Journal of Molecular Medicine-Jmm最新文献

{"title":"Correction to: Metanephric mesenchyme-derived Foxd1⁺ mesangial precursor cells alleviate mesangial proliferative glomerulonephritis.","authors":"Meiling Jin, Zhong Yin, Kai Wei, Yuansheng Xie, Xueyuan Bai, Bo Fu, Zhe Feng, Qinggang Li, Xiangmei Chen","doi":"10.1007/s00109-025-02526-z","DOIUrl":"https://doi.org/10.1007/s00109-025-02526-z","url":null,"abstract":"","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FATP1-mediated fatty acid uptake in renal tubular cells as a countermeasure for hypothermia.","authors":"Kie Horioka, Hiroki Tanaka, Shimpei Watanabe, Shinnosuke Yamada, Shuhei Takauji, Akira Hayakawa, Shotaro Isozaki, Keisuke Okaba, Namiko Ishii, Ayumi Motomura, Hiroyuki Inoue, Lynda Addo, Daisuke Yajima, Yoichiro Takahashi, Henrik Druid, Lasse Pakanen, Katja Porvari","doi":"10.1007/s00109-025-02525-0","DOIUrl":"https://doi.org/10.1007/s00109-025-02525-0","url":null,"abstract":"<p><p>Hypothermia is a condition in which body temperature falls below 35 °C, resulting from exposure to low environmental temperatures or underlying medical conditions. Postmortem examinations have revealed increased levels of fatty acids in blood and lipid droplet formation in renal tubules during hypothermia. However, the causes and implications of these findings are unclear. This study aimed to analyze the biological significance of these phenomena through lipidomics and transcriptomics analyses of specimens from emergency hypothermia patients and mouse hypothermia models. Both human hypothermia patients and murine models exhibited elevated plasma concentrations of fatty acids and their derivatives compared with controls. Hypothermic mouse kidneys displayed lipid droplet formation, with gene expression analysis revealing enhanced fatty acid uptake and β-oxidation in renal tubular cells. In primary cultured mouse renal proximal tubular cells, low temperatures increased the expression levels of Fatty acid transport protein 1 (FATP1), a fatty acid transporter, and boosted oxygen consumption via β-oxidation. Mice treated with FATP1 inhibitors showed a more rapid decrease in body temperature upon exposure to low temperatures compared with untreated mice. In conclusion, increased fatty acid uptake mediated by FATP1 in renal tubular cells plays a protective role during hypothermia. KEY MESSAGES: Low temperatures increase FATP1 expression and fatty acid uptake in renal proximal tubular cells, resulting in enhanced β-oxidation. Renal proximal tubular cells play an important role in the resistance to hypothermia via lipid uptake. Maintaining renal lipid metabolism is essential for cold stress adaptation.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage co-culture promotes cell reprogramming and prevents ferroptosis in aging fibroblasts for neurodegeneration therapy.","authors":"Lunjie Ma, Fei Fang, Haonan Wang, Ping Zhao, Hongchi Yu, Xiaoheng Liu","doi":"10.1007/s00109-025-02518-z","DOIUrl":"10.1007/s00109-025-02518-z","url":null,"abstract":"<p><p>Ferroptosis, a form of programmed cell death associated with lipid peroxidation and iron dependency, plays a critical role in affecting neuronal function in the aging-related neurodegenerative diseases. Macrophages, influenced by these changes, contribute significantly to the progression of aging nerve diseases. Induced neuronal reprogramming is an advanced technology, which can direct convert somatic cells, such as fibroblasts, into neurons, and offers a promising approach for drug screening aimed at correcting ferroptosis and combating aging-related nerve diseases. However, the efficiency of this reprogramming process remains a significant challenge. In this study, we aimed to manipulate macrophage phenotypes to enhance the direct conversion of fibroblasts into neurons. Specifically, we sought to correct ferroptosis through screening natural compounds using aged fibroblasts and utilizing macrophages to promote induced neuronal (iN) reprogramming. Our findings demonstrate that M2 macrophages effectively promote the direct reprogramming of fibroblasts into iNs. In a novel macrophage-fibroblast co-culture system, M2 macrophages facilitate iN reprogramming by reducing fibroblast adhesion forces and promoting asymmetric cell division. Furthermore, we discovered that manipulating matrix stiffness can induce polarization of macrophages towards the M2 phenotype, thereby enhancing fibroblast reprogramming into iNs. To facilitate these findings, we developed a mechano-cue-based drug screening chip, where soft hydrogels induced and maintained the phenotype of M2 macrophages and effectively promoted cell reprogramming. Using a combinatorial approach with 36 such chips, we screened natural compounds for their anti-aging properties, focusing on reversing fibroblast aging and inducing their conversion into neuronal cells. Notably, Vitexin, an apigenin flavone glycoside with a role as a platelet aggregation inhibitor, emerged as a promising candidate to achieve our therapeutic goals. This study highlights the potential of macrophage-mediated modulation of fibroblast reprogramming as a strategy to address ferroptosis-induced neuronal dysfunction in aging-related nerve diseases. KEY MESSAGE: This study highlights the potential of macrophage-mediated modulation of fibroblast reprogramming as a strategy to address ferroptosis-induced neuronal dysfunction in aging-related nerve diseases.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"301-310"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of CYLD in brain physiology and pathology.","authors":"Leonardo Nardi, Frank Bicker, Jannik Maier, Ari Waisman, Michael J Schmeisser","doi":"10.1007/s00109-025-02521-4","DOIUrl":"10.1007/s00109-025-02521-4","url":null,"abstract":"<p><p>A common hallmark of several neuropsychiatric conditions is an altered protein homeostasis. In this context, ubiquitination has emerged as one of the most important post-translational modifications, regulating various intracellular processes such as protein degradation, autophagy, protein activation, and protein-protein interactions. Ubiquitination can be reversed by the activity of several deubiquitinating enzymes (DUBs), and it is of utmost importance that both processes remain in balance. Understanding the extent to which this system is involved in specific brain disorders opens up new possibilities for treating a broader spectrum of patients by targeting this central hub. In recent years, the attention to one of those DUBs, called CYLD, has increased sharply, but with relatively little focus on the central nervous system (CNS): 55 results for \"CYLD Brain\" vs. 895 results for \"CYLD\" in total (NCBI Pubmed search, 17.01.2025). Thus, we aim to provide a first overview of the new findings from the past decade specifically related to the role of CYLD in the physiology and pathology of the CNS.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"255-263"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming.","authors":"Subash Khadka, Brandon Lukas, Claire Xin Sun, Sribalashubashini Muralimanoharan, Karthigayan Shanmugasundaram, Azad Khosh, Lindsey Barron, Claire Schenken, Nicholas Stansbury, Robert Schenken, Ron Firestein, Yang Dai, Thomas G Boyer","doi":"10.1007/s00109-025-02517-0","DOIUrl":"10.1007/s00109-025-02517-0","url":null,"abstract":"<p><p>Uterine fibroids (UFs) are the most common non-cutaneous tumors in women worldwide. UFs arise from genetic alterations in myometrial stem cells (MM SCs) that trigger their transformation into tumor-initiating cells (UF SCs). Mutations in the RNA polymerase II Mediator subunit MED12 are dominant drivers of UFs, accounting for 70% of these clinically significant lesions. Biochemically, UF driver mutations in MED12 disrupt CDK8/19 kinase activity in Mediator, but how Mediator kinase disruption triggers MM SC transformation remains unknown. Here, we show that pharmacologic inhibition of CDK8/19 in MM SCs removes a barrier to myogenic differentiation down an altered pathway characterized by molecular phenotypes characteristic of UFs, including oncogenic growth and extracellular matrix (ECM) production. These perturbations appear to be induced by transcriptomic changes, arising in part through epigenomic alteration and super-enhancer reprogramming, that broadly recapitulate those found in MED12-mutant UFs. Altogether, these findings provide new insights concerning the biological role of CDK8/19 in MM SC biology and UF formation. KEY MESSAGES: Mediator kinase inhibition in myometrial stem cells (MM SCs) induces spontaneous differentiation. Transcriptional changes upon Mediator kinase inhibition recapitulate those of MED12 mutant uterine fibroids (UFs). Such transcriptional changes are partially mediated by super-enhancer reprogramming. Mediator kinase functions to enforce cell states and its loss induces cellular plasticity.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"311-326"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hereditary non-spherocytic hemolytic anemia with GPI mutations successfully treated with allogeneic hematopoietic stem cell transplantation: a first report of two cases.","authors":"Huimin Li, Jiali Wang, Liucheng Rong, Jian Li, Yao Xue, Yongjun Fang, Yaping Wang","doi":"10.1007/s00109-025-02514-3","DOIUrl":"10.1007/s00109-025-02514-3","url":null,"abstract":"<p><p>Glucose phosphate isomerase (GPI) deficiency caused by GPI gene mutations is a rare heterogenous condition that causes hereditary non-spherocytic hemolytic anemia (HNSHA). Patients who suffer from severe anemia may need more effective treatment. Here, clinical data and genetic testing results of two cases of HNSHA with GPI mutations treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) were retrospectively analyzed. Specifically, two unrelated 6-year-old male patients with severe hemolytic anemia had hemoglobin (Hb) below the normal range despite frequent blood transfusions. Two novel missense mutations in the GPI gene were detected in them, respectively. They underwent peripheral blood stem cell (PBSC) transplantation successfully, and there was no anemia post-transplantation. In conclusion, HNSHA caused by mutations of the GPI gene is inherited in an autosomal recessive (AR) manner. Allo-HSCT offers an acceptable therapeutic efficacy and improvement of quality of life in HNSHA patients with GPI mutations. Our study expands the genetic spectrum of GPI deficiency. KEY MESSAGES: We reported for the first time that two cases of hereditary non-spherocytic hemolytic anemia with GPI mutations successfully treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two novel missense mutations in GPI gene were detected in each of the two cases, respectively, which were predicted to be pathogenic or damaging. Our study expands the genetic spectrum of GPI deficiency. Allo-HSCT offers an acceptable therapeutic efficacy and improvement of quality of life in HNSHA patients with GPI mutations.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"265-271"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kat7 accelerates osteoarthritis disease progression through the TLR4/NF-κB signaling pathway.","authors":"Zhen Liu, Lijie Qiu, Yongqiang Zhang, Gang Zhao, Xuecheng Sun, Wenming Luo","doi":"10.1007/s00109-025-02519-y","DOIUrl":"10.1007/s00109-025-02519-y","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a common degenerative bone and joint disease with an unclear pathogenesis. Our study identified that the histone acetyltransferase encoded by Kat7 is upregulated in the affected articular cartilage of OA patients and in a mice model of medial meniscal instability-induced OA. Chondrocyte-specific knockdown of Kat7 expression exhibited a protective effect on articular cartilage integrity. In vitro experiments demonstrated that KAT7 promotes cartilage catabolism, inhibits cartilage anabolism, and induces chondrocyte senescence and apoptosis. Conversely, knocking down Kat7 was shown to protect chondrocyte function. Corresponding in vivo results indicated that silencing Kat7 effectively enhances cartilage anabolism, prevents articular cartilage damage, and significantly slows OA progression. Mechanistically, KAT7 activates the TLR4/NF-κB signaling pathway, and inhibition of this pathway reverses the catabolic effects and restores anabolic activity in the presence of Kat7 overexpression. Collectively, these findings confirm the critical role of KAT7 in the pathogenesis of OA and suggest that Kat7 represents a potential therapeutic target for OA treatment. KEY MESSAGES: There is a lack of clinically effective drugs for the treatment of osteoarthritis (OA). Kat7 plays a key role in the development of OA. Knocking down Kat7 expression can alleviate the progression of OA. Kat7 accelerates the progression of OA by activating the TLR4/NF-KB signaling pathway.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"273-284"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucose enrichment reduces lifespan and promotes tau phosphorylation in human tau-expressing C. elegans, unaffected by O-β-GlcNAcylation induction.","authors":"Waqar Ahmad, Khadija Shabbiri","doi":"10.1007/s00109-025-02522-3","DOIUrl":"10.1007/s00109-025-02522-3","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is associated with the formation of tau-hyperphosphorylated neurofibrillary tangles (NFTs). Impaired glucose metabolism has been proposed as a major risk factor in AD severity, with many enzymes and pathways associated with glucose metabolism found to be compromised. The use of additional glucose has been suggested to reduce AD severity. However, the exact role of glucose metabolism in disease progression is still under investigation. In this study, we found that adding glucose to tau-expressing worms not only shortens their lifespan but also induces tau phosphorylation on critical serine and threonine residues. Increased phosphorylation of tau is associated with the formation of NFTs and increased disease severity. O-β-GlcNAcylation may inhibit phosphorylation. We hypothesized that high glucose levels might induce tau O-β-GlcNAcylation, thereby protecting against tau phosphorylation. Contrary to our expectations, glucose increased tau phosphorylation but not O-β-GlcNAcylation. Increasing O-β-GlcNAcylation, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene, interferes with and reduces tau phosphorylation. Conversely, reducing O-β-GlcNAcylation by suppressing the O-GlcNAc transferase (ogt-1) gene increases tau phosphorylation. Our results suggest that glucose addition may induce selective O-β-GlcNAcylation on some proteins but not on tau. High levels of glucose exacerbate disease progression by promoting tau hyperphosphorylation. The effects of glucose cannot be effectively managed by manipulating O-β-GlcNAcylation in tau models of AD in C. elegans. Our observations indicate that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression. KEY MESSAGES: Formation of tau hyperphosphorylated neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) in aged patients. Glucose metabolism may affect the AD pathogenesis. Glucose was found to induce tau phosphorylation. Glucose intake was not able to induce overall O-β-GlcNAcylation. Collectively, higher glucose levels in diet were associated with induced disease severity.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"327-338"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD155 promotes the advancement of hepatocellular carcinoma by suppressing the p53-mediated ferroptosis via interacting with CD96.","authors":"Zhenhui Lu, Jingzhe Yu, Tuoyu Lu, Siyuan Deng, Xuzhen Zheng, Baiyu Ji, Xiangyang Wu, Yingzi Yu","doi":"10.1007/s00109-025-02515-2","DOIUrl":"10.1007/s00109-025-02515-2","url":null,"abstract":"<p><p>This work researched the influence and mechanism of CD155 on hepatocellular carcinoma advancement. CD155 expression and its effect on survival of hepatocellular carcinoma patients were analyzed based on the GEPIA2 database. String software predicted the interacting between CD155 and CD96, which was further verified by co-immunoprecipitation experiment. The function of CD155 and CD96 on the proliferation, migration, and invasion of hepatocellular carcinoma cells (HCC) was explored by colony formation, wound healing, and transwell assays. To research the effect of CD155 and CD96 on ferroptosis, ferroptosis-related factors in HCC were investigated. CD155 and p53 were both silenced in HCC to explore whether CD155 regulates hepatocellular carcinoma progression by acting on p53. Xenograft tumor study was conducted to examine the impact of CD155 on the in vivo growth of HCC. It was discovered that, CD155 up-regulation predicted poor survival of hepatocellular carcinoma patients. CD155 could be interacted with CD96. The proliferation, migration, and invasion of HCC were heightened by CD155. However, ferroptosis was suppressed by CD155, as CD155 decreased p53 and iron but increased SLC7A11, GPX4 and GSH in HCC. In fact, CD96 silencing abolished these effects of CD155. The suppressed malignant behaviors and the enhanced ferroptosis in HCC induced by CD155 silencing were abrogated by p53 silencing. In vivo, CD155 silencing suppressed growth and enhanced ferroptosis of hepatocellular carcinoma, which were counteracted by p53 silencing. Thus, CD155 might facilitate hepatocellular carcinoma advancement through blocking the p53-mediated ferroptosis via interacting with CD96. CD155 might be a promising target for treating hepatocellular carcinoma. KEY MESSAGES: CD155 was up-regulated in hepatocellular carcinoma, predicting poor survival. CD155 protein could be interacted with CD96 protein. Proliferation and invasion of liver cancer cells were facilitated by CD155. Proliferation and invasion of liver cancer cells were decreased by CD96 loss. CD155 promoted liver cancer by suppressing p53-mediated ferroptosis via CD96.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"285-299"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of endosomal RANKL-LGR4 signaling during osteoclast differentiation.","authors":"Beom Chang Kim, Yong Jin Cho, Yuria Jang, Kang Yeol Ko, Chang-Moon Lee, Wonbong Lim","doi":"10.1007/s00109-025-02523-2","DOIUrl":"10.1007/s00109-025-02523-2","url":null,"abstract":"<p><p>Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also known as GPR48) is a membrane receptor that negatively regulates the RANK signaling cascade during osteoclastogenesis. Traditionally, cell signaling and endocytic membrane trafficking via membrane receptors have been considered distinct processes; however, they are now recognized to be closely and bidirectionally linked. The present study investigated the difference between membrane-bound and endosomal LGR4 signaling and whether the LGR4 signaling pathway influences RANK-RANKL signaling during RANKL-induced osteoclastogenesis. We used CRISPR-Cas9 to create LGR4 conditional knock-out (CKO) in RAW 264.7 cells and Drg2 knockout (KO) in mice to study the impacts of LGR4 and DRG2 on osteoclastogenesis. LGR4 was endocytosed into endosomes after binding to RANKL in RAW 264.7 s osteoclast precursor cells. Within the early endosomes, internalized LGR4 activates LGR4-RANKL signaling. When bound to RANKL, LGR4 is endocytosed and localized in the RAB5-positive endosomes. In Lgr4 CKO RAW 264.7 cells, early endosome signaling was increased and the inhibitory phosphorylation of GSK-3β was decreased, both in the whole lysate and endosome fraction. RANKL treatment increased nuclear translocation of NFATC1 in Lgr4 CKO RAW 264.7 cells and Drg2 KO mice. Overall, our results suggested that RANKL-LGR4 signaling is regulated by membrane-to-endosomal trafficking during osteoclastogenesis. KEY MESSAGES: Bone resorption by osteoclasts is essential for bone homeostasis and remodeling. However, the mechanisms underlying the regulation of osteoclastogenesis are not yet fully understood. The present study investigated the difference between membrane-bound and endosomal LGR4 signaling, and whether the LGR4 signaling pathway influences RANK-RANKL signaling during RANKL-induced osteoclastogenesis. Our results suggested that RANKL-LGR4 signaling is regulated by membrane-to-endosomal trafficking during osteoclastogenesis.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"339-354"},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}