The Journal of Clinical Investigation最新文献

{"title":"Axon guidance cue SLIT2 regulates the murine skeletal stem cell niche through sympathetic innervation.","authors":"Zuoxing Wu,Na Li,Zhengqiong Luo,Zihan Chen,Xuemei He,Jie Han,Xixi Lin,Fan Shi,Haitao Huang,Baohong Shi,Yu Li,Xin Wang,Lin Meng,Dachuan Zhang,Lanfen Chen,Dawang Zhou,Weinan Cheng,Matthew B Greenblatt,Ren Xu","doi":"10.1172/jci193014","DOIUrl":"https://doi.org/10.1172/jci193014","url":null,"abstract":"Sympathetic tone is a central signaling axis inhibiting osteogenesis; however, the combination of durable local and systemic sympathetic effects on bone argues that multiple mechanisms, including yet-undiscovered pathways, are involved. Here, we found that sympathetic nerves constituted a component of the skeletal stem cell (SSC) niche: mice with conditional deletion of the classical axonal repellent Slit2 in sympathetic nerves (Slit2th mice), but not in bone stem/progenitor cells or sensory nerves, showed osteopenia due to an increase in sympathetic innervation and an associated decrease in SSCs. Mice with increased skeletal sympathetic innervation displayed impaired SSC niche function in an SSC orthotopic transplantation and engraftment system. Follistatin-like 1 (FSTL1) is a SLIT2-regulated soluble factor suppressing SSC self-renewal and osteogenic capacity. Accordingly, ablation of Fstl1 in sympathetic neurons enhanced SSC-driven osteogenesis and attenuated the bone loss seen in Slit2th mice. Together, the findings indicate that SLIT2 is a regulator of a sympathetic nerve-mediated SSC niche.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PIM3-mediated phosphorylation stabilizes myeloid leukemia factor 2 to promote metastasis in osteosarcoma.","authors":"Cuiling Zeng,Xin Wang,Jinkun Zhong,Yu Zhang,Ju Deng,Wenqiang Liu,Weixuan Chen,Xinhao Yu,Dian Lin,Ruhua Zhang,Shang Wang,Jianpei Lao,Qi Zhao,Li Zhong,Tiebang Kang,Dan Liao","doi":"10.1172/jci191040","DOIUrl":"https://doi.org/10.1172/jci191040","url":null,"abstract":"Osteosarcoma is the most common primary malignant bone cancer, characterized by a high incidence of lung metastasis and a lack of therapeutic targets. Here, by combining an in vivo CRISPR activation screen with the interactome of STUB1, a tumor suppressor in osteosarcoma, we identified that myeloid leukemia factor 2 (MLF2) promotes osteosarcoma metastasis. Mechanistically, MLF2 disrupted the interaction between BiP and IRE1α, thereby activating the IRE1α/XBP1-S-MMP9 axis. The E3 ligase STUB1 ubiquitinated MLF2 at Lys119 and targeted it for proteasomal degradation, whereas PIM3-mediated phosphorylation of MLF2 at Ser65 enhanced its stabilizing interaction with USP21. Our findings demonstrate that the PIM3/MLF2 axis is a critical regulator of osteosarcoma lung metastasis. We propose PIM3 as a potential therapeutic target for patients with osteosarcoma lung metastasis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFN-γ signaling stimulates intestinal crypt hyperplasia in celiac disease.","authors":"Alexa R Weingarden","doi":"10.1172/jci198412","DOIUrl":"https://doi.org/10.1172/jci198412","url":null,"abstract":"Celiac disease, an enteropathy driven by a maladaptive immune response to dietary gluten, is marked by increased proliferation in intestinal crypts, or crypt hyperplasia. However, it is unknown whether this phenomenon is a compensatory response to loss of villus epithelial cells or if it is driven by independent mechanisms. In this issue of the JCI, Stamnaes et al. demonstrated that in untreated celiac disease, crypt cells had increased expression of proteins involved in the IFN response, with decreased expression of fatty acid metabolism pathways. These expression patterns were recapitulated in mice treated with IFN-γ, but not mice with intestinal epithelial cell-specific knockout of the IFN-γ receptor. The findings suggest that crypt cells were reprogrammed directly by IFN-γ signaling, independent of changes to epithelial villi.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CARMN orchestrates angiogenesis from behind the opera scenes: signing love letters to the endothelium.","authors":"Shivangi Pande,George Ishak,Fahimeh Varzideh,Gaetano Santulli","doi":"10.1172/jci197708","DOIUrl":"https://doi.org/10.1172/jci197708","url":null,"abstract":"Chronic limb-threatening ischemia (CLTI), the advanced stage of peripheral artery disease (PAD), remains a leading cause of morbidity and limb loss. Effective vascular regeneration strategies will require increased understanding of molecular mechanisms underlying angiogenesis. Recent evidence revealed a new role for the vascular smooth muscle cell-enriched (VSMC-enriched) long noncoding RNA (lncRNA) CARMN in endothelial angiogenesis and postischemic vascular repair. CARMN was downregulated in both human CLTI muscle tissue and murine ischemia models. In VSMCs, CARMN deficiency suppressed a specific miRNA-mediated paracrine signaling axis that regulates Hedgehog signaling. In mice, deleting CARMN caused impariment in capillary growth and blood flow recovery after limb ischemia, an effect that was reversed by restoring miR-143-3p or silencing the Hedgehog inhibitor HHIP. The identification of lncRNA-mediated crosstalk between VSMCs and endothelial cells in PAD pathophysiology reveals possible therapeutic targets for CLTI and underscores the translational potential of RNA-based strategies in ischemic vascular disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D cultured human medium spiny neurons functionally integrate and rescue motor deficits in Huntington's disease mice.","authors":"Yuting Mei,Yuan Xu,Xinyue Zhang,Ban Feng,Yingying Zhou,Qian Cheng,Yuan Li,Xingsheng Peng,Mengnan Wu,Lianshun Xie,Lei Xiao,Wenhao Zhou,Yuejun Chen,Man Xiong","doi":"10.1172/jci187941","DOIUrl":"https://doi.org/10.1172/jci187941","url":null,"abstract":"Dysfunction of striatal medium spiny neurons (MSNs) is implicated in several neurological disorders, including Huntington's disease (HD). Despite progress in characterizing MSN pathology in HD, mechanisms underlying MSN susceptibility remain unknown, driving the need for MSNs derived from human pluripotent stem cells (hPSCs), especially subtypes in research and therapy. Here, we established a scalable 3D-default culture system to produce striatal MSNs efficiently from hPSCs by activation of the endogenous sonic hedgehog (SHH) pathway. These cells expressed canonical markers of striatal progenitors and dopamine D1 (D1) and dopamine D2 (D2) MSNs and presented dynamic specification and transcriptional signatures that closely resemble endogenous MSNs at single-cell resolution, both in vitro and post-transplantation in HD mice with quinolinic acid (QA) lesions. Grafted human cells survived and matured into D1-/D2-like MSNs and projected axons to endogenous targets including globus pallidus externus, globus pallidus internus, and substantia nigra pars reticulata to reconstruct the basal ganglia pathways. Functionally, they displayed spontaneous synaptic currents, received regulation from host cortex and thalamus, and were modulated by dopamine to either enhance or reduce neuronal excitability, similar to the endogenous D1-/D2-MSNs, subsequently improving behavior in QA-lesioned HD mice. Our study presents a method for generating authentic MSNs, providing a reliable cell source for HD cell therapy, mechanistic studies, and drug screening.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Citrullination in tumor immunity and therapy.","authors":"Michael R Pitter,Weiping Zou","doi":"10.1172/jci196348","DOIUrl":"https://doi.org/10.1172/jci196348","url":null,"abstract":"Peptidyl arginine deiminases (PADs) catalyze the conversion of arginine residues into peptidyl citrulline, a posttranslational modification known as protein citrullination (or arginine deimination). This process alters the charge of proteins from positive to neutral, thereby affecting their folding, stability, conformation, and function. PAD2 and PAD4 can translocate into the nucleus and citrullinate both cytoplasmic and nuclear proteins. In this Review, we focus on PAD2- and PAD4-mediated citrullination in immune cell subsets within the tumor microenvironment. We discuss how citrullination regulates immune cell function and tumor immunity and explore the potential of targeting citrullination as a strategy for cancer immunotherapy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A PP2A molecular glue overcomes ras/mapk inhibitor resistance in kras-mutant non-small cell lung cancer.","authors":"Brynne Raines,Stephanie Tseng-Rogenski,Amanda C Dowdican,Irene Peris,Matthew Hinderman,Kaitlin P Zawacki,Kelsey Barrie,Gabrielle Hodges Onishi,Alexander M Dymond,Tahra K Luther,Sydney Musser,Behirda Karaj Majchrowski,J Chad Brenner,Aqila Ahmed,Derek J Taylor,Caitlin M O'Connor,Goutham Narla","doi":"10.1172/jci193790","DOIUrl":"https://doi.org/10.1172/jci193790","url":null,"abstract":"The effectiveness of RAS/MAPK inhibitors in treating metastatic KRAS-mutant NSCLC is often hindered by the development of resistance driven by disrupted negative feedback mechanisms led by phosphatases like PP2A. PP2A is frequently suppressed in lung cancer to maintain elevated RAS/MAPK activity. Despite its established role in regulating oncogenic signaling, targeting PP2A with RAS/MAPK to prevent resistance has not been previously demonstrated. In this study, we aimed to establish a treatment paradigm by combining a PP2A molecular glue with a RAS/MAPK inhibitor to restore PP2A activity and counteract resistance. We demonstrated that KRASG12C and MEK1/2 inhibitors disrupted PP2A carboxymethylation and destabilized critical heterotrimeric complexes. Furthermore, genetic disruption of PP2A carboxymethylation enhanced intrinsic resistance to MEK1/2 inhibition both in vitro and in vivo. We developed RPT04402, a PP2A molecular glue that selectively stabilizes PP2A-B56α heterotrimers. In both commercial cell lines and a patient-derived model, combining RPT04402 with a RAS/MAPK inhibitor slowed proliferation and enhanced apoptosis. In mouse xenografts, this combination induced tumor regressions, extended median survival, and delayed the onset of treatment resistance. These findings highlight that promoting PP2A stabilization and RAS/MAPK inhibition presents a promising therapeutic strategy to improve treatment outcomes and overcome resistance in metastatic KRAS-mutant NSCLC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy.","authors":"Natalia Dominik,Stephanie Efthymiou,Christopher J Record,Xinyu Miao,Renee Q Lin,Jevin M Parmar,Annarita Scardamaglia,Reza Maroofian,Simon A Lowe,Gabriel N Aughey,Abigail D Wilson,Riccardo Curro,Ricardo P Schnekenberg,Shahryar Alavi,Leif Leclaire,Yi He,Kristina Zhelcheska,Yohanns Bellaiche,Isabelle Gaugué,Mariola Skorupinska,Liedewei Van de Vondel,Sahar I Da'as,Valentina Turchetti,Serdal Güngör,Gavin V Monahan,Ehsan Ghayoor Karimiani,Yalda Jamshidi,Phillipa J Lamont,Camila Armirola-Ricaurte,Haluk Topaloglu,Albena Jordanova,Mashaya Zaman,Selina H Banu,Wilson Marques,Pedro J Tomaselli,Busra Aynekin,Ali Cansu,Huseyin Per,Ayten Güleç,Javeria Raza Alvi,Tipu Sultan,Arif Khan,Giovanni Zifarelli,Shahnaz Ibrahim,Grazia M S Mancini,M M Motazacker,Esther Brusse,Vincenzo Lupo,Teresa Sevilla,A Nazli Başak,Seyma Tekgul,Robin J Palvadeau,Jonathan Baets,Yesim Parman,Arman Çakar,Rita Horvath,Tobias B Haack,Jan-Hendrik Stahl,Kathrin Grundmann-Hauser,Joohyun Park,Stephan Zuchner,Nigel G Laing,Lindsay A Wilson,Alexander M Rossor,James Polke,Fernanda Barbosa Figueiredo,André Pessoa,Fernando Kok,Antônio Rodrigues Coimbra-Neto,Marcondes C Franca,Gianina Ravenscroft,Sherifa A Hamed,Wendy K Chung,Alan M Pittman,Daniel P Osborn,Michael Hanna,Andrea Cortese,Mary M Reilly,James Ec Jepson,Nathalie Lamarche-Vane,Henry Houlden","doi":"10.1172/jci184474","DOIUrl":"https://doi.org/10.1172/jci184474","url":null,"abstract":"Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Here, we identify 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families. The ARHGAP19 protein acts as a negative regulator of the RhoA GTPase. In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels. Combined in vitro and in vivo studies reveal that human ARHGAP19, and conserved ARHGAP19 orthologs in Drosophila and Zebrafish, influence motoneuron morphology and promote locomotor capacity. Transcriptomic studies further demonstrate that ARHGAP19 regulates cellular pathways associated with motor proteins and the cell cycle. Taken together, our findings establish ARHGAP19 variants as a cause of inherited neuropathy acting through a loss-of-function mechanism.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulated thyroid hormone synthesis machinery drives thyrocyte cell death independent of ER stress.","authors":"Crystal Young,Xiaohan Zhang,Xiaofan Wang,Aaron P Kellogg,Kevin Pena,August Z Cumming,Xiao-Hui Liao,Dennis Larkin,Hao Zhang,Emma Mastroianni,Helmut Grasberger,Samuel Refetoff,Peter Arvan","doi":"10.1172/jci187044","DOIUrl":"https://doi.org/10.1172/jci187044","url":null,"abstract":"It is now recognized that patients and animal models expressing genetically-encoded misfolded mutant thyroglobulin (TG, the protein precursor for thyroid hormone synthesis) exhibit dramatic swelling of the endoplasmic reticulum (ER) with ER stress and cell death in thyrocytes - seen both in homozygotes (with severe hypothyroidism) and heterozygotes (with subclinical hypothyroidism). The thyrocyte death phenotype is exacerbated upon thyroidal stimulation (by thyrotropin, TSH), as cell death is inhibited upon treatment with exogenous thyroxine. TSH stimulation might contribute to cytotoxicity by promoting ER stress, or by an independent mechanism. Here we've engineered knockout mice completely lacking Tg expression. Like other animals/patients with mutant TG, these animals rapidly develop severe goitrous hypothyroidism; however, thyroidal ER stress is exceedingly low - lower even than that seen in wildtype mice. Nevertheless, mice lacking TG exhibit abundant thyroid cell death, which depends upon renegade thyroidal iodination - it is completely suppressed in a genetic model lacking effective iodination, or in Tg-KO mice treated with propylthiouracil (iodination inhibitor), or iodide deficiency. Thyrocytes in culture are killed not in the presence of H2O2 alone, but rather upon peroxidase-mediated iodination, with cell death blocked by propylthiouracil. Thus, in the thyroid gland bearing Tg mutation(s), TSH-stimulated iodination activity triggers thyroid cell death.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kidney-specific claudin-2 deficiency leads to medullary nephrocalcinosis in mice.","authors":"Christine V Behm,Duuamene Nyimanu,Ony Araujo Galdino,Sadhana Kanoo,Young Chul Kim,Natalia Lopez,Helen Goodluck,Peter S Rowe,Andrew P Evan,André J Sommer,Matthew N Barr,Tracy Punshon,Volker Vallon,Brian P Jackson,James C Williams,Alan Sl Yu","doi":"10.1172/jci197807","DOIUrl":"https://doi.org/10.1172/jci197807","url":null,"abstract":"Deposits of hydroxyapatite called Randall's plaques are found in the renal papilla of calcium oxalate kidney stone formers and likely serve as the nidus for stone formation, but their pathogenesis is unknown. Claudin-2 is a paracellular ion channel that mediates calcium reabsorption in the renal proximal tubule. To investigate the role of renal claudin-2, we generated kidney tubule-specific claudin-2 conditional knockout mice (KS-Cldn2 KO). KS-Cldn2 KO mice exhibited transient hypercalciuria in early life. Normalization of urine calcium was accompanied by a compensatory increase in expression and function of renal tubule calcium transporters, including in the thick ascending limb. Despite normocalciuria, KS-Cldn2 KO mice developed papillary hydroxyapatite deposits, beginning at 6 months of age, that resembled Randall's plaques and tubule plugs. Bulk chemical tissue analysis and laser ablation-inductively coupled plasma mass spectrometry revealed a gradient of intrarenal calcium concentration along the corticomedullary axis in normal mice, that was accentuated in KS-Cldn2 KO mice. Our findings provide evidence for the \"vas washdown\" hypothesis for Randall's plaque formation, and identify the corticomedullary calcium gradient as a target for therapies to prevent kidney stone disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}