Secreted modular calcium-binding protein 2 promotes high fat diet (HFD)-induced hepatic steatosis through enhancing lipid deposition, fibrosis and inflammation via targeting TGF-β1

Yuting, Yun; Lifeng, Feng; Hao, Qiwei

doi:10.1016/j.bbrc.2018.12.006

Cited by 22 publications

(21 citation statements)

References 31 publications

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“…SMOC2 has been identified as a key player in NAFLD progression. SMOC2 mRNA and protein levels were higher in liver samples of patients with NAFLD and in mice fed with high fat diet (354). SMOC2knockdown mice fed with high fat diet showed lower collagen deposition compared to control animals, associated with a lower expression of TGF-b1 and a-SMA, and lower levels of proinflammatory cytokines IL-1b, IL-4, IL-6, MCP-1, and TNF-a in serum and liver samples.…”

Section: Sparcmentioning

confidence: 87%

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

et al. 2020

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Chronic liver disease when accompanied by underlying fibrosis, is characterized by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognized as a source of potent damage-associated molecular pattern (DAMP)s with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating immune responses. A growing body of evidence shows that ECM proteins themselves are capable of modulating immunity either directly via ligation with immune cell receptors including integrins and TLRs, or indirectly through release of immunoactive molecules such as cytokines which are stored within the ECM structure. Notably, ECM deposition and remodeling during injury and fibrosis can result in release or formation of ECM-DAMPs within the tissue, which can promote local inflammatory immune response and chemotactic immune cell recruitment and inflammation. It is well described that the ECM and immune response are interlinked and mutually participate in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to describe the known pro-/anti-inflammatory and fibrogenic properties of ECM proteins and DAMPs, with particular reference to the immunomodulatory properties of the ECM in the context of chronic liver disease. Finally, we discuss the importance of developing novel biotechnological platforms based on decellularized ECM-scaffolds, which provide opportunities to directly explore liver ECM-immune cell interactions in greater detail.

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Section: Sparcmentioning

confidence: 87%

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

et al. 2020

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“…In addition, it has been verified that SMOC2 regulates the activation of TGFβ and NF‐κB signalings 29,37 . Based on the preliminary result that SMOC2 was targeted by miR‐17‐5p in Ang II‐induced podocytes, we hypothesized that miR‐17‐5p‐SMOC2 axis regulated the activation of TGFβ and NF‐κB signalings in Ang II‐induced podocytes, which was verified by a series of rescue assays.…”

Section: Discussionmentioning

confidence: 68%

“…Since it has been reported that SMOC2 participated in the regulation of the activation of TGFβ and NF‐κB signalings, 29 we then hypothesized that miR‐17‐5p‐SMOC2 axis also regulated TGFβ and NF‐κB signaling activation in Ang II‐induced podocytes. To verify our hypothesis, we detected the levels of key proteins associated with TGFβ and NF‐κB signaling.…”

Section: Resultsmentioning

confidence: 96%

“…Besides, we identified that SMOC2 (secreted modular calcium‐binding protein 2) was targeted by miR‐17‐5p in Ang II‐induced podocytes. SMOC2 is a matricellular protein that enhances matrix assembly and promotes endothelial cell proliferation, migration, and angiogenic activity 29,35 . Previously, research on SMOC2 has verified that SMOC2 is involved in the regulation of some diseases by forming the miRNA‐mRNA axis with specific miRNAs 36 .…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐17‐5p restrains the dysfunction of Ang‐II induced podocytes by suppressing secreted modular calcium‐binding protein 2 via NF‐κB and TGFβ signaling

Yi²,

2021

Environmental Toxicology

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Glomerulonephritis, also known as nephritis syndrome (nephritis for short), is a common kidney disease. Previous research has proved that microRNAs (miRNAs) frequently regulate various diseases including nephritis. Nonetheless, the biological function and molecular mechanism of miR‐17‐5p are unclear in nephritis. In the current study, RT‐qPCR analysis showed that miR‐17‐5p was downregulated in Ang II‐induced podocytes. Also, according to the results from RT‐qPCR analysis, CCK‐8 assay, flow cytometric analysis, western blot analysis, and ELISA miR‐17‐5p elevation alleviated Ang II‐induced podocyte injury. Besides, luciferase reporter assay, western blot and RT‐qPCR analyses revealed that SMOC2 was targeted by miR‐17‐5p in Ang II‐induced podocytes. Additionally, rescue assays demonstrated that overexpressed SMOC2 counteracted the influence of overexpressed miR‐17‐5p on cell injury of Ang II‐induced podocytes. Moreover, our data suggested that miR‐17‐5p‐SMOC2 axis regulated TGFβ and NF‐κB signaling activation in Ang II‐induced podocytes. SMOC2 regulated cell viability, apoptosis and extracellular matrix (ECM) deposition in Ang II‐induced podocytes via TGFβ signaling, and SMOC2 regulated inflammation in Ang II‐induced podocytes through NF‐κB signaling. Overall, our study demonstrated that miRNA‐17‐5p restrained the dysfunction of Ang‐II induced podocytes by suppressing SMOC2 via the NF‐κB and TGFβ signaling.

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“…SMOC2 is an important structural anchor in the ECM networks of cartilage, like other members of the BM40/SPARC family, but SMOC2 can also interact with receptors on the cell surface, acting as a regulator of cell–matrix interaction to activate or inactivate some signaling pathways. Previous evidence demonstrated that SMOC2 is involved in the pathways fibroblast growth factor or vascular endothelial growth factor signaling [ 28 ] , TGF-β1-SMAD2/3 [ 29, 30 ] , WNT/β-catenin [ 31 ] , and BMP-SMAD1/5/9 [ 14, 23, 32 ] , which play an important role in chondrogenesis. Considering the importance of the BMP-SMAD1/5/9 pathway in endochondral bone formation [ 33–36 ] , we assessed whether the mutant Smoc2 affected the BMP-SMAD1/5/9 pathway.…”

Section: Discussionmentioning

confidence: 99%

A variant inSMOC2,inhibiting BMP signaling by competitively binding to BMPR1B, causes multiple epiphyseal dysplasia

Long

Lin

Shi

et al. 2020

Preprint

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Abstract： Previously study showed that SMOC, a matricellular protein, inhibits BMP 20 signaling downstream of its receptor via activation of mitogen-activated protein kinase 21 (MAPK) signaling. In our study, exome sequencing revealed a missense mutation 22 (c.1076T>G, p.Leu359Arg) in EC domain of SMOC2 in a Chinese family with 23 multiple epiphyseal disease (MED). The pathogenicity of this SMOC2 variant was 24 verified by Smoc2 L359R/L359R knock-in mice. Of note, decreasing phosphorylation of 25 SMAD1/5/9 was detected in growth plates and primary chondrocytes from 26Smoc2 L359R/L359R mice. Furthermore, binding affinity of mutant SMOC2 with collagen 27 IX and HSPG in the extracellular matrix of cartilage were reduced while binding 28 affinity with BMPRIB was intact. In addition, in contrast to previously results, that 29 SMOC2 cannot antagonize BMP activity in the presence of a constitutively activated 30 BMP receptor. These results support that SMOC2 with p.Leu359Arg variant act as an 31 antagonist of canonical BMP pathway by competitively binding with BMP receptors. 32 33 Introduction 34Multiple epiphyseal dysplasia (MED, MIM 132400) is a genotypically and 35 phenotypically heterogeneous skeletal dysplasia and chondrodysplasia that affects 36 epiphysis of long bones [1, 2] . MED is characterized by early-onset arthritis, especially in 37 hip and knee joints, which results in joint pain and stiffness, waddling gait in early 38 childhood, and mild to moderate shortness of stature. Eight disease genes, which may 39 be inherited in an autosomal dominant or recessive pattern, have been identified. 40Autosomal dominant variants include collagen oligomeric matrix protein (COMP) [3, 4] , 41 collagen type IX α-1 (COL9A1) [5] , collagen type IX α-2 (COL9A2) [6] , collagen type IX 42 α-3 (COL9A3) [7] , matrilin-3 (MATN3) [8] , and collagen type II α-1 (COL2A1) [9] . 43Autosomal recessive variants are the sulfate transporter gene (SLC26A2) and 44 calcium-activated nucleotidase-1 (CANT1) [10, 11] . All proteins encoded by the known 45 MED-associated genes are involved in maintaining the structural integrity of the 46 cartilage extracellular matrix (ECM). All variants in these genes account for the 47 molecular basis of about 70% of MED cases [11] . However, a number of MED cases 48 have no identifiable genetic mutation, and additional genetic etiologies of MED remain 49 to be identified. 50 SPARC-related modular calcium binding 2 (SMOC2) and SMOC1, its closest 51 homolog, are members of the protein family BM-40 (also known as secreted protein 52 acidic and rich in cysteines [SPARC] or osteonectin) [12, 13] . BM-40 is a prototypic 53 collagen-binding matricellular protein that participates in regulating cell-matrix 54 4 interactions, in particular influencing bone mineralization, wound repair and other 55 biological functions. The BM-40 family of modular extracellular proteins is 56 characterized by a follistatin-like (FS) domain as well as an extracellular 57 calcium-binding (EC) domain with two EF-hand calcium-b...

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Secreted modular calcium-binding protein 2 promotes high fat diet (HFD)-induced hepatic steatosis through enhancing lipid deposition, fibrosis and inflammation via targeting TGF-β1

Cited by 22 publications

References 31 publications

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

MicroRNA‐17‐5p restrains the dysfunction of Ang‐II induced podocytes by suppressing secreted modular calcium‐binding protein 2 via NF‐κB and TGFβ signaling

A variant inSMOC2,inhibiting BMP signaling by competitively binding to BMPR1B, causes multiple epiphyseal dysplasia

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