American Journal of Pathology最新文献

{"title":"Interpreting Deep Learning–Based Prediction of the BRAF V600E Mutation Using Diagnostic Whole Slide Images in Skin Cutaneous Melanoma","authors":"Vibha R. Rao ,&nbsp;Vy Nguyen ,&nbsp;Thuy L. Phung ,&nbsp;Shrey S. Sukhadia","doi":"10.1016/j.ajpath.2025.11.004","DOIUrl":"10.1016/j.ajpath.2025.11.004","url":null,"abstract":"<div><div>Deep learning (DL) models have shown promise in predicting molecular alterations directly from hematoxylin and eosin–stained whole slide images in a variety of solid tumors, offering a rapid alternative to conventional molecular testing. However, these models often offer limited insight into their decision-making process, undermining transparency and eroding clinical trust. Interpreting model predictions is essential for a meaningful application of DL in clinical pathology. This is showcased by interpreting the outputs of a weakly supervised DL model, XpressO-melanoma, that predicts <em>BRAF</em> V600E mutation status from whole slide images of skin cutaneous melanoma. The morphologic plausibility of the model's segmentations of the tumor regions of interest and their prediction of <em>BRAF</em> V600E status were evaluated and compared against the pathologists' annotations for the same. The work resulted into four interpretation categories that associate model's performance (ie, area under the curve of 0.8 and precision and recall of 0.7) with the regions of interest that revealed meaningful diagnostic patterns as well as those that required annotation refinements. The work coheres with the White House's National AI [Artificial Intelligence] Action Plan that identifies interpretability as a national research priority and paves the way for a human-DL collaboration in clinical pathology for a better translation of DL techniques in clinical pathology in the near future.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 716-730"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145755023","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}

{"title":"Systemic Disease Progression and Neurodegeneration in the Gbe1ys/ys Mouse Model of Glycogen Storage Disease Type IV","authors":"Su Jin Choi ,&nbsp;Rebecca L. Koch ,&nbsp;Rebecca A. Gibson ,&nbsp;Fiona E. Weaver ,&nbsp;Yadav Adhikari ,&nbsp;William Eisner ,&nbsp;Aarav Mehta ,&nbsp;William R. Jeck ,&nbsp;Jeong-A Lim ,&nbsp;Priya S. Kishnani","doi":"10.1016/j.ajpath.2025.11.006","DOIUrl":"10.1016/j.ajpath.2025.11.006","url":null,"abstract":"<div><div>Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by glycogen branching enzyme (GBE1) deficiency, resulting in the accumulation of insoluble polyglucosan. The <em>Gbe1</em>^{<em>ys/ys</em>} mouse model, carrying the p.Y329S variant, recapitulates features of adult-onset GSD IV, also known as adult polyglucosan body disease. However, the natural progression of the disease in this model is not fully understood. This study presents a longitudinal analysis of <em>Gbe1</em>^{<em>ys/ys</em>} mice from 1 to 12 months of age, quantitatively tracking polyglucosan accumulation and correlating it with progressive histopathologic, motor, and behavioral changes. Polyglucosan bodies were detected as early as 1 month, with significant neurodegeneration and astrogliosis by 6 months. Notably, serum neurofilament light chain levels increased with disease progression, identifying neurofilament light chain as a potential noninvasive biomarker of neurodegeneration in GSD IV. Systemic involvement, including severe splenomegaly and gastrointestinal abnormalities, indicates broader effects of GBE1 deficiency beyond the central nervous system. These findings provide important insights into the natural history of GSD IV, establish key disease milestones for therapeutic intervention, and refine the clinical understanding of GSD IV and adult polyglucosan body disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 731-744"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773339","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}

{"title":"Neurogenic Inflammation and Immune Dysregulation in Psoriasis","authors":"Hemraj Singh,&nbsp;Rajeev Taliyan","doi":"10.1016/j.ajpath.2025.11.005","DOIUrl":"10.1016/j.ajpath.2025.11.005","url":null,"abstract":"<div><div>Psoriasis is a chronic, immune-mediated inflammatory disorder characterized by keratinocyte hyperproliferation and systemic immune dysregulation. The neuroimmune axis, linking sensory nerve activity, neuropeptide signaling, and immune responses, is central to disease pathogenesis. Structural remodeling of sensory nerves enhances the release of neuropeptides such as Substance P, calcitonin gene–related peptide, vasoactive intestinal peptide, and neuropeptide Y, which activate dendritic cells, promote T-cell proliferation, and stimulate keratinocyte cytokine production, sustaining a neurogenic inflammatory loop. Psychological stress exacerbates inflammation through hypothalamic–pituitary–adrenal (HPA) axis dysregulation, altering cortisol signaling and systemic immune responses. Intracellular pathways, including mitogen-activated protein kinase, PI3KAktmTOR, JAKSTAT, and NF-κB, along with epigenetic modifications, integrate neural and immune signals, contributing to disease chronicity and heterogeneity. Targeting neuroimmune interactions through neuropeptide antagonists, neuromodulation, stress management, and precision immunotherapies reduces cutaneous inflammation and addresses systemic comorbidities. This review synthesizes molecular, cellular, and clinical insights into the neuroimmune-HPA axis network in psoriasis, highlighting its therapeutic potential for personalized and multidisciplinary management.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 633-643"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754997","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}

{"title":"Delayed Bone Fracture Healing in Hybid (Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization)–Deficient Mice","authors":"Suguru Wakana ,&nbsp;Takako Negishi-Koga ,&nbsp;Masahiro Momoeda ,&nbsp;Haruka Kaneko ,&nbsp;Takahiro Sasahara ,&nbsp;Chiho Yoshinaga ,&nbsp;Yuka Kenzaki ,&nbsp;Yoko Endo ,&nbsp;Hiroyuki Yoshida ,&nbsp;Muneaki Ishijima ,&nbsp;Yasunori Okada","doi":"10.1016/j.ajpath.2025.11.007","DOIUrl":"10.1016/j.ajpath.2025.11.007","url":null,"abstract":"<div><div>Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), essential for HA degradation, has been reported to promote endochondral ossification in developing bone but to inhibit intramembranous ossification. However, little is known about the role of HYBID in long bone fracture healing, which requires both types of ossification. The role of genetic <em>Hybid</em> depletion in healing was examined in a murine model of femoral diaphyseal fracture. On micro–computed tomography, bridging of fracture gaps was delayed in <em>Hybid</em>-deficient (<em>Hybid</em>^−/−) mice compared to wild-type mice. On histologic analysis, the resorption of cartilaginous callus was retarded due to decreased osteoclasts/chondroclasts and blood vessels at the chondro-osseous junction of cartilaginous and bony callus in Hybid deficiency, with delayed fusion of fracture gaps. At 2 weeks after fracture, Hybid was highly expressed by osteoblasts and hypertrophic chondrocytes in callus of wild-type mice, and <em>Il</em><em>6</em> was overexpressed at 1 week, followed by transforming growth factor β1 (<em>Tgfb1</em>) and bone morphogenic protein 2 (<em>Bmp2</em>) expression at 2 and 3 weeks. High–molecular-weight HA accumulated in the callus tissue of the <em>Hybid</em>^−/− mice. In both groups, fracture healing was promoted with injections of low–molecular-weight HA around the calluses of the fractured femora. These data suggest that fracture healing is delayed in HYBID deficiency due to impaired endochondral ossification, and that HYBID-mediated HA depolymerization is involved in bone fracture healing.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 766-779"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761829","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}

{"title":"Targeting Skeletal Muscle in Duchenne Muscular Dystrophy","authors":"Christopher Dostal ,&nbsp;Johanna Reiner ,&nbsp;Ana I. Antunes Goncalves ,&nbsp;Laura S. Sousa ,&nbsp;Marlene Knapp ,&nbsp;Joel Fischlein ,&nbsp;Jessica Marksteiner ,&nbsp;Jakob Sauer ,&nbsp;Gavin Y. Oudit ,&nbsp;Anja Wagner ,&nbsp;Dietmar Abraham ,&nbsp;Karlheinz Hilber ,&nbsp;Klaus Kratochwill ,&nbsp;Bruno K. Podesser ,&nbsp;Attila Kiss","doi":"10.1016/j.ajpath.2025.11.002","DOIUrl":"10.1016/j.ajpath.2025.11.002","url":null,"abstract":"<div><div>Duchenne muscular dystrophy (DMD) is a severe X-linked disorder with progressive myofiber degeneration and fibrosis from dystrophin deficiency. Current therapies are largely supportive with limited anti-fibrotic benefit, prompting new strategies. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. Open-access proteomic and transcriptomic data sets were integrated for <em>in silico</em> analyses, including differential gene expression, weighted gene co-expression network analysis, and pathway enrichment, to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine data sets. Therapeutic effects were tested with empagliflozin (EMPA) in <em>mdx</em> mice (30 mg/kg per day for 4 weeks, starting at 12 weeks) and DMD^<em>mdx</em> rats (10 mg/kg per day for 4 months, starting at 5 months), with vehicle controls. Validation used quantitative RT-PCR, grip-strength testing, and histologic fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included <em>COL3A1</em>, <em>COL5A2</em>, and <em>TGF</em><em>B</em><em>1</em>. EMPA reduced <em>Tgfb1</em> expression in DMD rats and significantly decreased collagen deposition in skeletal muscle. Functional testing showed longer grip duration in EMPA-treated mice. Immune profiling revealed shifts in T cells and macrophages, indicating immunomodulation. Findings were consistent across species and data modalities analyzed. These results demonstrate that EMPA modulates fibrosis, inflammation, and muscle endurance in DMD models. These data support repurposing SGLT2i as a promising therapeutic strategy for DMD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 745-765"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145755018","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}

{"title":"Mechanistic Insights into Glucocorticoid-Induced Ocular Hypertension Using Differences in Mouse Strain Responsiveness","authors":"Pinkal D. Patel ,&nbsp;Gaurang C. Patel ,&nbsp;J. Cameron Millar ,&nbsp;Sherri Feris ,&nbsp;Stacy Curry ,&nbsp;Eldon E. Geisert ,&nbsp;Abbot F. Clark","doi":"10.1016/j.ajpath.2025.11.009","DOIUrl":"10.1016/j.ajpath.2025.11.009","url":null,"abstract":"<div><div>Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents. Unfortunately, many people experience negative adverse effects associated with long term GC therapy, developing GC-induced ocular hypertension (GC-OHT), which can lead to secondary glaucoma. Approximately 40% of the treated individuals are susceptible to GC-OHT. Seventy years since this discovery, the molecular mechanisms underlying GC-OHT remain unclear. We previously developed a mouse model of GC-OHT delivering the potent GC dexamethasone and observed strain-specific disparities in the development of GC-OHT. We now compare phenotypic and transcriptomic differences between five genetically distinct inbred mouse strains to identify biomarkers of GC susceptibility, and to better understand the molecular mechanisms of GC-OHT. Like humans, mouse strains differ in their ability to develop GC-OHT. Phenotypic characterization revealed that C57BL/6J and C3H/HeJ mice are GC responders and more susceptible to develop GC-OHT. Dexamethasone treatment in these strains led to elevated intraocular pressure compared with the GC nonresponder strains DBA/2J.<em>Gpnmb</em>^<em>+</em>, 129P3/J, and BALB/cJ. Transcriptomic analysis of responder and nonresponder mouse strains revealed novel trabecular meshwork biomarkers of GC-OHT susceptibility involving enrichment of molecular pathways unique to this response. The present study identifies putative mechanisms underlying GC-OHT and provides insight into the pathogenesis of the clinically similar but more prevalent primary open-angle glaucoma.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 780-800"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773209","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}

{"title":"Emerging Mechanistic Roles of STING Signaling in Kidney Diseases","authors":"Chenjian Gu ,&nbsp;Ying Maggie Chen","doi":"10.1016/j.ajpath.2025.12.001","DOIUrl":"10.1016/j.ajpath.2025.12.001","url":null,"abstract":"<div><div>Stimulator of interferon genes (STING), an effector protein anchored in the endoplasmic reticulum, translocates to Golgi upon activation. Canonically recognized for its central function in innate immune defense against cytosolic endogenous or exogenous double-stranded DNA from damaged host cells or pathogens, STING is now known to have noncanonical functions beyond innate immune surveillance. These novel noncanonical functions of STING include modulating autophagy, maintaining endoplasmic reticulum and mitochondrial calcium homeostasis, interacting with endoplasmic reticulum stress sensor protein, and regulating Golgi proton efflux and integrity of the secretory pathway. Recent research in murine models has linked aberrant STING activation to kidney disorders, including acute kidney injury, podocytopathies, chronic kidney disease, apolipoprotein L1–mediated kidney disease, autosomal dominant polycystic kidney disease, and autosomal dominant tubulointerstitial kidney disease. This review summarizes the diverse functions of STING in addition to interferon signaling, highlighting its emerging importance in the pathogenesis of kidney disease and underscoring its promise as a drug target.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 644-656"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780011","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}

{"title":"Loss of Angptl4 Protects Mice from Intestinal Colitis and Tumorigenesis with Alternative Activation of Macrophages","authors":"Jeong-ah Yoo ,&nbsp;Yun Hye Kim ,&nbsp;Min Seon Choe ,&nbsp;Hamza Sghayare ,&nbsp;Qiwei Zhang ,&nbsp;Gaeun Kwon ,&nbsp;Yeeun Kim ,&nbsp;Seoyeon Lee ,&nbsp;Chaewon Lee ,&nbsp;Hoon-Ki Sung ,&nbsp;Joe Eun Son","doi":"10.1016/j.ajpath.2025.11.003","DOIUrl":"10.1016/j.ajpath.2025.11.003","url":null,"abstract":"<div><div>Angiopoietin-like 4 (<em>Angptl4</em>) is a secreted glycoprotein involved in the regulation of various homeostatic and disease processes. In the intestine, prior studies have suggested protective roles for <em>Angptl4</em> in inflammation using <em>Angptl4</em> knockout mouse models; however, phenotypic variability—such as perinatal lethality and intestinal inflammation accompanied by lymphatic defects in only a subset of animals—has complicated the interpretation of its role in intestinal pathogenesis. In this study, the impact of <em>Angptl4</em> deficiency was examined using a subset of <em>Angptl4</em> knockout mice that survive postnatally without overt abnormalities. It was found that loss of <em>Angptl4</em> confers protection against colitis and colitis-associated colorectal tumorigenesis. These protective effects were associated with the alternative activation of anti-inflammatory M2-like macrophages. Similarly, in a genetic model of intestinal tumorigenesis, <em>Angptl4</em> deficiency resulted in reduced tumor burden and attenuated inflammation, accompanied by increased M2-like macrophages. Analysis of human colorectal cancer data sets further revealed that low <em>ANGPTL4</em> expression is associated with improved survival outcomes as well as reduced expression of inflammation-related marker genes. Collectively, the findings uncover a previously unrecognized protective effect of <em>Angptl4</em> deficiency against intestinal pathogenesis via anti-inflammatory mechanisms, suggesting <em>Angptl4</em> as a potential therapeutic target and prognostic biomarker for colorectal cancer and inflammatory bowel disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 683-699"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754987","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}

{"title":"Iron and Bile Acids Synergize to Exacerbate Congenital Cholestatic Liver Injury via Ferroptosis","authors":"Yudai Ohta ,&nbsp;Yohei Kanamori ,&nbsp;Ayato Maeda ,&nbsp;Mohamed Fathi Saleh ,&nbsp;Akihiro Nita ,&nbsp;Takashi Matsumoto ,&nbsp;Keiichi I. Nakayama ,&nbsp;Toshiro Moroishi","doi":"10.1016/j.ajpath.2025.11.008","DOIUrl":"10.1016/j.ajpath.2025.11.008","url":null,"abstract":"<div><div>Pediatric cholestatic liver diseases are rare but serious conditions that frequently progress to liver fibrosis and cirrhosis and often require transplantation. Despite the clinical importance of these diseases, the mechanisms driving disease progression remain poorly understood. Hepatic iron accumulation was identified as a pathologic feature associated with congenital cholestatic liver disease in mice with a liver-specific deletion of <em>Yap</em>, a gene critical for bile duct development. Further hepatic iron overload induced by liver-specific deletion of <em>Fbxl5</em>, a key regulator of cellular iron homeostasis, exacerbated cholestatic liver injury and fibrosis in <em>Yap</em>-deficient mice. Mechanistically, iron overload enhanced the susceptibility to bile acid–induced cytotoxicity via ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation. This ferroptotic process was confirmed by the suppression of bile acid–induced cell death through iron chelation and lipid peroxide scavenging in <em>ex vivo</em> liver slice cultures. Furthermore, both dietary iron restriction and antioxidant treatment mitigated liver injury <em>in vivo</em>. These findings identify iron accumulation as a key driver of disease progression and highlight iron metabolism and ferroptosis as potential therapeutic targets in congenital cholestatic liver disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 700-715"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761850","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}

{"title":"Matrix Gla Protein Expression in Pericytes and Myofibroblasts Contributes to Renal Fibrosis","authors":"Kyoungmi Bak ,&nbsp;Hyunyun Kim ,&nbsp;Jocelyn S. Garland ,&nbsp;Patrick A. Norman ,&nbsp;Andrew G. Day ,&nbsp;Francis Migneault ,&nbsp;Marie-Josée Hébert ,&nbsp;Rachel M. Holden ,&nbsp;Monzur Murshed","doi":"10.1016/j.ajpath.2025.12.003","DOIUrl":"10.1016/j.ajpath.2025.12.003","url":null,"abstract":"<div><div>Renal fibrosis is the main pathologic change observed with the progression of chronic kidney disease (CKD), which predicts kidney outcomes. The ability to detect fibrosis early in the disease course may be crucial to identify those at the highest risk of CKD progression. Clinical studies have observed increased serum matrix Gla protein (MGP), a potent inhibitor of soft tissue calcification, in patients with CKD. In a cross-sectional study of patients with CKD, serum MGP levels were found to be associated with albuminuria and waist circumference after controlling for kidney function. To examine the impact of MGP on the progression of CKD, various mouse models were used in the current study. Using Cre-reporter, <em>Rosa</em>^{<em>Tomato</em>}<em>;Mgp-Cre</em> mice and a new knock-in model expressing hemagglutinin epitope-tagged MGP, it was identified that pericytes and myofibroblasts in healthy and folic acid (FA)–injured kidneys produce MGP. FA injection in <em>Mgp</em>^{<em>–/–</em>} mice induced significantly less renal fibrosis in comparison to the control mice because of a reduced number of pericytes and attenuated Notch signaling. In a complementary experiment, restoration of <em>Mgp</em> expression in myofibroblasts in <em>Mgp</em>^{<em>–/–</em>} mice leads to renal fibrosis as severe as in control mice. This work suggests that MGP expression in myofibroblasts exacerbates renal fibrosis in FA-injured kidneys.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 669-682"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888550","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}