Eosinophils-Induced Lumican Secretion by Synovial Fibroblasts Alleviates Cartilage Degradation via the TGF-β Pathway Mediated by Anxa1 BindingChen, Zhou, Yuan
et alAdv Sci (Weinh) (2025)
Abstract: The innate immune response is crucial in the progression of temporomandibular joint osteoarthritis (TMJOA). Yet, the roles of eosinophils in TMJOA remain unclear, underscoring the need for further investigation into their potential impact and mechanism. Addressing the clinical observation that eosinophil numbers in synovial fluid are higher in healthy individuals than in those with TMJOA, the vital regulation of this cell population in TMJOA by using an ovalbumin (OVA)-induced hyper-eosinophilia asthma rats is explored and a rat model of antibody-mediated eosinophil depletion in vivo, and co-culture system of synovial fibroblasts, chondrocytes, and eosinophils in vitro. The abnormal synovial proliferation, cartilage degradation, and subchondral bone erosion are effectively inhibited in OVA-induced asthmatic rats appearing in the local accumulation of eosinophils in the synovium. Conversely, the reduction in synovial eosinophils exacerbated TMJOA in rats treated with TRFK. Mechanistically, the protective effect of eosinophils against TMJOA is attributed to their promotion of Lumican secretion in the synovium, where Lumican binds to Annexin A1 in chondrocytes, inhibits transforming growth factor β2 Annexin A1 and Smad2/3 phosphorylation. These results illustrate OVA/IL-5-induced eosinophils' crucial role in TMJOA, identifying Lumican as a key anti-TMJOA target. Collectively, these findings revealed the signature and mechanism in eosinophils that stimulate TMJOA resolution.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.
Novel De Novo BRCA2 Variant in an Early-Onset Ovarian Cancer Reveals a Unique Tumor Evolution PathwayMiolo, Canil, Polano
et alInt J Mol Sci (2025) 26 (5)
Abstract: Ovarian cancer (OC) is a highly heterogeneous malignancy, often characterized by complex genomic alterations that drive tumor progression and therapy resistance. In this paper, we report a novel de novo BRCA2 germline variant NM_000059.3:c.(8693_8695delinsGT) associated with early-onset OC that featured two regions with differential MMR (Mismatch Repair) gene expression. To date, only six cases of de novo BRCA2 variants have been reported, none of which were associated with early-onset high-grade serous OC. The immunohistochemical analysis of MMR genes revealed two distinct tumor areas, separated by a clear topographic boundary, with the heterogeneous expression of MLH1 and PMS2 proteins. Seventy-five percent of the tumor tissue showed positivity, while the remaining 25% exhibited a complete absence of expression, underscoring the spatial variability in MMR gene expression within the tumor. Integrated comparative spatial genomic profiling identified several tumor features associated with the genetic variant as regions of loss of heterozygosity (LOH) that involved BRCA2 and MLH1 genes, along with a significantly higher mutational tumor burden in the tumor area that lacked MLH1 and PMS2 expression, indicating its further molecular evolution. The following variants were acquired: c.6572C>T in NOTCH2, c.1852C>T in BCL6, c.191A>T in INHBA, c.749C>T in CUX1, c.898C>A in FANCG, and c.1712G>C in KDM6A. Integrated comparative spatial proteomic profiles revealed defects in the DNA repair pathways, as well as significant alterations in the extracellular matrix (ECM). The differential expression of proteins involved in DNA repair, particularly those associated with MMR and Base Excision Repair (BER), highlights the critical role of defective repair mechanisms in driving genomic instability. Furthermore, ECM components, such as collagen isoforms, Fibrillin-1, EMILIN-1, Prolargin, and Lumican, were found to be highly expressed in the MLH1/PMS2-deficient tumor area, suggesting a connection between DNA repair deficiencies, ECM remodeling, and tumor progression. Thus, the identification of the BRCA2 variant sheds light on the poorly understood interplay between DNA repair deficiencies and ECM remodeling in OC, providing new insights into their dual role in shaping tumor evolution and suggesting potential targets for novel therapeutic strategies.
Compositional changes of the lung extracellular matrix in acute respiratory distress syndromeFan, Moser, Jongman
et alAm J Physiol Cell Physiol (2025)
Abstract: Acute respiratory distress syndrome (ARDS) is pathologically characterized by diffuse alveolar damage (DAD) and is associated with high morbidity and mortality rates. Remodeling of the extracellular matrix (ECM), which is pivotal for tissue repair and organ recovery, may play a large role in persistent ARDS. This study investigated the compositional changes in the ECM in different DAD stages in ARDS. Paraffin-embedded lung sections collected during autopsy or from post-transplant lungs were obtained from patients with ARDS (n=28) admitted to the University Medical Center Groningen between 2010-2020. Sections were stained histochemically, and immunohistochemically for collagen III α1 chain (Col IIIa1), IV α3 chain (Col IVa3), VI α1 chain (Col VIa1), periostin (PSTN), lumican (LUM), and fibronectin (FN). The sections were divided into 118 regions based on DAD stages (54 early vs 64 advanced). The differences in the expression of selected proteins were compared between DAD stages or across ARDS duration (<7days, 7-14days, >14days). The fiber pattern of Col VIa1 was analyzed using CellProfiler. Higher tissue density, lower proportional areas of Col IIIa1, Col IVa3, and LUM, and more concentrated Col VIa1 fibers were observed in the advanced DAD stage than in the early DAD stage. Areas with higher proportions of total collagen and FN, and lower proportional areas of Col IIIa1, Col IVa3, and LUM were detected in lung regions from patients with ARDS >14days duration. These findings revealed proportional changes in ECM components, strongly suggesting that dynamic changes in ECM proteins play a role in pathophysiology of ARDS during progression.
The relationship between serum Lumican levels and myocardial fibrosis in patients with hypertrophic cardiomyopathyHancıoğlu, Özcan, Dönmez
et alBiomark Med (2025) 19 (6), 187-195
Abstract: Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young individuals. Lumican, is an indicator of fibrosis. We aimed to evaluate the relation between serum Lumican levels and presence and extent of myocardial fibrosis in HCM.The patients diagnosed with HCM between June 2022 and March 2023 were enrolled consecutively in this prospective study. Age and gender-matched healthy individuals formed control group. Two groups were generated according to extent of late gadolinium enhancement (LGE) in HCM patients.A total of 114 patients were enrolled. Serum Lumican, NT-proBNP levels and maximum wall thickness were revealed as independent risk factors associated with LGE. A cut-off value of 9.06 for Lumican was associated with 67.8% sensitivity and 65.5% specificity in prediction of LGE.Myocardial fibrosis is one of the important mechanisms in HCM pathophysiology. LGE on cardiac magnetic resonance imaging allows comprehensive evaluation of myocardial fibrosis, the support of diagnosis with a biomarker would be beneficial in clinical practice. Our study revealed that serum Lumican level is an independent predictor of severe LGE in HCM patients. Further studies with larger patient numbers may clarify the importance of Lumican in HCM pathophysiology.
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