RESUMEN
With increasing age, there is a notable increase in the differentiation of bone marrow-derived mononuclear cells (BMMs) into osteoclasts, accompanied by a concurrent rise in both osteoclast quantity and activity. This escalation in osteoclastic activity accelerates bone resorption, which in turn contributes to age-related bone loss and metabolic bone disorders, notably osteoporosis. Our study confirms that elevated IL-19 expression promotes aging-induced bone loss in aged mice and sheds light on the regulatory mechanisms upstream of IL-19 expression and secretion. Primarily, it is the methylation status of the IL-19 gene's promoter region that impacts Atonal BHLH Transcription Factor 1 (Atoh1)'s ability to bind to the promoter. We found that this specific mechanism involves reduced expression and binding affinity of Dnmt1 to the IL-19 promoter region. The findings of our study suggest that targeting IL-19 could be a potential strategy for managing bone loss-related conditions and enhance the current understanding of how DNA methylation levels contribute to age-related bone loss.
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The interplay between liver and bone metabolism remains largely uncharacterized. Here, we uncover a mechanism of liver-bone crosstalk regulated by hepatocyte SIRT2. We demonstrate that hepatocyte SIRT2 expression is increased in aged mice and elderly humans. Liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss in mouse models of osteoporosis. We identify leucine-rich α-2-glycoprotein 1 (LRG1) as a functional cargo in hepatocyte-derived small extracellular vesicles (sEVs). In SIRT2-deficient hepatocytes, LRG1 levels in sEVs are upregulated, leading to increased transfer of LRG1 to bone-marrow-derived monocytes (BMDMs), and in turn, to inhibition of osteoclast differentiation via reduced nuclear translocation of NF-κB p65. Treatment with sEVs carrying high levels of LRG1 inhibits osteoclast differentiation in human BMDMs and in mice with osteoporosis, resulting in attenuated bone loss in mice. Furthermore, the plasma level of sEVs carrying LRG1 is positively correlated with bone mineral density in humans. Thus, drugs targeting hepatocyte-osteoclast communication may constitute a promising therapeutic strategy for primary osteoporosis.
Asunto(s)
Osteoporosis , Sirtuina 2 , Anciano , Animales , Humanos , Ratones , Comunicación , Hígado/metabolismo , Osteoclastos , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Sirtuina 2/metabolismoRESUMEN
Background: Hair follicles harbor a rich autologous stem cell pool and human hair follicle-derived mesenchymal stem cells (hHF-MSCs) have multi-lineage differentiation potential. Many sources of MSCs include hHF-MSCs have been attractive candidates for cell therapy, regenerative medicine and tissue engineering. The present study is to explore the effect of intravenous transplantation of hHF-MSCs on bone mass in osteoporotic mice and its mechanism, and provides prospects for clinical applications for the treatment of osteoporosis with hHF-MSCs. Methods: Physically pull out about 20 hairs with intact hair follicles from the occipital area of the scalp of healthy volunteers, and extract hair follicle-derived fibroblast-like cells. These cells were cultured and characterized in vitro. Intravenous injection of hHF-MSCs was performed on ovariectomy-induced and age-related osteoporotic SCID mice for osteoporosis treatment. The mice were sacrificed 7 weeks after the second injection and samples were collected. The long bones and L1 vertebrae were collected for micro-CT scan, histomorphometry and immunohistochemical analysis. Peripheral serum were collected for ELISA analysis and antibody array. Results: Hair follicle-derived fibroblast-like cells were defined as hHF-MSCs. Intravenous transplantation of hHF-MSCs can better restores trabecular bone mass in osteoporotic mice. The double calcein labeling assay, trap staining of bones and ELISA analysis in peripheral serum showed enhanced bone formation and weakened bone resorption after transplantation. Antibody array and immunohistochemical analysis showed that several cytokines including OPG, Wnt2b, Noggin, VCAM-1 and RANKL might be involved in this process. Conclusion: Human HF-MSCs transplantation can combat trabecular bone loss induced by menopause and aging in mice. And the above mechanism that hHF-MSCs transplantation inhibits bone resorption and promote bone formation is related to OPG, Wnt2b, VCAM-1, Noggin and RANKL.
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Protein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation-deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPß) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPß as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPß ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPß-target gene LCN2. Importantly, hepatic deacetylated C/EBPß and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPß protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPß-LCN2 signaling pathway is a potential therapy for ALD.
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Given the huge cost, long research and development (R&D) time and uncertain side effects of discovering new drugs, drug repositioning of those approved to treat diseases clinically as new drugs for other pathological conditions, especially cancers, is a potential alternative strategy. Disulfiram (DSF), an old drug used to treat alcoholism, has been found to exhibit anticancer activity and improve chemotherapeutic efficacy in cancers by an increasing number of studies. In addition, the combination of DSF and copper may be a more effective therapeutic strategy. In this study, we report the toxicity of the disulfiram/copper (DSF/Cu) complex to human osteosarcoma (OS) both in vitro and in vivo. DSF/Cu significantly inhibited the proliferation and clonogenicity of OS cell lines. Furthermore, the generation of reactive oxygen species (ROS) was triggered by DSF/Cu, and cell arrest, autophagy and apoptosis were induced in an ROS-dependent manner. The underlying mechanism of this process was explored, and DSF/Cu may mainly inhibit OS by inducing apoptosis by activating the ROS/JNK pathway. DSF/Cu also inhibited OS growth in a xenograft model with low levels of organ-related toxicities. These results suggest that the DSF/Cu complex could be an efficient and safe option for the treatment of OS in the clinic.
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Apoptosis/efectos de los fármacos , Cobre/farmacología , Disulfiram/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Osteosarcoma/metabolismo , Osteosarcoma/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Emerging evidence indicates that osteoclasts from osteosarcoma patients have higher tartrate resistant acid phosphatase (TRAP) activity. Exosomes are important mediators of the cell-to-cell communication. However, whether osteosarcoma cell-derived exosomes mediate the osteoclastogenesis of bone marrow-derived monocytes (BMDMs) and its mechanisms are largely unknown. In this research, we validated the communication between osteosarcoma cells and BMDMs. Here, we found that osteosarcoma cell-derived exosomes can be transfered to BMDMs to promote osteoclast differentiation. The miR-501-3p is highly expressed in exosomes derived from osteosarcoma and could be transferred to BMDMs through the exosomes. Moreover, osteosarcoma-derived exosomal miR-501-3p mediate its role in promoting osteoclast differentiation and aggravates bone loss in vitro and in vivo. Mechanistically, osteosarcoma cell-derived exosomal miR-501-3p could promote osteoclast differentiation via PTEN/PI3K/Akt signaling pathway. Collectively, our results suggest that osteosarcoma-derived exosomal miR-501-3p promotes osteoclastogenesis and aggravates bone loss. Therefore, our study reveals a novel mechanism of osteoclastogenesis in osteosarcoma patients and provides a novel target for diagnosis or treatment.
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Neoplasias Óseas/metabolismo , Exosomas/metabolismo , MicroARNs/fisiología , Osteoclastos , Osteosarcoma/metabolismo , Animales , Diferenciación Celular , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Monocitos , Osteoblastos , Osteoclastos/metabolismo , Osteoclastos/patología , Osteogénesis , Cultivo Primario de CélulasRESUMEN
As a research hotspot in recent years, bone mesenchymal stem cells (BMSCs) play an important role in the process of a variety of human diseases, including cancers. However, in osteosarcoma, the role of BMSCs and their communication with tumour cells are not clear. In this study, we validated the communication of osteosarcoma (OS) cells with BMSCs. The results showed that the conditioned medium of osteosarcoma cell line U2OS (U2OS-CM) induces the carcinoma-associated fibroblasts (CAFs)-like transformation of BMSCs and promotes the proliferation, migration and invasion of BMSCs. Mechanistically, treatment of human bone mesenchymal stem cells (hBMSCs) with U2OS-CM results in a significant increase in the IL-6 expression and phosphorylation of STAT3. Furthermore, blockade of the IL-6/STAT3 signalling in hBMSCs rescues the transformation of CAF phenotype induced by U2OS-CM. And, human IL-6 can directly increase the expression of the CAF marker genes in hMSCs. Meanwhile, IL-6/STAT3 signalling involves in promoting effects of U2OS-CM on the proliferation, migration and invasion of BMSCs. In summary, our results suggest that BMSCs communicate with OS cells through IL-6/STAT3 signalling and play an important role in the progress of osteosarcoma.