Low expression of ZFP36L1 in osteosarcoma promotes lung metastasis by inhibiting the SDC4-TGF-ß signaling feedback loop.

ZFP36L1, which is a negative regulator of gene transcripts, has been proven to regulate the progression of several carcinomas. However, its role in sarcoma remains unknown. Here, by using data analyses and in vivo experiments, we found that ZFP36L1 inhibited the lung metastasis of osteosarcoma (OS). Knockdown of ZFP36L1 promoted OS cell migration by activating TGF-ß signaling and increasing SDC4 expression. Intriguingly, we observed a positive feedback loop between SDC4 and TGF-ß signaling. SDC4 protected TGFBR3 from matrix metalloproteinase (MMP)-mediated cleavage and therefore relieved the inhibition of TGF-ß signaling by soluble TGFBR3, while TGF-ß signaling positively regulated SDC4 transcription. We also proved that ZFP36L1 regulated SDC4 mRNA decay through adenylate-uridylate (AU)-rich elements (AREs) in its 3'UTR. Furthermore, treatment with SB431542 (a TGF-ß receptor kinase inhibitor) and MK2 inhibitor III (a MAPKAPK2 inhibitor that increases the ability of ZFP36L1 to degrade mRNA) dramatically inhibited OS lung metastasis, suggesting a promising therapeutic approach for the treatment of OS lung metastasis.

Soluble vascular endothelial glycocalyx proteoglycans as potential therapeutic targets in inflammatory diseases.

Reducing the activity of cytokines and leukocyte extravasation is an emerging therapeutic strategy to limit tissue-damaging inflammatory responses and restore immune homeostasis in inflammatory diseases. Proteoglycans embedded in the vascular endothelial glycocalyx, which regulate the activity of cytokines to restrict the inflammatory response in physiological conditions, are proteolytically cleaved in inflammatory diseases. Here we critically review the potential of proteolytically shed, soluble vascular endothelial glycocalyx proteoglycans to modulate pathological inflammatory responses. Soluble forms of the proteoglycans syndecan-1, syndecan-3 and biglycan exert beneficial anti-inflammatory effects by the removal of chemokines, suppression of proinflammatory cytokine expression and leukocyte migration, and induction of autophagy of proinflammatory M1 macrophages. By contrast, soluble versikine and decorin enhance proinflammatory responses by increasing inflammatory cytokine synthesis and leukocyte migration. Endogenous syndecan-2 and mimecan exert proinflammatory effects, syndecan-4 and perlecan mediate beneficial anti-inflammatory effects and glypican regulates Hh and Wnt signaling pathways involved in systemic inflammatory responses. Taken together, targeting the vascular endothelial glycocalyx-derived, soluble syndecan-1, syndecan-2, syndecan-3, syndecan-4, biglycan, versikine, mimecan, perlecan, glypican and decorin might be a potential therapeutic strategy to suppress overstimulated cytokine and leukocyte responses in inflammatory diseases.

Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function.

CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.

NMR Structural Study of Syndecan-4 Transmembrane Domain with Cytoplasmic Region.

Syndecan-4 (SDC4) consists of transmembrane heparan sulfate proteoglycan (HSPG) belonging to the syndecan family. It is present in most cell types of Mammalia. Its structure contains a heparan-sulfate-modified extracellular domain, a single transmembrane domain, and a short C-terminal cytoplasmic domain. Regarding the overall cellular function of SDC4, other cells or ligands can bind to its ecto-domain. In addition, 4,5-bisphosphate phosphatidylinositol (PIP2) or protein kinase Cα can bind to its cyto-domain to activate downstream signaling pathways. To understand the signal transduction mechanism of syndecan, it is important to know the interactions between their actual structure and function in vivo. Therefore, it is important to identify the structure of SDC4 to understand the ligand binding behavior of SDC4. In this study, expression and purification were performed to reveal structures of the short ecto-domain, the transmembrane domain, and the cytoplasmic domain of Syd4-eTC (SDC4). Solution-state NMR spectroscopy and solid-state NMR spectroscopy were used to study the structure of Syd4-eTC in membrane environments and to demonstrate the interaction between Syd4-eTC and PIP2.

Engineered Biomimetic Fibrillar Fibronectin Matrices Regulate Cell Adhesion Initiation, Migration, and Proliferation via α5ß1 Integrin and Syndecan-4 Crosstalk.

Cells regulate adhesion to the fibrillar extracellular matrix (ECM) of which fibronectin is an essential component. However, most studies characterize cell adhesion to globular fibronectin substrates at time scales long after cells polarize and migrate. To overcome this limitation, a simple and scalable method to engineer biomimetic 3D fibrillar fibronectin matrices is introduced and how they are sensed by fibroblasts from the onset of attachment is characterized. Compared to globular fibronectin substrates, fibroblasts accelerate adhesion initiation and strengthening within seconds to fibrillar fibronectin matrices via α5ß1 integrin and syndecan-4. This regulation, which additionally accelerates on stiffened fibrillar matrices, involves actin polymerization, actomyosin contraction, and the cytoplasmic proteins paxillin, focal adhesion kinase, and phosphoinositide 3-kinase. Furthermore, this immediate sensing and adhesion of fibroblast to fibrillar fibronectin guides migration speed, persistency, and proliferation range from hours to weeks. The findings highlight that fibrillar fibronectin matrices, compared to widely-used globular fibronectin, trigger short- and long-term cell decisions very differently and urge the use of such matrices to better understand in vivo interactions of cells and ECMs. The engineered fibronectin matrices, which can be printed onto non-biological surfaces without loss of function, open avenues for various cell biological, tissue engineering and medical applications.

Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival.

Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane proteoglycan, is highly expressed in intestinal subtype gastric tumors and that this signature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

Secreted phospholipase A2 XIIA triggers a mitochondrial damage-induced senescence in chronic obstructive pulmonary disease fibroblasts.

RATIONALE: Lung fibroblast senescence is involved in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the mechanisms underlining this phenomenon are still poorly understood. Secreted phospholipases (sPLA2, a subclass of phospholipases) are secreted by senescent cells and can in turn induce senescence. However, their role in fibroblasts senescence in COPD is unknown. OBJECTIVES: The aim of this study was to analyze the role of sPLA2 in pulmonary fibroblast senescence. METHODS: Fibroblasts were isolated from patients with COPD and control subjects, and senescence markers and inflammatory profile was analyzed. sPLA2 levels were quantified in serum of COPD and controls. MAIN RESULTS: In comparison with non-smokers and smoker controls, senescent lung COPD fibroblasts exhibited a higher mRNA and protein expression of the sPLA2 isoform XIIA and of syndecan 4 (one of its receptors). sPLA2 XIIA induced in turn senescence of non-senescent pulmonary fibroblasts via a pathway involving consecutively syndecan 4, activation of MAPK and p-serine 727 STAT-3, increased mitochondrial ROS production, and activation of AMPK/p53. This pathway was associated with a specific inflammatory secretome (IL-10, IL-12 and TNFα), globally suggesting occurrence of a mitochondrial damage-induced senescence. COPD fibroblasts were more susceptible to this sPLA2 XIIA effect than cells from controls subjects. sPLA2 XIIA levels were significantly higher in serum from COPD patients as compared to controls. CONCLUSION: sPLA2 XIIA is involved in senescence in COPD and could be a potential target to dampen this process.

Unravelling the Effects of Syndecan-4 Knockdown on Skeletal Muscle Functions.

The remodelling of the extracellular matrix plays an important role in skeletal muscle development and regeneration. Syndecan-4 is a cell surface proteoglycan crucial for muscle differentiation. Syndecan-4-/- mice have been reported to be unable to regenerate following muscle damage. To investigate the consequences of the decreased expression of Syndecan-4, we have studied the in vivo and in vitro muscle performance and the excitation-contraction coupling machinery in young and aged Syndecan-4+/- (SDC4) mice. In vivo grip force was decreased significantly as well as the average and maximal speed of voluntary running in SDC4 mice, regardless of their age. The maximal in vitro twitch force was reduced in both EDL and soleus muscles from young and aged SDC4 mice. Ca2+ release from the sarcoplasmic reticulum decreased significantly in the FDB fibres of young SDC4 mice, while its voltage dependence was unchanged regardless of age. These findings were present in muscles from young and aged mice as well. On C2C12 murine skeletal muscle cells, we have also found altered calcium homeostasis upon Syndecan-4 silencing. The decreased expression of Syndecan-4 leads to reduced skeletal muscle performance in mice and altered motility in C2C12 myoblasts via altered calcium homeostasis. The altered muscle force performance develops at an early age and is maintained throughout the life course of the animal until old age.

Differential effects of temperature and mTOR and Wnt-planar cell polarity pathways on syndecan-4 and CD44 expression in growth-selected turkey satellite cell populations.

Satellite cells (SCs) comprise a heterogeneous population of muscle stem cells. Thermal stress during the first week after hatch alters proliferation, myogenesis, and adipogenesis of SCs of turkey pectoralis major (p. major) muscle via mechanistic target of rapamycin (mTOR) and wingless-type mouse mammary tumor virus integration site family/planar cell polarity (Wnt/PCP) pathways. Pivotal genes in mTOR and Wnt/PCP pathways are mTOR and frizzled-7 (Fzd7), respectively. The objective of this study was to determine the differential effects of thermal stress on SDC4 and CD44 expression in turkey p. major muscle SCs and how the expression of SDC4 and CD44 is modulated by the mTOR and Wnt/PCP pathways. Satellite cells were isolated from the p. major muscle of 1-week-old faster-growing modern-commercial (NC) turkeys and slower-growing historic Randombred Control Line 2 (RBC2) turkeys, and were challenged with hot (43°C) and cold (33°C) thermal stress for 72 h of proliferation followed by 48 h of differentiation. The NC line SCs were found to contain a lower proportion of SDC4 positive and CD44 negative (SDC4+CD44-) cells and a greater proportion of SDC4 negative and CD44 positive (SDC4-CD44+) cells compared to the RBC2 line at the control temperature (38°C) at both 72 h of proliferation and 48 h of differentiation. In general, at 72 h of proliferation, the proportion of SDC4+CD44- cells decreased with heat stress (43°C) and increased with cold stress (33°C) relative to the control temperature (38°C) in both lines, whereas the proportion of SDC4-CD44+ cells increased with heat stress and decreased with cold stress. In general, the expression of SDC4 and CD44 in the NC SCs showed greater response to both hot and cold thermal stress compared to the RBC2 cells. Knockdown of mTOR or Fzd7 expression increased the proportion of SDC4+CD44- cells while the proportion of SDC4-CD44+ cells decreased during differentiation with line differences being specific to treatment temperatures. Thus, differential composition of p. major muscle SCs in growth-selected commercial turkey may be resulted, in part, from the alteration in SDC4 and CD44 expression. Results indicate differential temperature sensitivity and mTOR and Wnt/PCP pathway responses of growth-selected SC populations and this may have long-lasting effect on muscle development and growth.

SDC4-rs1981429 and ATM-rs228590 may provide early biomarkers of breast cancer risk.

In Australia, 13% of women are diagnosed with breast cancer (BC) in their lifetime with approximately 20,000 women diagnosed with the disease in 2021. BC is characterised by complex histological and genomic influences with recent advances in cancer biology improving early diagnosis and personalised treatment interventions. The Phosphatidyl-inositol-3-kinase/Protein kinase B (PI3K/AKT) pathway is essential in apoptosis resistance, cell survival, activation of cellular responses to DNA damage and DNA repair. Heparan sulfate proteoglycans (HSPGs) are ubiquitous molecules found on the cell surface and in the extracellular matrix with essential functions in regulating cell survival, growth, adhesion and as mediators of cell differentiation and migration. HSPGs, particularly the syndecans (SDCs), have been linked to cancers, making them an exciting target for anticancer treatments. In the PI3K/AKT pathway, syndecan-4 (SDC4) has been shown to downregulate AKT Serine/Threonine Kinase (AKT1) gene expression, while the ATM Serine/Threonine Kinase (ATM) gene has been found to inhibit this pathway upstream of AKT. We investigated single-nucleotide polymorphisms (SNPs) in HSPG and related genes SDC4, AKT1 and ATM and their influence on the prevalence of BC. SNPs were genotyped in the Australian Caucasian Genomics Research Centre Breast Cancer (GRC-BC) population and in the Griffith University-Cancer Council Queensland Breast Cancer Biobank (GU-CCQ BB) population. We identified that SDC4-rs1981429 and ATM-rs228590 may influence the development and progression of BC, having the potential to become biomarkers in early BC diagnosis and personalised treatment.

Syndecan-4 and stromal cell-derived factor-1 alpha functionalized endovascular scaffold facilitates adhesion, spreading and differentiation of endothelial colony forming cells and functions under flow and shear stress conditions.

Acellular vascular scaffolds with capture molecules have shown great promise in recruiting circulating endothelial colony forming cells (ECFCs) to promote in vivo endothelialization. A microenvironment conducive to cell spreading and differentiation following initial cell capture are key to the eventual formation of a functional endothelium. In this study, syndecan-4 and stromal cell-derived factor-1 alpha were used to functionalize an elastomeric biomaterial composed of poly(glycerol sebacate), Silk Fibroin and Type I Collagen, termed PFC, to enhance ECFC-material interaction. Functionalized PFC (fPFC) showed significantly greater ECFCs capture capability under physiological flow. Individual cell spreading area on fPFC (1474 ± 63 µm2 ) was significantly greater than on PFC (1187 ± 54 µm2 ) as early as 2 h, indicating enhanced cell-material interaction. Moreover, fPFC significantly upregulated the expression of endothelial cell specific markers such as platelet endothelial cell adhesion molecule (24-fold) and Von Willebrand Factor (11-fold) compared with tissue culture plastic after 7 days, demonstrating differentiation of ECFCs into endothelial cells. fPFC fabricated as small diameter conduits and tested using a pulsatile blood flow bioreactor were stable and maintained function. The findings suggest that the new surface functionalization strategy proposed here results in an endovascular material with enhanced endothelialization.

Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4.

Emerging evidence suggests that osteoarthritis is associated with high cholesterol levels in some osteoarthritis patients. However, the specific mechanism under this metabolic osteoarthritis phenotype remains unclear. We find that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse's cartilage. By using Lrp3-/- mice in vivo and LRP3 lentiviral-transduced chondrocytes in vitro, we identify that LRP3 positively regulate chondrocyte extracellular matrix metabolism, and its deficiency aggravate the degeneration of cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuate anterior cruciate ligament transection induced osteoarthritis progression in rats and Lrp3 knockout-induced osteoarthritis progression in mice. LRP3 knockdown upregulate syndecan-4 by activating the Ras signaling pathway. We identify syndecan-4 as a downstream molecular target of LRP3 in osteoarthritis pathogenesis. These findings suggest that cholesterol-LRP3- syndecan-4 axis plays critical roles in osteoarthritis development, and LRP3 gene therapy may provide a therapeutic regimen for osteoarthritis treatment.

High expression of syndecan-4 is related to clinicopathological features and poor prognosis of pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic adenocarcinoma (PAAD) is a leading cause of cancer-related mortality in adults. Syndecan-4 (SDC4) is involved in cancer pathogenesis. Therefore, this study aimed to explore the expression and clinical significance of SDC4 in PAAD. METHODS: Differentially expressed genes (DEGs) between PAAD and normal pancreas were screened from the GTEx and TCGA databases, and the correlationship between the DEGs and prognosis were analyzed. The prognostic value of the screened SDC4, SERPINE1, and SLC2A1 was evaluated using the Kaplan-Meier curve and SDC4 was subsequently selected as the better candidate. Also, SDC4 expression was analyzed in PAAD tissues, the other risk factors affecting postoperative survival were analyzed using Cox regression analysis, and SDC4-mediated pathways enrichment was identified by GSVA and GSEA. SDC4 expression in PAAD tissues and adjacent normal tissues of selected PAAD patients was detected by RT-qPCR and immunohistochemistry. The correlation between SDC4 and clinical features was evaluated by the χ2 test. RESULTS: SDC4 was highly expressed in PAAD tissues. Elevated SDC4 was correlated with reduced overall survival. SDC4 enrichment pathways included spliceosome function, proteasome activity, pentose phosphate pathway, base excision repair, mismatch repair, DNA replication, oxidative phosphorylation, mitotic spindle formation, epithelial-mesenchymal transition, and G2M checkpoints. SDC4 was elevated in PAAD tissues of PAAD patients compared with adjacent normal tissues. High SDC4 expression was related to metastatic differentiation, TNM stage, lymphatic metastasis, and lower 3-year survival rate. SDC4 was an independent risk factor affecting postoperative survival. CONCLUSION: SDC4 was highly expressed in PAAD and was related to clinicopathological features and poor prognosis, which might be an important index for PAAD early diagnosis and prognosis.

Cardiomyocyte-specific overexpression of syndecan-4 in mice results in activation of calcineurin-NFAT signalling and exacerbated cardiac hypertrophy.

BACKGROUND: Cardiomyocyte hypertrophy is a hallmark of cardiac dysfunction in patients with aortic stenosis (AS), and can be triggered by left ventricular (LV) pressure overload in mice by aortic banding (AB). Syndecan-4 is a transmembrane heparan sulphate proteoglycan which is found increased in the myocardium of AS patients and AB mice. The role of syndecan-4 in cardiomyocyte hypertrophy is not well understood. PURPOSE OF THE STUDY: We developed mice with cardiomyocyte-specific overexpression of syndecan-4 (Sdc4-Tg) and subjected these to AB to examine the role of syndecan-4 in hypertrophy and activation of the pro-hypertrophic calcineurin-NFAT signalling pathway. METHODS AND RESULTS: Sdc4-Tg mice showed exacerbated cardiac remodelling upon AB compared to wild type (WT). At 2-6 weeks post-AB, Sdc4-Tg and WT mice showed similar hypertrophic growth, while at 20 weeks post-AB, exacerbated hypertrophy and dysfunction were evident in Sdc4-Tg mice. After cross-breeding of Sdc4-Tg mice with NFAT-luciferase reporter mice, we found increased NFAT activation in Sdc4-Tg hearts after AB. Immunoprecipitation showed that calcineurin bound to syndecan-4 in Sdc4-Tg hearts. Isolated cardiomyocytes from Sdc4-Tg mice showed alterations in Ca2+ fluxes, suggesting that syndecan-4 regulated Ca2+ levels, and thereby, activating the syndecan-4-calcineurin complex resulting in NFAT activation and hypertrophic growth. Similarly, primary cardiomyocyte cultures from neonatal rats showed increased calcineurin-NFAT-dependent hypertrophic growth upon viral Sdc4 overexpression. CONCLUSION: Our study of mice with cardiomyocyte-specific overexpression of Sdc4 have revealed that syndecan-4 is important for activation of the Ca2+-dependent calcineurin-NFAT signalling pathway, hypertrophic remodelling and dysfunction in cardiomyocytes in response to pressure overload.

Role of syndecan-4 in breast cancer pathophysiology.

Expression of the cell surface heparan sulfate proteoglycan syndecan-4 is dysregulated in breast cancer, the most frequent malignancy in women. High expression of syndecan-4 correlates with a worse survival in the subgroup of estrogen receptor negative and estrogen/progesterone-receptor negative patients. Aberrant expression of syndecan-4 in breast cancer involves both transcriptional and posttranscriptional mechanisms, including estrogen- and growth factor-dependent regulation, mutations in GAPVD1, NUP153, PDE4DIP, and RREB1, as well as targeting by microRNAs. At the functional level, syndecan-4 plays an important role in various stages of breast cancer progression by interacting with ligands as diverse as plasma proteins, extracellular matrix proteins, growth factors, and surface receptors, as well as members of the integrin family. Mechanisms including integrin recycling, ectodomain shedding, and crosstalk with other syndecans expand the repertoire of syndecan-4 function. Through these interactions, syndecan-4 regulates cellular processes such as adhesion, migration, and invasion. Additional possible functions of syndecan-4 in cells of the microenvironment contribute to the complexity of its pathophysiology. Notably, syndecan-4 expression is modulated by drugs used in breast cancer treatment, such as trastuzumab and zoledronate. Overall, these findings mark syndecan-4 as a novel pathogenesis factor and promising target for therapeutic interventions in breast cancer.

Decreased differentiation capacity and altered expression of extracellular matrix components in irradiation-mediated senescent human breast adipose-derived stem cells.

Radiotherapy is widely used for the treatment of breast cancer. However, we have shown that ionizing radiation can provoke premature senescence in breast stromal cells. In particular, breast stromal fibroblasts can become senescent after irradiation both in vitro and in vivo and they express an inflammatory phenotype and an altered profile of extracellular matrix components, thus facilitating tumor progression. Adipose-derived stem cells (ASCs) represent another major component of the breast tissue stroma. They are multipotent cells and due to their ability to differentiate in multiple cell lineages they play an important role in tissue maintenance and repair in normal and pathologic conditions. Here, we investigated the characteristics of human breast ASCs that became senescent prematurely after their exposure to ionizing radiation. We found decreased expression levels of the specific mesenchymal cell surface markers CD105, CD73, CD44, and CD90. In parallel, we demonstrated a significantly reduced expression of transcription factors regulating osteogenic (i.e., RUNX2), adipogenic (i.e., PPARγ), and chondrogenic (i.e., SOX9) differentiation; this was followed by an analogous reduction in their differentiation capacity. Furthermore, they overexpress inflammatory markers, that is, IL-6, IL-8, and ICAM-1, and a catabolic phenotype, marked by the reduction of collagen type I and the increase of MMP-1 and MMP-13 expression. Finally, we detected changes in proteoglycan expression, for example, the upregulation of syndecan 1 and syndecan 4 and the downregulation of decorin. Notably, all these alterations, when observed in the breast stroma, represent poor prognostic factors for tumor development. In conclusion, we showed that ionizing radiation-mediated prematurely senescent human breast ASCs have a decreased differentiation potential and express specific changes adding to the formation of a permissive environment for tumor growth.

A reduction of Syndecan-4 in macrophages promotes atherosclerosis by aggravating the proinflammatory capacity of macrophages.

BACKGROUND: Cardiovascular diseases (CVDs) are a significant cause of mortality worldwide and are characterized by severe atherosclerosis (AS) in patients. However, the molecular mechanism of AS formation remains elusive. In the present study, we investigated the role of syndecan-4 (SDC4), a member of the syndecan family, in atherogenesis. METHODS AND RESULTS: The expression of SDC4 decreased in mouse severe AS models. Moreover, knockout of SDC4 accelerated high-cholesterol diets (HCD)-induced AS in ApoE-/- mice. Mechanistically, the decrease of SDC4 increased macrophage proinflammatory capacity may be through the PKCα-ABCA1/ABCG1 signaling pathway. CONCLUSION: These findings provide evidence that SDC4 reduction links macrophages and inflammation to AS and that SDC4 in macrophages provides a therapeutic target for preventing AS formation.

Altered Distribution and Expression of Syndecan-1 and -4 as an Additional Hallmark in Psoriasis.

Syndecans act as independent co-receptors to exert biological activities and their altered function is associated with many pathophysiological conditions. Here, syndecan-1 and -4 were examined in lesional skin of patients with psoriasis. Immunohistochemical staining confirmed altered syndecan-1 distribution and revealed absence of syndecan-4 expression in the epidermis. Fibronectin (FN)-known to influence inflammation and keratinocyte hyperproliferation via α5ß1 integrin in psoriasis-was also decreased. Syndecan-1 and -4 expression was analyzed in freshly isolated lesional psoriatic human keratinocytes (PHK) characterized based on their proliferation and differentiation properties. mRNA levels of syndecan-1 were similar between healthy and PHK, while syndecan-4 was significantly decreased. Cell growth and release of the pro-inflammatory Tumor Necrosis Factor-alpha (TNFα) were selectively and significantly induced in PHKs plated on FN. Results from co-culture of healthy keratinocytes and psoriatic fibroblasts led to the speculation that at least one factor released by fibroblasts down-regulate syndecan-1 expression in PHK plated on FN. To assay if biological treatments for psoriasis target keratinocyte proliferation, gelatin-based patches enriched with inteleukin (IL)-17α or TNFα blockers were prepared and tested using a full-thickness healthy epidermal model (Phenion®). Immunohistochemistry analysis showed that both blockers impacted the localisation of syndecan-1 within the refined epidermis. These results provide evidence that syndecans expression are modified in psoriasis, suggesting that they may represent markers of interest in this pathology.

Syndecan-4 is correlated with disease activity and serological characteristic of rheumatoid arthritis.

OBJECTIVES: To describe the feature of expression of syndecan-4 in serum, synovial fluid (SF) and synovium in rheumatoid arthritis (RA) patients, and to analyze the correlation of syndecan-4 with disease activity and serological characteristic of RA. METHODS: Syndecan-4 in sera of 60 RA patients, 20 osteoarthritis (OA) patients, 20 healthy controls, and in SF of 25 RA patients and 25 OA patients were tested by enzyme linked immunosorbant assay. The expressions of syndecan-4 in synovium of RA and OA patients were detected by immunohistochemistry. The expression of syndecan-4 on synovial fibroblasts from RA and OA patients were detected by immunofluorescence. The correlation between serum syndecan-4 concentration and disease activity were analyzed in RA patients. RESULTS: The serum syndedcan-4 concentration was significantly higher in RA patients than in OA patients and healthy controls, and was higher in rheumatoid factor (RF)-positive RA patients than in RF-negative ones. Syndecan-4 concentration in SF of RA patients was comparable with OA patients. Syndecan-4 expression in synovial tissue was similar between RA and OA patients. The syndecan-4 concentration was significantly lower in SF than in serum of RA and OA patients. Syndecan-4 concentration in both serum and SF was positively correlated with disease activity of RA patients. CONCLUSION: The serum syndecan-4 concentration was higher in RA patients than in OA patients, and significantly higher in RF-positive RA patients than in RF-negative ones. Syndecan-4 concentration in both serum and SF was positively correlated with disease activity of RA patients.

Integrin α11ß1 and syndecan-4 dual receptor ablation attenuate cardiac hypertrophy in the pressure overloaded heart.

Pathological myocardial hypertrophy in response to an increase in left ventricular (LV) afterload may ultimately lead to heart failure. Cell surface receptors bridge the interface between the cell and the extracellular matrix (ECM) in cardiac myocytes and cardiac fibroblasts and have been suggested to be important mediators of pathological myocardial hypertrophy. We identify for the first time that integrin α11 (α11) is preferentially upregulated among integrin ß1 heterodimer-forming α-subunits in response to increased afterload induced by aortic banding (AB) in wild-type (WT) mice. Mice were anesthetized in a chamber with 4% isoflurane and 95% oxygen before being intubated and ventilated with 2.5% isoflurane and 97% oxygen. For pre- and postoperative analgesia, animals were administered 0.02-mL buprenorphine (0.3 mg/mL) subcutaneously. Surprisingly, mice lacking α11 develop myocardial hypertrophy following AB comparable to WT. In the mice lacking α11, we further show a compensatory increase in the expression of another mechanoreceptor, syndecan-4, following AB compared with WT AB mice, indicating that syndecan-4 compensated for lack of α11. Intriguingly, mice lacking mechanoreceptors α11 and syndecan-4 show ablated myocardial hypertrophy following AB compared with WT mice. Expression of the main cardiac collagen isoforms col1a2 and col3a1 was significantly reduced in AB mice lacking mechanoreceptors α11 and syndecan-4 compared with WT AB.NEW & NOTEWORTHY Despite their putative importance in stress sensing, the specific integrin α-subunit(s) involved in cardiac hypertrophy has not been identified. Here, we show that α11 and syndecan-4 are critical and interdependent mediators of the hypertrophic response to increased LV afterload. We demonstrate in cells lacking both receptors an interdependent reduction in cell attachment to the major cardiac extracellular matrix components, suggesting that their interplay represents an important mechanism for stress sensing in cardiac cells.