntos
Osso e Ossos , Proteínas Associadas aos Microtúbulos , Camundongos , Animais , Proteínas Associadas aos Microtúbulos/metabolismo , Diferenciação Celular , Osso e Ossos/metabolismo , Osteoblastos/metabolismo , Proliferação de Células
20.
Bone ; 181: 117040, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38316336

RESUMO

The intermittent administration of parathyroid hormone (PTH) exerts potent bone anabolic effects, which increase bone mineral density (BMD) and reduce fracture risk in osteoporotic patients. However, the underlying mechanisms remain unclear. Tmem119 has been proposed as a factor that is closely linked to the osteoblast phenotype, and we previously reported that PTH enhanced the expression of Tmem119 in mouse osteoblastic cells. However, roles of Tmem119 in the bone anabolic effects of PTH in vivo remain unknown. We herein investigated the roles of Tmem119 in bone anabolic effects of PTH using Tmem119-deficient mice. Tmem119 deficiency significantly reduced PTH-induced increases in trabecular bone volume and cortical BMD of femurs. Effects of Tmem119 deficiency on bone mass seemed predominant in female mice. Histomorphometric analyses with calcein labeling showed that Tmem119 deficiency significantly attenuated PTH-induced increases in the rates of bone formation and mineralization as well as numbers of osteoblasts. Moreover, Tmem119 deficiency significantly blunted PTH-induced decreases in phosphorylation of ß-catenin and increases in alkaline phosphatase activity in osteoblasts. In conclusion, the present results indicate that Tmem119 is involved in bone anabolic effects of PTH through osteoblastic bone formation partly related to canonical Wnt-ß-catenin signaling in mice.


Assuntos
Anabolizantes , Hormônio Paratireóideo , Humanos , Animais , Feminino , Camundongos , Hormônio Paratireóideo/farmacologia , Hormônio Paratireóideo/metabolismo , Osteogênese , Anabolizantes/farmacologia , Anabolizantes/metabolismo , beta Catenina/metabolismo , Osso e Ossos/metabolismo , Osteoblastos/metabolismo , Densidade Óssea , Proteínas de Membrana/metabolismo
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