关键词： Bone morphogenetic protein 2   Bone regeneration   Cell differentiation   Mesenchymal stem cells   Multivariate Analysis   Periodontal ligament  

摘要： Understanding the molecular mechanisms regulating osteo/cementogenic differentiation is critical for optimizing cell-based strategies in periodontal regeneration. This study employed multivariate statistical modeling to investigate, in vitro, the interaction between bone morphogenetic protein 2 (BMP2) and asporin (ASPN) in human periodontal ligament stem cells (hPDLSCs) and its impact on mineralization potential. Four primary hPDLSC populations—two with high osteo/cementogenic potential (HOP) and two with low potential (LOP)—were cultured under standard (SDM) and osteo/cementogenic (OM) conditions. Mineralization was assessed using Alizarin Red Staining (AR-S) and alkaline phosphatase (ALP) activity, while gene expression of ASPN, BMP2, osteocalcin (OCN), and runt-related transcription factor 2 (RUNX2) was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). BMP2 protein levels were measured using the Luminex system. Data analysis incorporated Principal Component Analysis (PCA), Linear Discriminant Analysis (LDA), Pearson correlations, correlation networks, and multivariate regression models in RStudio. HOP cells exhibited higher mineralization and BMP2 expression compared to LOP cells (p < 0.05). ASPN negatively correlated with BMP2 expression and mineralization, particularly in LOP cells (p < 0.01), reinforcing its inhibitory role. Multivariate modeling identified BMP2 as a key positive regulator of osteo/cementogenesis, while ASPN emerged as a significant inhibitory factor (p < 0.001). This study highlights the potential of multivariate models as powerful tools for uncovering molecular interactions and identifying novel therapeutic targets, paving the way for advancements in periodontal regeneration and cell-based therapies. Created in BioRender. Sacramento, C. (2025).

摘要： Fibrosis is an important feature of adipose tissue in obese individuals; nevertheless, roles of obesity-associated extracellular matrix (ECM) deposition in breast cancer progression largely remain elusive. Here, we show that expression of Hsp47, a chaperone protein involving collagen secretion, is induced in adipose tissue from obese humans and mice. Adipocyte-specific Hsp47 deletion (Adi-KO) suppresses the high-fat diet (HFD)-induced obesity and mammary tumor progression, accompanied by a reduction in ECM deposition. Matrisome analyses lead to the identification of asporin as a new target of Hsp47 in adipose tissue. Co-immunoprecipitation results confirm that the recruitment of Hsp47 enhances asporin secretion in adipocytes. We further show that knockout of asporin suppresses HFD-induced mammary tumor growth, while exogenous of asporin partially rescues tumor growth in the decellularized mammary gland derived from Hsp47 Adi-KO mice. These results indicate that asporin at least partially mediates Hsp47 function in HFD-associated tumor progression. Digital spatial profiling (DSP) analyses show that Hsp47 depletion significantly increases the accumulation of CD8 T cells in tumor and tumor-associated adipose tissues. These results implicate that Hsp47, along with-it mediated ECM deposition, suppresses the anti-tumor immunity under HFD conditions. These findings reveal Hsp47 as a novel target for mitigating obesity-associated breast cancer progression.

关键词： ASPN   Docetaxel chemoresistance   Metastasis   Prostate cancer   Wnt/β-catenin signaling  

摘要： Aims: Prostate cancer (PCa) remains a significant challenge in oncology due to high rates of drug resistance following standard treatment with docetaxel-based chemotherapy. Asporin (ASPN) has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. Studies indicated that abnormal activation of the Wnt/β-catenin signaling pathway is prevalent in PCa. This study investigated the important role of ASPN in regulating Wnt/β-catenin signaling pathway in docetaxel resistance and metastasis of PCa. Methods: The impacts of ASPN on the docetaxel chemoresistance and metastasis of PCa cells were investigated in vitro and in vivo assays. Lastly, the underlying mechanism of ASPN was revealed by Western blot, protein immunocoprecipitation, Immunofluorescence, Immunohistochemical staining, liquid chromatography-mass spectrometry, and rescue experiments. Results: In present study, we reported that ASPN is highly expressed in PCa cells and tissues. Functional and molecular analyses showed that ASPN is activated by TGFβ and interacts with STMN1. ASPN increases the expression of β-catenin and promotes its nuclear accumulation by mediating the activation of the Wnt/β-catenin signaling pathway, thereby enhancing the stemness and epithelial-mesenchymal transition (EMT) of PCa cells, ultimately facilitating the docetaxel resistance and metastasis of PCa cells. Conclusions: Our findings identify ASPN as a novel upstream regulatory factor of Wnt/β-catenin signaling pathway, suggesting that targeting the ASPN/STMN1/β-catenin axis could be a promising strategy for PCa intervention. © 2025 Elsevier Ltd

关键词： fetal-like cellular reprogramming   regeneration   aging   mesenchyme   asporin   intestinal stem cells   extracellular matrix   TGF-β signaling   CD44   Wnt signaling  

摘要： Mesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in epithelial conversion into a fetal-like regenerative state after damage is not known. We modeled epithelial regeneration by culturing intestinal epithelium on decellularized small intestinal scaffolds (iECM) and identify asporin (Aspn), an ECM-bound proteoglycan, as a critical mediator of epithelial fetal-like reprogramming. After damage, transient increase in Aspn expression by the pericryptal fibroblasts induces epithelial transforming growth factor b (TGF-b)-signaling via CD44 and promotes timely epithelial reprogramming. Temporal control of Aspn is lost in old mice, and after damage, the persistently high level of Aspn stagnates epithelium in the regenerative state. Increase in Wnt signaling can resolve the stagnated regenerative program of the old epithelium, promoting restoration of tissue function. In summary, we establish a platform for modeling epithelial injury responses ex vivo and show that the mesenchymal Aspn-producing niche modulates tissue repair by regulating epithelial fetal-like reprogramming.

关键词： 冠心病   慢性心力衰竭   松弛素-2   Asporin   磷脂酰肌醇蛋白聚糖   病情严重程度  

摘要： 目的探究冠心病(CHD)合并慢性心力衰竭(CHF)患者血清松弛素-2(relaxin-2)、Asporin、磷脂酰肌醇蛋白聚糖(glypican-4)水平变化及其与病情严重程度的相关性。方法选取2021年6月至2023年9月在四川省南充市中医医院确诊为CHD合并CHF患者92例作为CHD-CHF组,另选取同期在四川省南充市中医医院进行诊治的92例CHD患者作为CHD组。根据纽约心脏病协会心功能分级将CHD合并CHF患者分为心功能Ⅰ~Ⅱ级组(24例),心功能Ⅲ级组(41例),心功能Ⅳ组(27例)。采用酶联免疫吸附试验检测血清relaxin-2、Asporin、glypican-4水平。采用Spearman相关分析血清relaxin-2、Asporin、glypican-4水平与心功能分级的相关性;采用Pearson相关分析血清relaxin-2、Asporin、glypican-4水平与心功能相关指标的相关性。绘制受试者工作特征(ROC)曲线评估血清relaxin-2、Asporin、glypican-4单独及联合检测对CHD合并CHF病情严重程度的诊断价值。结果CHD-CHF组血清relaxin-2水平低于CHD组,Asporin、glypican-4水平均高于CHD组,差异均有统计学意义(P<0.05)。心功能Ⅳ级组、心功能Ⅲ级组、心功能Ⅰ~Ⅱ级组血清relaxin-2依次升高,Asporin、glypican-4水平均依次降低,差异均有统计学意义(P<0.05)。心功能Ⅳ级组、心功能Ⅲ级组、心功能Ⅰ~Ⅱ级组左室舒张末期内径(LVEDD)、左室前后径(LAD)均依次降低,左室射血分数(LVEF),左室相对室壁厚度(RWT)均依次升高,差异均有统计学意义(P<0.05)。Spearman相关分析结果显示,血清relaxin-2水平与心功能分级呈负相关(P<0.05),血清Asporin、glypican-4水平与心功能分级均呈正相关(P<0.05)。Pearson相关分析结果显示,血清relaxin-2水平与LVEDD、LAD均呈负相关(P<0.05),与LVEF、RWT均呈正相关(P<0.05);血清Asporin、glypican-4水平与心功能分级、LVEDD、LAD均呈正相关(P<0.05),与LVEF、RWT均呈负相关(P<0.05)。ROC曲线分析结果显示,血清relaxin-2、Asporin、glypican-4单独及联合检测诊断CHD合并CHF病情严重程度的曲线下面积(AUC)分别为0.757、0.771、0.776、0.845,3项联合诊断的AUC大于3项单独诊断的AUC(Z=2.329、2.119、2.068,P<0.05)。结论CHD合并CHF患者血清relaxin-2水平降低,Asporin、glypican-4水平升高,与患者心功能分级显著相关,可作为临床评估CHD合并CHF患者病情严重程度的生物指标。

关键词： PRELP   Proteoglycan gene signature   asporin   decorin   podocan   syndecan-1  

摘要： Solid tumors present a formidable challenge in oncology, necessitating innovative approaches to improve therapeutic outcomes. Proteoglycans, multifaceted molecules within the tumor microenvironment, have garnered attention due to their diverse roles in cancer progression. Their unique ability to interact with specific membrane receptors, growth factors, and cytokines provides a promising avenue for the development of recombinant proteoglycan-based therapies that could enhance the precision and efficacy of cancer treatment. In this study, we performed a comprehensive analysis of the proteoglycan gene landscape in human breast carcinomas. Leveraging the available wealth of genomic and clinical data regarding gene expression in breast carcinoma and using a machine learning model, we identified a unique gene expression signature composed of five proteoglycans differentially modulated in the tumor tissue: Syndecan-1 and asporin (upregulated) and decorin, PRELP and podocan (downregulated). Additional query of the breast carcinoma data revealed that serglycin, previously shown to be increased in breast carcinoma patients and mouse models and to correlate with a poor prognosis, was indeed decreased in the vast majority of breast cancer patients and its levels inversely correlated with tumor progression and invasion. This proteoglycan gene signature could provide novel diagnostic capabilities in breast cancer biology and highlights the need for further utilization of publicly available datasets for the clinical validation of preclinical experimental results.

关键词： Randall's plaque   Carotid atherosclerosis   Bioinformatics   Immune infiltration   Osteoblast differentiation  

摘要： Increasing evidence suggested nephrolithiasis has a close linkage with carotid atherosclerosis (CAS), with Randall's plaque (RP) being a precursor to kidney stones. Our study aimed to examine the crosstalk genes and potential molecular mechanisms between RP and CAS. We obtained microarray data for RP and CAS from the Gene Expression Omnibus (GEO) and used weighted gene co-expression network analysis (WGCNA) and differential gene expression (DEG) analysis to identify shared genes. By integrating WGCNA and DEG analysis, Asporin (ASPN) was identified as the key gene connecting RP and CAS, with its diagnostic potential assessed via a receiver operating characteristic (ROC) curve. Immune infiltration studies showed a significant correlation between ASPN and various immune cells in RP and CAS. ASPN was found to be less expressed in RP and CAS tissues compared to normal tissues, as confirmed by immunohistochemistry (IHC) and quantitative reverse-transcription PCR (qRT-PCR). The rat model confirmed the human tissue findings. ASPN can elucidate the shared pathogenic mechanisms underlying the two conditions, including immune response and osteoblast differentiation.

关键词： 椎间盘   再生   椎间盘退变   分子治疗   基因治疗   脊柱退行性疾病   生物材料治疗  

摘要： 椎间盘退变(IVDD)的传统治疗方法以对症治疗为主,并不能恢复椎间盘的生理结构与功能。因此,越来越多学者开始关注再生医学及其衍生治疗方法在IVDD中的应用。从组织学角度,早期IVDD表现为细胞外基质(ECM)合成与分解代谢失衡,细胞数量变化不大、组织结构较为完整,使用外源性分子或基因治疗进行干预,可实现ECM再生;随着IVDD的进展,细胞数量逐渐减少,此时补充健康细胞并促进ECM合成是治疗的关键;疾病进展到后期,表现为细胞数量明显减少,组织结构紊乱,可使用具有一定机械强度、可负载细胞的生物材料补充ECM与健康细胞,进而实现IVDD的修复。分子、细胞、基因治疗,联合新型生物材料的应用,通过相互弥补短板、协同放大治疗效果的方式治疗IVDD,是未来IVDD修复的发展方向。

关键词： Temporomandibular joint   Osteoarthritis   Smad proteins   Mandibular condyle   Mechanical stress  

摘要： Objectives: The present study aimed to elucidate the pathogenesis of temporomandibular joint (TMJ) osteoarthritis (TMJ-OA) in a mouse model. We investigated morphological and histological changes in the head of mandible cartilage and early immunohistochemical (IHC) changes in transforming growth factor (TGF)-(3, phosphorylated Smad-2/3 (p-Smad2/3), a TGF-(3 signaling molecule, and asporin. Methods: TMJ-OA was induced in a mouse model through unilateral partial discectomy. Micro-computed tomography (micro-CT) and safranin-O staining were performed to morphologically and histologically evaluate the degeneration of the head of mandible caused by TMJ-OA. IHC staining for TGF-(3, p-Smad2/3, and asporin was performed to evaluate the changes in protein expression. Results: In the experimental group, three-dimensional (3D) morphometry revealed an enlarged head of mandible and safranin-O staining showed degeneration of cartilage tissue in the early stages of TMJ-OA compared to the control group. IHC staining revealed that TGF-(3, p-Smad2/3, and asporin expression increased in the head of mandible cartilage before the degeneration of cartilage tissue, and subsequently decreased for a short period. Conclusion: The findings suggested a negative feedback relationship between the expression of asporin and the TGF-(3/Smad transduction pathway, which may be involved in the degeneration of the head of mandible in the early stages of TMJ-OA. Asporin is a potential biomarker of the early stages of TMJ-OA, which ultimately leads to the irreversible degeneration of TMJ tissues.