Microfibrillar-associated Protein Research Articles

Microfibrillar-associated protein 4 as a predictive biomarker of treatment response in patients with chronic inflammatory diseases initiating biologics: secondary analyses based on the prospective BELIEVE cohort study.

Currently, there are no reliable biomarkers for predicting treatment response in chronic inflammatory diseases (CIDs). To determine whether serum microfibrillar-associated protein 4 (MFAP4) levels can predict the treatment response to biological therapy in patients with CIDs. The BELIEVE study was originally designed as a prospective, multi-center cohort study of 233 patients with either rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, Crohn's disease, or ulcerative colitis, initiating treatment with a biologic agent (or switching to another). Clinical assessment and blood sample collection were performed at baseline and 14-16 weeks after treatment initiation. The primary analyses included participants with available blood samples at baseline; missing data were handled as non-responders. The patients were stratified into the upper tertile of serum MFAP4 (High MFAP4) versus a combined category of middle and lower tertiles (Other MFAP4). The primary outcome was the proportion of patients with clinical response to biologic therapy after 14-16 weeks. 211 patients were included in the primary analysis population. The mean age was 43.7 (SD: 14.8) years, and 120 (59%) were female. Positive treatment response was observed in 41 (59%) and 69 (49%) for High MFAP4 and Other MFAP4, respectively. When adjusting for pre-specified variables (CID, age, sex, smoking status, and BMI), the adjusted OR was 2.28 (95% CI: 1.07 to 4.85) for a positive treatment outcome in the High MFAP4 group. A high MFAP4 status before initiating biological treatment is associated with a positive clinical response, when adjusting for confounding factors.

Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-πinteraction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model.

Corrigendum: Microfibrillar-associated protein 4 interaction with inflammation and clinical characteristics in neuropsychiatric systemic lupus erythematosus

Corrigendum: Microfibrillar-associated protein 4 interaction with inflammation and clinical characteristics in neuropsychiatric systemic lupus erythematosus

Microfibrillar-associated protein 4 interaction with inflammation and clinical characteristics in neuropsychiatric systemic lupus erythematosus

ObjectivesCentral nervous system (CNS) proteins such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are released into the body fluids following CNS injury. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein. Recently we reported expression of MFAP4 in CNS and alteration of levels in patients with acute neuroinflammation. We aimed to determine the levels of MFAP4 in a predominantly population-based cohort of systemic lupus erythematosus (SLE) patients, including neuropsychiatric SLE (NPSLE), and to evaluate MFAP4 as a marker of inflammation.MethodsIn total 208 SLE patients, 44 of those with NPSLE, and 50 age- and sex-matched healthy controls (HC) were recruited. MFAP4 was measured using AlphaLISA immunoassay. NfL, GFAP and a panel of inflammatory mediators were measured using Simoa HD-1 digital ELISA or a Luminex 200 instrument.ResultsMFAP4 levels were elevated in patients with NPSLE compared to patients with non-NPSLE (p = 0.031), more prominent in NPSLE patients with CNS involvement (p = 0.017). NfL and GFAP were higher in the total SLE cohort (p < 0.001, p < 0.001, respectively) as well as NPSLE subgroup (p < 0.001, p < 0.001, respectively), and in the subgroup of NPSLE patients with CNS involvement (p < 0.001, p < 0.001), compared to HC. NfL and GFAP levels correlated positively with MFAP4 in the NPSLE as well as the non-NPSLE subgroup (ρ = 0.44, p = 0.003, ρ = 0.25, p = 0.004). VEGF was reduced in NPSLE patients compared to HC (p = 0.015). MMP-9 was elevated in NPSLE compared to non-NPSLE (p = 0.048). Inflammatory markers including IFN-α, IL-6, IL-10 and TNF-α, were elevated in the NPSLE group compared to HC (p < 0.001, p = 0.0026, p = 0.042, p = 0.007, respectively). In NPSLE patients the levels of MFAP4 correlated with TNF-α (p = 0.016) and IL-17 (p = 0.0044) and with markers of blood brain barrier (BBB) disruption MMP-7 (p = 0.005) and VEGF (p < 0.001). In NPSLE patients with CNS manifestations MMP-3 and VEGF correlated with MFAP4 (p = 0.011, p = 0.0004, respectively).ConclusionLevels of MFAP4 correlated with NfL, GFAP and proinflammatory cytokines and in NPSLE additionally with markers of BBB disruption, suggesting that MFAP4 is a marker of inflammation and vascular re-organization. Correlation of NfL and GFAP with MFAP4 may reflect CNS tissue damage.

Deciphering peri-implantitis: Unraveling signature genes and immune cell associations through bioinformatics and machine learning.

Early diagnosis of peri-implantitis (PI) is crucial to understand its pathological progression and prevention. This study is committed to investigating the signature genes, relevant signaling pathways and their associations with immune cells in PI. We analyzed differentially expressed genes (DEGs) from a PI dataset in the gene expression omnibus database. Functional enrichment analysis was conducted for these DEGs. Weighted Gene Co-expression Network Analysis was used to identify specific modules. Least absolute shrinkage and selection operator and support vector machine recursive feature elimination were ultimately applied to identify the signature genes. These genes were subsequently validated in an external dataset. And the immune cells infiltration was classified using CIBERSORT. A total of 180 DEGs were screened from GSE33774. Weighted Gene Co-expression Network Analysis revealed a significant association between the MEturquoise module and PI (cor = 0.6, P < .0001). Least absolute shrinkage and selection operator and support vector machine recursive feature elimination algorithms were applied to select the signature genes, containing myeloid-epithelial-reproductive tyrosine kinase, microfibrillar-associated protein 5, membrane-spanning 4A 4A, tribbles homolog 1. In the validation on the external dataset GSE106090, all these genes achieved area under curve values exceeding 0.95. GSEA analysis showed that these genes were correlated with the NOD-like receptor signaling pathway, metabolism of xenobiotics by cytochrome P450, and arachidonic acid metabolism. CIBERSORT revealed elevated levels of macrophage M2 and activated mast cells in PI. This study provides novel insights into understanding the molecular mechanisms of PI and contributes to advancements in its early diagnosis and prevention.

MFAP4-Deficiency Aggravates Age-Induced Changes in Resistance Artery Structure, While Ameliorating Hypertension.

Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) has previously been observed as protective against aberrant arterial remodeling. We hypothesized that MFAP4-deficiency would reduce age- and hypertension-dependent arterial changes in extracellular matrix composition and stiffening. Mesenteric arteries were isolated from old (20-23 months) littermate Mfap4+/+ and Mfap4-/- mice, and 2-photon excitation microscopy imaging was used to quantify elastin and collagen volumes and dimensions in the vascular wall. Ten-week-old littermate Mfap4+/+ and Mfap4-/- mice were subjected to 20 days of continuous Ang II (angiotensin II) infusion and hypertension was monitored using invasive blood pressure measurements. Arterial stiffness, responses to vascular constrictors, and myogenic tone were monitored using wire- or pressure-myography. Collagen contents were assessed by Western blotting. MFAP4-deficiency significantly increased collagen volume and elastin fragmentation in aged mesenteric arteries without affecting arterial stiffness. MFAP4-deficient mice exhibited reduced diastolic pressure in Ang II-induced hypertension. There was no significant effect of MFAP4-deficiency on mesenteric artery structural remodeling or myogenic tone, although collagen content in mesenteric arteries was tendentially increased in hypertensive Mfap4+/+ mice relative to Mfap4-/- mice. Increased efficacy of vasoconstrictors (phenylephrine, thromboxane) and reduced stiffness were observed in Ang II-treated Mfap4-/- mouse mesenteric arteries in ex vivo myography recordings. MFAP4-deficiency reduces the elastin/collagen ratio in the aging resistance artery without affecting arterial stiffness. In contrast, MFAP4-deficiency reduces the stiffness of resistance arteries and ameliorates Ang II-induced hypertension.

Extracellular matrix analysis of fibrosis: A step towards tissue engineering for urethral stricture disease.

The urogenital tract is a target for many congenital and acquired diseases, both benign and oncogenic. In males, the urethra that transports urine and semen can be obstructed by a fibrotic disease called urethral stricture disease (USD). In severe USD, the whole organ including the vascular embedding, the corpus spongiosum (CS), is affected. Recurrent or severe USD is treated by reconstructive surgery. Tissue engineering may improve the outcome of urethral reconstruction in patients with complicated USD. Currently in urethral reconstruction only the epithelial layer is replaced, no substitution for the CS is provided, while the CS is important for mechanical support and vascularization. To develop a tissue engineering strategy for the CS, it is necessary to know the protein composition of the CS. As the extracellular matrix (ECM) plays an important role in the formation of fibrosis, we analyzed the distribution and localization of ECM components in human healthy and fibrotic CS tissue using immunohistology. The morphology of components of the elastic network were affected in USD. After decellularization a clear enrichment of proteins belonging to the ECM was found. In the proteomic analysis collagens COL15A1 and COL4A2 as well as inter-alpha-trypsin inhibitor ITIH4 were upregulated in fibrotic samples. The glycoproteins Periostin (POSTN), Microfibrillar-associated protein 5 (MFAP5) and EMILIN2 are downregulated in fibrotic tissue. To our knowledge this is the first proteomic study of ECM proteins of the CS in healthy and in USD. With these results a regenerating approach for tissue engineered CS can be developed, including relevant ECM proteins that reduce fibrosis and promote healthy healing in urethral reconstructive surgery.

Role and new insights of microfibrillar-associated protein 4 in fibrotic diseases.

Fibrosis is one of the most worrisome complications of chronic inflammatory diseases, leading to tissue damage, organ failure, and ultimately, death. The most notable pathological characteristic of fibrosis is the excessive accumulation of extracellular matrix (ECM) components such as collagen and fibronectin adjacent to foci of inflammation or damage. The human microfibrillar-associated protein 4 (MFAP4), an important member of the superfamily of fibrinogen-related proteins, is considered to have an extremely important role in ECM transformation of fibrogenesis. This review summarizes the structure, characteristics, and physiological functions of MFAP4 and the importance of MFAP4 in various fibrotic diseases. Meanwhile, we elaborated the underlying actions and mechanisms of MFAP4 in the development of fibrosis, suggesting that a better understand of MFAP4 broadens novel perspective for early screening, diagnosis, prognostic risk assessment, and treatment of fibrotic diseases.

Circulating biomarkers associated with aortic diameter in male and female thoracic aortic disease patients: a cross-sectional study

Abstract Background As thoracic aortic disease (TAD) is generally asymptomatic, biomarkers are needed to provide insight into early progression. Purpose We aimed to examine the association between circulating blood biomarkers and the maximal thoracic aortic diameter (TADmax). Methods In this cross-sectional study, consecutive adult patients with a thoracic aortic diameter ≥ 40 mm and/or genetically proven hereditary TAD (HTAD) visiting our specialized outpatient clinic between 2017-2020, were prospectively included. Venous blood sampling and computed tomography angiography and/or transthoracic echocardiography of the aorta were performed. Linear regression analyses were performed and estimates were presented as mean difference in TADmax in mm per doubling of standardized biomarker level. Results In total 158 patients were included (median age 61 [50.3-68.8] years, 37.3% female). HTAD diagnosis was confirmed in 36/158 (22.7%) patients. TADmax was 43.9 ± 5.2 mm in males versus 41.9 ± 5.1 in females, p=0.030. In unadjusted analysis, significant associations with TADmax were found for interleukin-6 (IL-6) (1.15 (95%CI 0.33-1.96), p=0.006), growth-differentiation factor-15 (GDF-15) (1.01 (95%CI 0.18-1.84), p=0.018), microfibrillar-associated protein 4 (MFAP4) (-0.88 (95%CI -1.71—0.05), p=0.039) and triiodothyronine (T3) (-2.00 (95%CI -3.01—0.99), p&amp;lt;0.001). The association fherer MFAP4 was stronger in females (p=0.020) and for homocysteine an inverse association was observed when compared to males (p=0.008). When adjusted for age, sex, hyperlipidaemia and HTAD, total cholesterol (1.10 (95%CI 0.27-1.93), p=0.010) and T3 (-1.20 (95%CI -2.14—0.25), p=0.014) were significantly associated with TADmax. Conclusions Circulating biomarkers indicative of inflammation, lipid metabolism and thyroid function, might be associated with thoracic aortic disease severity. Possible distinct biomarker patterns for males and females warrant further investigation.Figure 1Table 1

Microfibrillar-associated protein 4 as a potential marker of acute relapse in inflammatory demyelinating diseases of the central nervous system: Pathological and clinical aspects

Background: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). Objectives: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. Methods: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) (n = 3), progressive MS (n = 3), neuromyelitis optica spectrum disorder (NMOSD) (n = 2), and controls (n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). Results: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. (p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON (n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = −0.41, p = 0.017). Conclusion: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.

The construction and validation of ECM-related prognosis model in laryngeal squamous cell carcinoma

BackgroundLaryngeal squamous cell carcinoma (LSCC) is a kind of common and aggressive tumor with high mortality. The application of molecular biomarkers is useful for the early diagnosis and treatment of LSCC. MethodsThe expression and clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Principal components analysis (PCA) was used to discriminate between LSCC and normal samples. The hub genes were screened out through univariate and multivariate cox analyses. The Kaplan-Meier (K-M) and receiver operating characteristic (ROC) curve was used to validate the predictive performance. The single sample gene set enrichment analysis (ssGSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to determine the enrichment function. Protein-Protein Interaction (PPI) network was constructed in STRING. The immune analysis was performed by ESTIMATE, IPS and xCELL. The drug sensitivity was identified with GSCA database. ResultsWe identified that 47 extracellular matrix (ECM) genes were differentially expressed in LSCC compared with normal group. Univariate and multivariate cox analysis determined that leucine-rich glioma-inactivated 4 (LGI4), matrilin 4 (MATN4), microfibrillar-associated protein 2 (MFAP2) and fibrinogen like 2 (FGL2) were closely related to the disease free survival (DSS) of LSCC. ROC curve determined that the risk model has a good predictive performance. PPI network showed the top 100 genes with high correlation of hub genes. The ssGSEA, GO and KEGG enrichment analyses determined that immune response was significantly involved in the development of LSCC. Immune infiltration analysis showed that most immune cells and immune checkpoints were inhibited in high risk score group. Drug sensitivity analysis showed that MATN4, FGL2 and LGI4 were negatively related to various drugs, while MFAP2 was positively related to many drugs. ConclusionWe established a risk model constructed with four ECM-related genes, which could effectively predict the prognosis of LSCC.

MFAP2 promotes the progression of oral squamous cell carcinoma by activating the Wnt/β-catenin signaling pathway through autophagy.

Microfibrillar-associated protein 2 (MFAP2) is a small glycoprotein that is involved in vascular development and metabolic disease. The present study aims to explore the regulatory role of MFAP2 in the development and progression of oral squamous cell carcinoma (OSCC), including the underlying mechanisms. MFAP2 expression and its association with the progression of OSCC are explored using bioinformatics. MFAP2 expression in OSCC tissues is detected by immunohistochemical staining. SCC15 cell migration, invasion, apoptosis, proliferation, and viability are detected by wound healing, Transwell, flow cytometry, colony formation, and cell counting kit-8 assays. An in vivo experiment is used to detect tumor formation. Western blot analysis is used to determine MFAP2's regulatory role in autophagy and the Wnt/β-catenin signaling pathway. MFAP2 is highly expressed in SCC15 cells and OSCC tissues, which correlates positively with the poor prognosis of patients with OSCCs. Functionally, MFAP2 promotes oncogenic autophagy to increase cell invasion, migration, and proliferation but inhibits apoptosis in SCC15 cells and promotes tumor growth in vivo. Mechanistically, MFAP2 upregulates autophagy and Wnt/β-catenin signaling to stimulate OSCC development. Intriguingly, regulation of Wnt/β-catenin signaling dependent on autophagy contributes to the malignant behaviors of SCC15 cells. MFAP2 could serve as a novel biomarker for OSCC and could affect OSCC tumorigenesis and development via autophagic regulation of Wnt/β-catenin signaling.

Tricellulin, α-Catenin and Microfibrillar-Associated Protein 5 Exhibit Concomitantly Altered Immunosignals along with Vascular, Extracellular and Cytoskeletal Elements after Experimental Focal Cerebral Ischemia.

Along with initiatives to understand the pathophysiology of stroke in detail and to identify neuroprotective targets, cell-stabilizing elements have gained increasing attention. Although cell culture experiments have indicated that tricellulin, α-catenin and microfibrillar-associated protein 5 (MFAP5) contribute to cellular integrity, these elements have not yet been investigated in the ischemic brain. Applying immunofluorescence labeling, this study explored tricellulin, MFAP5 and α-catenin in non-ischemic and ischemic brain areas of mice (24, 4 h of ischemia) and rats (4 h of ischemia), along with collagen IV and fibronectin as vascular and extracellular matrix constituents and microtubule-associated protein 2 (MAP2) and neurofilament light chain (NF-L) as cytoskeletal elements. Immunosignals of tricellulin and notably MFAP5 partially appeared in a fiber-like pattern, and α-catenin appeared more in a dotted pattern. Regional associations with vascular and extracellular constituents were found for tricellulin and α-catenin, particularly in ischemic areas. Due to ischemia, signals of tricellulin, MFAP5 and α-catenin decreased concomitantly with MAP2 and NF-L, whereby MFAP5 provided the most sensitive reaction. For the first time, this study demonstrated ischemia-related alterations in tricellulin, MFAP5 and α-catenin along with the vasculature, extracellular matrix and cytoskeleton. Confirmatory studies are needed, also exploring their role in cellular integrity and the potential for neuroprotective approaches in stroke.

TWIST1 Promotes Colorectal Carcinoma Stemness and Oxaliplatin Resistance by Activating Microfibrillar-Associated Protein 2.

Colorectal carcinoma (CRC) is a fatal disease and ranks as the third most prevalent cancer globally. Stemness and drug resistance are the main causes of tumor recurrence in CRC. This study attempted to probe the impact of TWIST1 on CRC stemness and resistance to oxaliplatin and to uncover the underlying regulatory mechanism of TWIST1. mRNA expression data from The Cancer Genome Atlas-CRC were subjected to differential analysis. The target gene in the study was determined according to literature citation. ChIPBase was utilized to predict likely targets downstream of the target gene. Pearson was employed for correlation analysis. Quantitative real-time polymerase chain reaction was used to assess TWIST1 and microfibrillar-associated protein 2 (MFAP2) levels in CRC and normal cells. The cell viability was assayed through cell counting kit-8 and IC50 value was calculated. Flow cytometry was applied to assay the cell apoptosis. Apoptosis assays were applied to evaluate cell apoptosis. CD44, CD133, SOX-2, ERCC1, GST-π, MRP, and P-gp protein expression levels were assayed by Western blot. The targeting relationship between TWIST1 and MFAP2 was ascertained through dual-luciferase and chromatin immunoprecipitation (ChIP). TWIST1 possessed high expression in CRC tissue and cells. TWIST1 knockdown strikingly promoted cell apoptosis and reduced cell stemness and cell resistance to oxaliplatin. Bioinformatics prediction suggested that MFAP2, which was overexpressed in CRC tissue and cells, was the target gene downstream of TWIST1. Dual-luciferase and ChIP assays validated that there was a targeting relationship between TWIST1 and MFAP2. The results of the rescue assay demonstrated that TWIST1 fostered CRC stemness and oxaliplatin resistance by activating MFAP2 expression. These outcomes implied that TWIST1 enhanced CRC stemness and oxaliplatin resistance by activating the transcription of MFAP2. Therefore, TWIST1/MFAP2 axis possibly indicated a mechanism for regulating tumor progression.

Circulating biomarkers associated with aortic diameter in male and female patients with thoracic aortic disease: a cross-sectional study

ObjectiveAs thoracic aortic disease (TAD) is generally asymptomatic, biomarkers are needed to provide insight into early progression. We aimed to examine the association between circulating blood biomarkers and the maximal...

Matrisome gene-based subclassification of patients with liver fibrosis identifies clinical and molecular heterogeneities.

Excessive deposition and crosslinking of extracellular matrix increases liver density and stiffness, promotes fibrogenesis, and increases resistance to fibrinolysis. An emerging therapeutic opportunity in liver fibrosis is to target the composition of the extracellular matrix or block pathogenic communication with surrounding cells. However, the type and extent of extracellular changes triggering liver fibrosis depend on the underlying etiology. Our aim was to unveil matrisome genes not dependent on etiology, which are clinically relevant to liver fibrosis. We used transcriptomic profiles from liver fibrosis cases of different etiologies to identify and validate liver fibrosis-specific matrisome genes (LFMGs) and their clinical and biological relevance. Dysregulation patterns and cellular landscapes of LFMGs were further explored in mouse models of liver fibrosis progression and regression by bulk and single-cell RNA sequencing. We identified 35 LFMGs, independent of etiology, representing an LFMG signature defining liver fibrosis. Expression of the LFMG signature depended on histological severity and was reduced in regressive livers. Patients with liver fibrosis, even with identical pathological scores, could be subclassified into LFMG Low and LFMG High , with distinguishable clinical, cellular, and molecular features. Single-cell RNA sequencing revealed that microfibrillar-associated protein 4 + activated HSC increased in LFMG High patients and were primarily responsible for the LFMG signature expression and dysregulation. The microfibrillar-associated protein 4 + -activated HSC-derived LFMG signature classifies patients with liver fibrosis with distinct clinical and biological characteristics. Our findings unveil hidden information from liver biopsies undetectable using traditional histologic assessments.

Microfibrillar-associated protein 5 suppresses adipogenesis by inhibiting essential coactivator of PPARγ

Femoral head necrosis is responsible for severe pain and its incidence is increasing. Abnormal adipogenic differentiation and fat cell hypertrophy of bone marrow mesenchymal stem cells increase intramedullary cavity pressure, leading to osteonecrosis. By analyzing gene expression before and after adipogenic differentiation, we found that Microfibril-Associated Protein 5 (MFAP5) is significantly down-regulated in adipogenesis whilst the mechanism of MFAP5 in regulating the differentiation of bone marrow mesenchymal stem cells is unknown. The purpose of this study was to clarify the role of MAFP5 in adipogenesis and therefore provide a theoretical basis for future therapeutic options of osteonecrosis. By knockdown or overexpression of MFAP5 in C3H10 and 3T3-L1 cells, we found that MFAP5 was significantly down-regulated as a key regulator of adipogenic differentiation, and identified the underlying downstream molecular mechanism. MFAP5 directly bound to and inhibited the expression of Staphylococcal Nuclease And Tudor Domain Containing 1, an essential coactivator of PPARγ, exerting an important regulatory role in adipogenesis.

MP03-19 ROLE OF MICROFIBRILLAR-ASSOCIATED PROTEIN 4 IN PARTIAL BLADDER OUTFLOW OBSTRUCTION-RELATED BLADDER FIBROSIS

You have accessJournal of UrologyCME1 Apr 2023MP03-19 ROLE OF MICROFIBRILLAR-ASSOCIATED PROTEIN 4 IN PARTIAL BLADDER OUTFLOW OBSTRUCTION-RELATED BLADDER FIBROSIS Reine Kanaan, Anders Schlosser, Grith Lykke Sorensen, and Peter Zvara Reine KanaanReine Kanaan More articles by this author , Anders SchlosserAnders Schlosser More articles by this author , Grith Lykke SorensenGrith Lykke Sorensen More articles by this author , and Peter ZvaraPeter Zvara More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003214.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Partial bladder outflow obstruction (pBOO) causes remodeling of the bladder wall, with smooth muscle hypertrophy and an excessive deposition of extracellular matrix (ECM) proteins, leading to bladder fibrosis. Our understanding of the pathophysiology of this process is limited and no effective treatment to prevent or reverse bladder fibrosis exists. Microfibrillar-associated protein 4 (MFAP4) is an ECM glycoprotein, localized to elastic fiber-rich regions. It binds ECM components including elastin and collagen and contributes to the process of elastogenesis in healthy tissues. Emerging data suggest the involvement of MFAP4 in the pathogenesis of disease-induced tissue remodeling, including fibrosis. To determine its value as a potential therapeutic target, we compared MFAP4 expression in sham-operated bladders to bladders 6 weeks following pBOO. MFAP4 levels were then correlated with bladder function. METHODS: Partial BOO, was induced in 9 male Sprague Dawley rats, 5 underwent sham surgery. Six weeks following surgery, rats were placed in a metabolic cage overnight to record 12-hour micturition frequency and volume per void. Gene expression levels of MFAP4, alpha-smooth muscle actin (α-SMA) and collagen I were quantified in the bladder tissue using real-time PCR. RESULTS: The bladder/body ratio was significantly higher in the pBOO group (0.07±0.04) when compared to the SHAM group (0.024±0.003). Obstructed rats with increased MFAP4 expression demonstrated an increase in α-SMA expression. No significant increase in collagen I levels was recorded in the pBOO group. Animals with bladder overactivity as determined by frequent low volume micturitions (≥4 micturitions with <0.1 mL per void/12 hours) had higher MFAP4 expression than animals in the SHAM group, which exhibited normal micturition pattern. CONCLUSIONS: These initial observations show that pBOO lasting 6 weeks results in detrusor hypertrophy. Although bladder wall fibrosis did not develop within the 6-week timeframe, our data suggest that bladder remodeling following pBOO is associated with increased MFAP4 levels and that MFAP4 might be involved in the pathogenesis of pBOO-induced bladder dysfunction. Experiments addressing processes extending beyond 6 weeks post-pBOO and possible involvement of MFAP4 in their pathophysiology are ongoing. Source of Funding: Odense University hospital © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e31 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Reine Kanaan More articles by this author Anders Schlosser More articles by this author Grith Lykke Sorensen More articles by this author Peter Zvara More articles by this author Expand All Advertisement PDF downloadLoading ...

Serum MFAP4, a novel potential biomarker for liver cirrhosis screening, correlates with transient elastography in NAFLD patients.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in different countries. Liver fibrosis is considered as the most appropriate predictor of NAFLD-associated outcome. Microfibrillar-associated protein 4 (MFAP4) is a glycoprotein located in the extracellular matrix. Circulatory MFAP4 has been suggested as a noninvasive biomarker for the assessment of hepatitis C virus and alcoholic liver disease associated liver fibrosis. In this study, we aimed to investigate the association between serum MFAP4 and liver fibrosis severity in NAFLD patients. A case-control study was conducted in which NAFLD patients (n=25) and healthy participants (n=12) were recruited. Liver fibrosis/cirrhosis was assessed by transient elastography (TE) and biochemical parameters were collected. Serum MFAP4 was measured by sandwich ELISA based on two monoclonal anti-MFAP4 antibodies and calibrated with a standard of recombinant MFAP4. Serum MFAP4 levels increased with fibrosis severity and were highly upregulated in patients with cirrhosis (F4 fibrosis stage). In addition, serum MFAP4 levels positively correlated with TE measurement and showed significant association with the severely advanced fibrotic stage in NAFLD patients, in multiple linear regression analysis following adjustment for age, gender, and body mass index. This study suggests the use of MFAP4 as a potential diagnostic noninvasive biomarker for cirrhosis screening in NAFLD patients.

Declined plasma microfibrillar-associated protein 4 levels in acute coronary syndrome

BackgroundMicrofibrillar-associated protein (MFAP4), initially identified as an extracellular matrix protein, has been demonstrated in multiple human disorders, but it is yet to be discovered following acute coronary syndrome (ACS) in clinical practice. Therefore, this study aimed to investigate the relationship between circulating MFAP4 levels and coronary stenosis in ACS.MethodsWe performed the study in 148 ACS subjects, including 75 ST-segment elevation myocardial infarction (STEMI), 27 non-ST-segment elevation myocardial infarction (non-STEMI) and 46 unstable angina (UA). Clinical variables were collected and Gensini and Syntax stenosis scoring systems were applied to assess the severity of coronary stenosis. Kaplan–Meier and logistic regression analysis were used to analyze the relationship between MFAP4 and the severity of coronary stenosis or ACS outcomes. Spearman analysis was used to describe the correlation between MFAP4 and clinical parameters.ResultsCirculating MFAP4 levels were significantly decreased in the STEMI group (0.008 ng/ml) compared with the non-STEMI group (0.014 ng/ml) and UA group (0.019 ng/ml) (p < 0.001). After adjusting for confounding factors, we found that MFAP4 was an independent risk factor for STEMI (odds ratio = 0.395, 95% CI 0.174–0.895, p = 0.026). MFAP4 level was negatively correlated with Gensini score and Syntax score (r = − 0.311 and − 0.211, p < 0.001 and 0.01, respectively). Based on the MFAP4 level of 0.117 ng/ml, ACS patients were divided into two groups: the low-MFAP4 group (< 0.117 ng/ml, n = 60) and the high-MFAP4 group (≥ 0.117 ng/ml, n = 88). After the median follow-up of 165 days, Kaplan–Meier survival analysis revealed that the MACE-free rate was significantly lower in ACS patients with lower MFAP4 levels (p = 0.009).ConclusionsMFAP4 has a potential as a biomarker for the degree of coronary stenosis in ACS. Confirmation of observations in larger cohorts and longer follow-up periods is warranted.