American Journal of Pathology最新文献_第9页

Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice 肝Asah1基因消融破坏肝脂质稳态并促进小鼠纤维化性非酒精性脂肪性肝炎

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-20 DOI: 10.1016/j.ajpath.2024.11.003

Rui Zuo , Mi Wang , Yun-Ting Wang , YangPing ShenTu , Alexandra K. Moura , Ying Zhou , Kiana Roudbari , Jenny Z. Hu , Pin-Lan Li , JiuKuan Hao , Xiang Li , Yang Zhang

{"title":"Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice","authors":"Rui Zuo , Mi Wang , Yun-Ting Wang , YangPing ShenTu , Alexandra K. Moura , Ying Zhou , Kiana Roudbari , Jenny Z. Hu , Pin-Lan Li , JiuKuan Hao , Xiang Li , Yang Zhang","doi":"10.1016/j.ajpath.2024.11.003","DOIUrl":"10.1016/j.ajpath.2024.11.003","url":null,"abstract":"<div><div>Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of chronic liver conditions, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to fibrosis/cirrhosis. Here, the GSE163211 data set was analyzed, and <em>Asah1</em> (encoding acid ceramidase) was identified as a crucial lysosomal gene that positively correlated with NAFLD stages in obese patients. To evaluate the role of <em>Asah1</em> in the progression of NAFLD, <em>Asah1</em><sup>fl/fl</sup>/<em>Alb</em><sup>cre</sup> mice (hepatocyte-specific deletion of <em>Asah1</em>) and <em>Asah1</em> floxed (<em>Asah1</em><sup>fl/fl</sup>/wild-type) mice were fed with either a normal diet or a high-fat, high-cholesterol paigen diet (PD) for 20 weeks. Hepatocyte-specific <em>Asah1</em> ablation markedly aggravated PD-induced hepatic steatosis, hepatitis, and apoptosis, and resulted in marked fibrotic changes. In addition, <em>Asah1</em> gene ablation exacerbated PD-induced portal venous hemodynamic abnormality. In cultured hepatocytes, <em>Asah1</em> gene knockdown resulted in increased ceramide and cholesterol levels but did not affect triglyceride level. Knocking down <em>Asah1</em> gene also exhibited broad impacts on lipid homeostasis pathways, including lipogenesis, fatty acid uptake, fatty acid oxidation, and lipid transport. Furthermore, <em>Asah1</em> knockdown resulted in increased endoplasmic reticulum stress and lipid droplet biogenesis. Finally, <em>Asah1</em> gene knockdown impaired chaperone-mediated autophagy. These results suggest that <em>Asah1</em> functions as an important regulator of hepatic lipid homeostasis, and its deficiency exacerbates hepatocyte lipotoxicity and injury, and promotes the development of fibrotic nonalcoholic steatohepatitis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 542-560"},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cholangiocarcinoma Targeted Therapies 胆管癌靶向治疗：作用机制和耐药性。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-19 DOI: 10.1016/j.ajpath.2024.11.005

Haley Ellis , Chiara Braconi , Juan W. Valle , Nabeel Bardeesy

{"title":"Cholangiocarcinoma Targeted Therapies","authors":"Haley Ellis , Chiara Braconi , Juan W. Valle , Nabeel Bardeesy","doi":"10.1016/j.ajpath.2024.11.005","DOIUrl":"10.1016/j.ajpath.2024.11.005","url":null,"abstract":"<div><div>Cholangiocarcinoma is an aggressive bile duct malignancy with heterogeneous genomic features. Although most patients receive standard-of-care chemotherapy/immunotherapy, genomic changes that can be targeted with established or emerging therapeutics are common. Accordingly, precision medicine strategies are transforming the next-line treatment for patient subsets. Hotspot <em>IDH1</em> mutations and activating fibroblast growth factor receptor 2 fusions occur frequently, and small-molecule inhibitors against these alterations are US Food and Drug Administration approved. Translational and basic science studies have elucidated the mechanisms of response and resistance in cholangiocarcinoma, providing insights into these targets that extend to other cancers. Additional US Food and Drug Administration–approved and National Comprehensive Cancer Network guideline-recommended treatments for recurrent genomic changes include BRAF inhibition (<em>BRAF</em>-V600E) and trastumazab deruxtecan (human epidermal growth factor receptor 2 amplification). Furthermore, ongoing clinical trials show promising results with KRAS inhibition (<em>KRAS</em>-codon 12 mutations), PRTM5 inhibition, alone or with methylthioadenosine inhibition (5-methylthioadenosine phosphorylase deletion), and murine double minute 2 inhibition (murine double minute 2 amplification). Despite these advances, the rate, depth, and duration of response to each treatment need improvement. Moreover, many patients do not have currently targetable genotypes. This review examines the clinical efficacy and mechanisms of resistance associated with these treatments, as well as insights into the molecular and biological effects of pathway activation and inhibition, based on study of patient samples and preclinical models. It also explores strategies to overcome resistance and possible precision medicine approaches for additional patient subsets.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 437-452"},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gut Microbiome and Bile Acid Interactions 肠道微生物群和胆汁酸相互作用：胆管癌发展、免疫抵抗和治疗的机制意义。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-19 DOI: 10.1016/j.ajpath.2024.11.004

Nan Wu , Sareh Bayatpour , Phillip B. Hylemon , Sayed O. Aseem , Paul J. Brindley , Huiping Zhou

{"title":"Gut Microbiome and Bile Acid Interactions","authors":"Nan Wu , Sareh Bayatpour , Phillip B. Hylemon , Sayed O. Aseem , Paul J. Brindley , Huiping Zhou","doi":"10.1016/j.ajpath.2024.11.004","DOIUrl":"10.1016/j.ajpath.2024.11.004","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis. It indicates a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome. This leads to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review focuses on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. It also evaluates the therapeutic potential of targeting the gut microbiome and bile acid–mediated signaling pathways for the therapy and prophylaxis of CCA.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 397-408"},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia: New Insights from Single-Cell and Spatial Transcriptomics. 阿尔茨海默病和额颞叶痴呆的基因工程小鼠模型：来自单细胞和空间转录组学的新见解。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-19 DOI: 10.1016/j.ajpath.2024.11.006

Yuanpu Chiu, Shangzhou Xia, Haowen Qiao, Zhen Zhao

引用次数: 0

Development of CAR-T Therapies and Personalized Vaccines for the Treatment of Cholangiocarcinoma 开发用于治疗胆管癌的 CAR-T 疗法和个性化疫苗：当前进展、作用机制和挑战。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-14 DOI: 10.1016/j.ajpath.2024.10.021

Dan Li , Lalitya Andaloori , Matthew Crowe , Shaoli Lin , Jessica Hong , Neeha Zaidi , Mitchell Ho

{"title":"Development of CAR-T Therapies and Personalized Vaccines for the Treatment of Cholangiocarcinoma","authors":"Dan Li , Lalitya Andaloori , Matthew Crowe , Shaoli Lin , Jessica Hong , Neeha Zaidi , Mitchell Ho","doi":"10.1016/j.ajpath.2024.10.021","DOIUrl":"10.1016/j.ajpath.2024.10.021","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is a highly fatal malignancy with an increasing prevalence, a high mortality rate, poor overall survival, and limited responsiveness to conventional chemoradiotherapy. Targeted therapies addressing specific gene mutations have expanded treatment options for some patient populations. The introduction of chimeric antigen receptor–modified T-cell (CAR-T) immunotherapy and personalized vaccines have opened up a new avenue for managing various cancers. Considerable efforts have been dedicated to preclinical research and ongoing clinical trials of immunotherapeutic approaches including CAR-T therapy, vaccines, and antibody-based therapies such as antibody drug conjugates. However, the potential of CAR-T therapy and vaccines in treating advanced unresectable/metastatic cholangiocarcinoma remains largely unexplored. This article offers an overview of the current landscape of antibody-based immunotherapy, particularly CAR-T therapy and vaccines in the context of cholangiocarcinoma treatment. It outlines a framework for selecting CAR-T and vaccine targets and delves into the biology of promising targetable antigens, as well as potential future therapeutic targets.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 453-469"},"PeriodicalIF":4.7,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulation of Adiponectin and Resistin in Liver Transplantation Protects Grafts from Extended-Criteria Donors 调节肝移植中的脂肪连接蛋白和抵抗素可保护来自扩展标准捐献者的移植物。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.016

Araní Casillas-Ramírez , Cristina Maroto-Serrat , Francisco Sanus , Marc Micó-Carnero , Carlos Rojano-Alfonso , Margalida Cabrer , Carmen Peralta

{"title":"Regulation of Adiponectin and Resistin in Liver Transplantation Protects Grafts from Extended-Criteria Donors","authors":"Araní Casillas-Ramírez , Cristina Maroto-Serrat , Francisco Sanus , Marc Micó-Carnero , Carlos Rojano-Alfonso , Margalida Cabrer , Carmen Peralta","doi":"10.1016/j.ajpath.2024.10.016","DOIUrl":"10.1016/j.ajpath.2024.10.016","url":null,"abstract":"<div><div>The donor shortage increases liver transplantation (LT) waiting lists, making it crucial to consider extended-criteria donors, such as steatotic donors after brain death (DBDs) or cardiocirculatory death (DCDs). Nevertheless, steatosis, brain death, and cardiocirculatory death are key risk factors for poor LT outcomes. Herein, the role and therapeutic usefulness of several adipocytokines was investigated to protect such grafts from extended-criteria donors. Sprague rats with nutritionally induced steatosis were used in an experimental LT model with grafts from DBDs or DCDs. Adiponectin, resistin, and visfatin were measured and pharmacologically modulated, and effects on liver injury were assessed. Visfatin played no role under conditions of either DBD or DCD LT. Brain death increased adiponectin and reduced resistin. Adiponectin harmed steatotic and nonsteatotic DBD grafts, via a resistin-dependent mechanism; restraining adiponectin increased resistin, reducing damage. Resistin treatment protected both types of DBD grafts, whereas suppressing it increased damage. This adiponectin-resistin pathway was dependent on protein kinase C. In DCD LT, adiponectin and resistin were not modified in nonsteatotic grafts, but reduced in steatotic ones. Adiponectin or resistin treatments protected steatotic grafts: hepatic adiponectin activated AMP-activated protein kinase ; hepatic resistin increased phosphatidylinositol 3-kinase–Akt. Concomitant administration of both adipocytokines increased both signaling pathways, intensifying protection. These data suggest that pharmacologic modulation of adiponectin and resistin as therapies might potentially be translated to clinical studies to improve surgical outcomes for LT from extended-criteria donors.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 494-527"},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic Loss of HIF-Prolyl-Hydroxylase 1, but Not Pharmacological Inhibition, Mitigates Hepatic Fibrosis 基因缺失 HIF-Prolyl-Hydroxylase (PHD) 1（而非药物抑制）可减轻肝纤维化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.018

Christopher Tuffs , Mareen Dupovac , Katrin Richter , Sophia Holten , Thomas Schaschinger , Oliver Marg , Adisa Poljo , Ayse nur Tasdemir , Jonathan M. Harnoss , Adrian Billeter , Martin Schneider , Moritz J. Strowitzki

{"title":"Genetic Loss of HIF-Prolyl-Hydroxylase 1, but Not Pharmacological Inhibition, Mitigates Hepatic Fibrosis","authors":"Christopher Tuffs , Mareen Dupovac , Katrin Richter , Sophia Holten , Thomas Schaschinger , Oliver Marg , Adisa Poljo , Ayse nur Tasdemir , Jonathan M. Harnoss , Adrian Billeter , Martin Schneider , Moritz J. Strowitzki","doi":"10.1016/j.ajpath.2024.10.018","DOIUrl":"10.1016/j.ajpath.2024.10.018","url":null,"abstract":"<div><div>Liver fibrosis is characterized by excessive deposition of extracellular matrix due to chronic inflammation of the liver. Hepatic stellate cells (HSCs) become activated and produce increased amounts of extracellular matrix. Loss of HIF-prolyl-hydroxylase 1 (PHD1) attenuates HSC activation and fibrotic tissue remodeling in a murine model of biliary liver fibrosis. Herein, the protective effect of PHD1 deficiency (<em>PHD1</em><sup><em>−/−</em></sup>) in an additional (toxic) model of liver fibrosis was validated and the effect of dimethyloxalylglycine (DMOG), a pan-HIF-prolyl-hydroxylase inhibitor, on the development of liver fibrosis, was evaluated. Liver fibrosis was induced utilizing carbon tetrachloride in wild-type (WT) and <em>PHD1</em><sup><em>−/−</em></sup> mice treated with either vehicle or DMOG. To assess fibrosis development, expression of profibrotic genes in the livers was analyzed by Sirius red staining. When compared with WT mice, <em>PHD1</em><sup><em>−/−</em></sup> mice developed less-severe liver fibrosis. DMOG treatment did not prevent this liver fibrosis. <em>PHD1</em><sup><em>−/−</em></sup> mice had fewer α-SMA<sup>+</sup> cells and less macrophage infiltration compared with WT mice. Expression of profibrogenic and proinflammatory genes was reduced in livers from carbon tetrachloride–exposed <em>PHD1</em><sup><em>−/−</em></sup> mice. <em>In vitro</em> analyses of PHD1-deficient human HSCs revealed attenuated mRNA levels of profibrotic genes, as well as impaired migration and invasion. Although PHD1 deficiency attenuated activation of HSCs, pharmacologic PHD inhibition did not ameliorate fibrosis development. These data indicate that selective PHD1 inhibitors could prove effective in preventing and treating liver fibrosis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 480-493"},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Amyloid Cascade Hypothesis: A Conclusion in Search of Support. 淀粉样蛋白级联假说：寻找支持的结论

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-10 DOI: 10.1016/j.ajpath.2024.10.014

Rudy J Castellani, Pouya Jamshidi, Germán Plascencia-Villa, George Perry

{"title":"The Amyloid Cascade Hypothesis: A Conclusion in Search of Support.","authors":"Rudy J Castellani, Pouya Jamshidi, Germán Plascencia-Villa, George Perry","doi":"10.1016/j.ajpath.2024.10.014","DOIUrl":"10.1016/j.ajpath.2024.10.014","url":null,"abstract":"<p><p>The amyloid cascade hypothesis as the etiological underpinning of Alzheimer disease (AD) is supported by a large body of literature, the most influential of which are genetic studies of the 1980s and 1990s. Other evidence includes the neuropathology of Down syndrome, apparent toxicity of oligomeric amyloid-β (Aβ), interactions with apolipoprotein E, and the analogy of cardiac amyloidosis. On the other hand, there is considerable phenotypic heterogeneity among the rare familial AD kindreds, which tempers extrapolation to sporadic AD. Oligomer biology is still in the theoretical realm, with no clinical validation. Apolipoprotein E support for the amyloid cascade and other inferences from the literature are somewhat circular in their logic. Analogy with amyloidoses might also consider secondary amyloidosis, driven by systemic inflammation and treated by treating the underlying etiology. Much of the remaining literature supporting the amyloid cascade is dominated by hypothesis-generating studies. Importantly, we now have a developing evidence base from controlled clinical trials that can potentially inform the issue of Aβ as a cause or driver of disease in sporadic AD. Emerging data provide clear evidence of target engagement. Clinical outcome, however, has been either marginally positive or similar to placebo. Assuming these findings hold, it appears that Aβ neither drives nor mitigates the disease process.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma 胆管癌的遗传、表观遗传和微环境驱动因素

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-10 DOI: 10.1016/j.ajpath.2024.10.013

Vijay Putatunda , Apinya Jusakul , Lewis Roberts , Xin Wei Wang

{"title":"Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma","authors":"Vijay Putatunda , Apinya Jusakul , Lewis Roberts , Xin Wei Wang","doi":"10.1016/j.ajpath.2024.10.013","DOIUrl":"10.1016/j.ajpath.2024.10.013","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree that carries a poor prognosis. Multiple features at the genetic, epigenetic, and microenvironmental levels have been identified to better characterize CCA carcinogenesis. Genetic alterations, such as mutations in <em>IDH1</em>/<em>2</em>, <em>BAP1</em>, <em>ARID1A</em>, and <em>FGFR2</em>, play significant roles in CCA pathogenesis, with variations across different subtypes, races/ethnicities, and causes. Epigenetic dysregulation, characterized by DNA methylation and histone modifications, further contributes to the complexity of CCA, influencing gene expression and tumor behavior. Furthermore, CCA cells exchange autocrine and paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment, including cancer-associated fibroblasts and tumor-associated macrophages, further contributing to an immunosuppressive niche that supports tumorigenesis. This review explores the multifaceted genetic, epigenetic, and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 362-377"},"PeriodicalIF":4.7,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The miR-665/SOST Axis Regulates the Phenotypes of Bone Marrow Mesenchymal Stem Cells and Osteoporotic Symptoms in Female Mice miR-665/SOST 轴调控雌性小鼠骨髓间充质干细胞的表型和骨质疏松症状

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-10-24 DOI: 10.1016/j.ajpath.2024.07.022

Xingxing Zeng , Xianyu Yuan , Hongchun Liao , Yongfang Wei , Qinxuan Wu , Xi Zhu , Qingqing Li , Shijie Chen , Minghua Hu

{"title":"The miR-665/SOST Axis Regulates the Phenotypes of Bone Marrow Mesenchymal Stem Cells and Osteoporotic Symptoms in Female Mice","authors":"Xingxing Zeng , Xianyu Yuan , Hongchun Liao , Yongfang Wei , Qinxuan Wu , Xi Zhu , Qingqing Li , Shijie Chen , Minghua Hu","doi":"10.1016/j.ajpath.2024.07.022","DOIUrl":"10.1016/j.ajpath.2024.07.022","url":null,"abstract":"<div><div>Osteoporosis is a common degenerative skeletal disease among older people, especially postmenopausal women. Bone marrow mesenchymal stem cells (BMSCs), the progenitors of osteoblasts, are essential to the pathophysiology of osteoporosis. Herein, targeting miRNAs with differential expression in dysfunctional BMSCs was accomplished by bioinformatics analysis based on public databases. Target mRNAs were predicted and applied for signaling pathway and function enrichment annotations. <em>In vitro</em> and <em>in vivo</em> effects of selected miRNA on BMSC proliferation and osteogenesis were investigated, the putative binding between selected miRNA and predicted target mRNA was verified, and the co-effects of the miRNA/mRNA axis on BMSCs were determined. miRNA 665 (miR-665) was down-regulated in osteoporotic BMSCs compared with normal BMSCs and elevated in BMSCs experiencing osteogenic differentiation. In BMSCs, miR-665 overexpression promoted cell proliferation and osteogenic differentiation. miR-665 targeted the Wnt signaling inhibitor sclerostin (<em>SOST</em>) and inhibited <em>SOST</em> mRNA and protein expression. <em>SOST</em> overexpression inhibited BMSC cell proliferation and osteogenic differentiation. When co-transduced to BMSCs, <em>SOST</em> knockdown significantly reversed the effects of miR-665 on BMSCs. In ovariectomy (OVX)-induced osteoporosis model mice, OVX remarkably decreased bone mass, whereas miR-665 overexpression partially improved OVX-induced bone mass loss. miR-665 was down-regulated in osteoporotic BMSCs and up-regulated in osteogenically differentiated BMSCs. In conclusion, the miR-665/<em>SOST</em> axis modulates BMSC proliferation, osteogenic differentiation, and OVX-induced osteoporosis in mice, possibly through Wnt signaling.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2059-2075"},"PeriodicalIF":4.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0