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Syndecans are transmembrane heparan sulfate proteoglycans that integrate signaling at the cell surface. By interacting with cytokines, signaling receptors, proteases, and extracellular matrix proteins, syndecans regulate cell proliferation, metastasis, angiogenesis, and inflammation. We analyzed public gene expression datasets to evaluate the dysregulation and potential prognostic impact of Syndecan-3 in ovarian cancer. Moreover, we performed functional in vitro analysis in syndecan-3-siRNA-treated SKOV3 and CAOV3 ovarian cancer cells. In silico analysis of public gene array datasets revealed that syndecan-3 mRNA expression was significantly increased 5.8-fold in ovarian cancer tissues ( n = 744) and 3.4-fold in metastases ( n = 44) compared with control tissue ( n = 46), as independently confirmed in an RNAseq dataset on ovarian serous cystadenocarcinoma tissue ( n = 374, controls: n = 133, 3.5-fold increase tumor vs. normal). Syndecan-3 siRNA knockdown impaired 3D spheroid growth and colony formation as stemness-related readouts in SKOV3 and CAOV3 cells. In SKOV3, but not in CAOV3 cells, syndecan-3 depletion reduced cell viability both under basal conditions and under chemotherapy with cisplatin, or cisplatin and paclitaxel. While analysis of the SIOVDB database did not reveal differences in Syndecan-3 expression between patients, sensitive, resistant or refractory to chemotherapy, KM Plotter analysis of 1435 ovarian cancer patients revealed that high syndecan-3 expression was associated with reduced survival in patients treated with taxol and platin. At the molecular level, a reduction in Stat3 activation and changes in the expression of Wnt and notch signaling constituents were observed. Our study suggests that up-regulation of syndecan-3 promotes the pathogenesis of ovarian cancer by modulating stemness-associated pathways.

Background: Melanoma is the deadliest cutaneous malignant tumor with high risks. Though increasing evidence has widely referred to the involvement of long non-coding RNAs (lncRNAs) in the mechanism of tumor development, including melanoma, the functional roles of most lncRNAs in melanoma remain to be explored. In this study, we focus on disclosing the role of long intergenic non-protein coding RNA 1116 (LINC01116) in melanoma., Methods: Firstly, we detected LINC01116 expression through RT-qPCR. Functional analysis and animal experiments were carried out to assess the role of LINC01116 in vivo and in vitro. Western blot analysis was employed for detection of important markers regarding epithelial mesenchymal transition (EMT). In addition, RNA pulls down, RIP and luciferase reporter assays were performed to probe into the regulatory mechanism of LINC01116., Results: LINC01116 was significantly up regulated in melanoma cells. LINC01116 deficiency abrogated cell proliferation, migration, invasion and EMT in melanoma. Moreover, LINC01116 enhanced growth differentiation factor 11 (GDF11) and syndecan 3 (SDC3) expression through sponging microRNA-3612 (miR-3612). The oncogenic role of the LINC01116/miR-3612/GDF11/SDC3 axis in melanoma was finally demonstrated., Conclusion: Conclusively, LINC01116 sequestered miR-3612 and targeted GDF11 and SDC3 to contribute to the progression of melanoma., Competing Interests: Competing Interest No conflicts of interest exist., (Copyright © 2021. Published by Elsevier Inc.)

Prostate cancer (PCa) is the leading cause of cancer-associated mortality in men, and new biomarkers are still needed. The expression pattern and protein tissue localization of proteoglycans of the syndecan family (SDC 1-4) and syntenin-1 (SDCBP) were determined in normal and prostatic tumor tissue from two genetically engineered mouse models and human prostate tumors. Studies were validated using SDC 1-4 and SDCBP mRNA levels and patient survival data from The Cancer Genome Atlas and CamCAP databases. RNAseq showed increased expression of Sdc1 in Pb-Cre4/Pten f/f mouse Pca and upregulation of Sdc3 expression and downregulation of Sdc2 and Sdc4 when compared to the normal prostatic tissue in Pb-Cre4/Trp53 f/f -;Rb1 f/f mouse tumors. These changes were confirmed by immunohistochemistry. In human PCa, SDC 1-4 and SDCBP immunostaining showed variable localization. Furthermore, Kaplan-Meier analysis showed that patients expressing SDC3 had shorter prostate-specific survival than those without SDC3 expression (log-rank test, p = 0.0047). Analysis of the MSKCC-derived expression showed that SDC1 and SDC3 overexpression is predictive of decreased biochemical recurrence-free survival ( p = 0.0099 and p = 0.045, respectively), and SDC4 overexpression is predictive of increased biochemical recurrence-free survival ( p = 0.035). SDC4 overexpression was associated with a better prognosis, while SDC1 and SDC3 were associated with more aggressive tumors and a worse prognosis.

Osteoporosis is the most common age-related metabolic bone disorder, which is characterized by low bone mass and deterioration in bone architecture, with a propensity to fragility fractures. The best treatment for osteoporosis relies on stimulation of osteoblasts to form new bone and restore bone structure, however, anabolic therapeutics are few and their use is time restricted. Here, we report that Syndecan-3 increases new bone formation through enhancement of WNT signaling in osteoblasts. Young adult Sdc3 -/- mice have low bone volume, reduced bone formation, increased bone marrow adipose tissue, increased bone fragility, and a blunted anabolic bone formation response to mechanical loading. This premature osteoporosis-like phenotype of Sdc3 -/- mice is due to delayed osteoblast maturation and impaired osteoblast function, with contributing increased osteoclast-mediated bone resorption. Indeed, overexpressing Sdc3 in osteoblasts using the Col1a1 promoter rescues the low bone volume phenotype of the Sdc3 -/- mice, and also increases bone volume in WT mice. Mechanistically, SDC3 enhances canonical WNT signaling in osteoblasts through stabilization of Frizzled 1, making SDC3 an attractive target for novel bone anabolic drug development., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Syndecan-3 (SDC3) and Syndecan-4 (SDC4) are distributed throughout the nervous system (NS) and are favourable factors in motor neuron development. They are also essential for regulation of neurite outgrowth in the CNS. However, their roles in the reconstruction of the nodes of Ranvier after peripheral nerve injury (PNI) are still unclear. Present study used an in vivo model of end-to-side neurorrhaphy (ESN) for 1-3 months. The recovery of neuromuscular function was evaluated by grooming test. Expression and co-localization of SDC3, SDC4, and Nav1.6 channel (Nav1.6) at regenerating axons were detected by proximity ligation assay and confocal microscopy after ESN. Time-of-flight secondary ion mass spectrometry was used for imaging ions distribution on tissue. Our data showed that the re-clustering of sodium and Nav1.6 at nodal regions of the regenerating nerve corresponded to the distribution of SDC3 after ESN. Furthermore, the re-establishment of sodium and Nav1.6 correlated with the recovery of muscle power 3 months after ESN. This study suggested syndecans may involve in stabilizing Nav1.6 and further modulate the distribution of sodium at nodal regions after remyelination. The efficiency of sodium re-clustering was improved by the assistance of anionic syndecan, resulting in a better functional repair of PNI.

The role of TRPM2-AS lncRNA in OvC has not been explored. This study aimed to investigate whether and how TRPM2-AS contributes to the progression of OvC. First, qRT-PCR was employed to measure the expression of TRPM2-AS, miR-138-5p and SDC3 in OvC samples. A xenograft formation assay was subsequently performed to detect the tumor growth in vivo . The cell viability, colony formation, cell migration, cell invasion and cell apoptosis were later evaluated using a series of experiments. The western blot assay was utilized to detect the SDC3 protein expression and cell-apoptosis markers. Luciferase reporter gene assay, RIP, and RNA pull-down assays were performed to identify the association between TRPM2-AS, miR-138-5p and SDC3 . Findings indicated that the expression of TRPM2-AS and SDC3 was significantly upregulated in OvC tissues and cells, while miR-138-5p expression was significantly downregulated in OvC samples. Unlike miR-138-5p, TRPM2-AS and SDC3 were found to promote OvC development. It was also found that TRPM2-AS could sponge miR-138-5p to release SDC3 , thus promoting OvC progression. Apart from that, we discovered that both sh-TRPM2-AS and cisplatin could enhance the apoptosis of OvC cells. Overall, our findings suggested that the TRPM2-AS/miR-138-5p/ SDC3 axis was closely associated with OvC tumorigenesis and cisplatin resistance.

Background: Emerging studies have indicated that circular RNAs (circRNAs) play important roles in the development of many tumors. CircRNA-scavenger receptor class B member 1 (Circ-SCARB1) was consistently reported as an elevated circRNA in RCC tissues. This study focused on examining the biological function and molecular mechanism of circSCARB1 in RCC progression., Methods: Expressions of Circ-SCARB1, microRNA (miR)-510-5p, and syndecan 3 (SDC3) were detected using a quantitative real-time polymerase chain reaction (RT-PCR) and/or western blot. Cell proliferation and apoptosis were measured by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-diphenytetrazoliumromide and flow cytometry, respectively. Cell migration and invasion were measured using Transwell assays. The interaction between miR-510-5p and Circ-SCARB1 or SDC3 was verified using dual-luciferase reporter assays., Results: Circ-SCARB1 was elevated in 30 pairs of RCC tissues and multiple RCC cell lines. Knockdown of Circ-SCARB1 inhibited cell proliferation, migration, and invasion while inducing cell apoptosis. MiR-510-5p was confirmed to be a target of Circ-SCARB1; inhibition of cell progression by silencing Circ-SCARB1 was mediated by a direct interaction between Circ-SCARB1 and miR-510-5p. SDC3 was verified to be a gene target of miR-510-5p; transfection of miR-510-5p mimic not only suppressed the expression of SDC3 but also the cell proliferation and an SDC3 cotransfection partially restored cell proliferation. Additionally, the genetic knockdown of Circ- SCARB1 reduced the expression SDC3, and the addition of anti-miR-510-5p could partially reelevate SDC3 expression., Conclusion: Circ-SCARB1 promotes RCC progression via sequestering miR-510-5p and indirectly up-regulating SDC3 expression. This provides a novel perspective for the pathogenesis of RCC and potential therapeutic targets for the treatment of RCC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Syndecans are heparan sulfate proteoglycans that occur in membrane-bound or soluble forms. Syndecan-3, the least well-characterised of the syndecan family, is highly expressed on synovial endothelial cells in rheumatoid arthritis patients. Here, it binds pro-inflammatory chemokines with evidence for a role in chemokine presentation and leukocyte trafficking into the joint, promoting the inflammatory response. In this study, we explored the role of soluble syndecan-3 as a binder of chemokines and as an anti-inflammatory and therapeutic molecule., Methods: A human monocytic cell line and CD14+ PBMCs were utilised in both Boyden chamber and trans-endothelial migration assays. Soluble syndecan-3 was tested in antigen-induced and collagen-induced in vivo arthritis models in mice. ELISA and isothermal fluorescence titration assays assessed the binding affinities. Syndecan-3 expression was identified by flow cytometry and PCR, and levels of shedding by ELISA., Results: Using in vitro and in vivo models, soluble syndecan-3 inhibited leukocyte migration in vitro in response to CCL7 and its administration in murine models of rheumatoid arthritis reduced histological disease severity. Using isothermal fluorescence titration, the binding affinity of soluble syndecan-3 to inflammatory chemokines CCL2, CCL7 and CXCL8 was determined, revealing little difference, with K d s in the low nM range. TNFα increased cell surface expression and shedding of syndecan-3 from cultured human endothelial cells. Furthermore, soluble syndecan-3 occurred naturally in the sera of patients with rheumatoid arthritis and periodontitis, and its levels correlated with syndecan-1., Conclusions: This study shows that the addition of soluble syndecan-3 may represent an alternative therapeutic approach in inflammatory disease.

Objective: The endothelial glycocalyx constitutes part of the endothelial barrier but its degradation leaves endothelial cells exposed to transmigrating cells and circulating mediators that can damage the barrier or promote intercellular gaps. Syndecan proteins are key components of the endothelial glycocalyx and are shed during disease states where expression and activity of proteases such as thrombin are elevated. We tested the ability of thrombin to cleave the ectodomains of syndecans and whether the products could act directly on endothelial cells to alter barrier function., Approach and Results: Using transmission electron microscopy, we illustrated the presence of glycocalyx in human lung microvasculature. We confirmed expression of all syndecan subtypes on the endothelial surface of agarose-inflated human lungs. ELISA and western blot analysis suggested that thrombin can cleave syndecan-3/-4 ectodomains to produce fragments. In vivo, syndecan-3 ectodomain fragments increased extravasation of albumin-bound Evans blue in mouse lung, indicative of plasma protein leakage into the surrounding tissue. Syndecan-3/-4 ectodomain fragments decreased transendothelial electrical resistance, a measure of cell-cell adhesive barrier integrity, in a manner sensitive to a Rho kinase inhibitor. These effects were independent of glycosylation and thrombin receptor PAR1. Moreover, these cleavage products caused rapid VE-cadherin-based adherens junction disorganization and increased F-actin stress fibers, supporting their direct effect on endothelial paracellular permeability., Conclusions: We suggest that thrombin can cleave syndecan-3/4 ectodomain into fragments which interact with endothelial cells causing paracellular hyperpermeability. This may have important implications in the pathogenesis of vascular dysfunction during sepsis or thrombotic disease states where thrombin is activated., Competing Interests: The authors have declared that no competing interests exist.

In the human genome, miR-451a, miR-144-5p (passenger strand), and miR-144-3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs is significantly associated with poor prognosis of patients with renal cell carcinoma (RCC) (miR-451a: P = .00305; miR-144-5p: P = .00128; miR-144-3p: P = 9.45 × 10 -5 ). We previously reported that miR-451a acted as an antitumor miRNA in RCC cells. Involvement of the passenger strand of the miR-144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR-144-5p and miR-144-3p significantly reduced cancer cell migration and invasive abilities, suggesting these miRNAs acted as antitumor miRNAs in RCC cells. Analyses of miR-144-5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes (FAM64A, F2, TRIP13, ANKRD36, CENPF, NCAPG, CLEC2D, SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR-144-5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP, SDC3, SH2D1A, GZMH, KIF21B, TMC8, GAB3, HLA-DPB2, PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR-144-5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR-451a, miR-144-5p, and miR-144-3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The skeletal muscle stem cell niche provides an environment that maintains quiescent satellite cells, required for skeletal muscle homeostasis and regeneration. Syndecan-3, a transmembrane proteoglycan expressed in satellite cells, supports communication with the niche, providing cell interactions and signals to maintain quiescent satellite cells., Results: Syndecan-3 ablation unexpectedly improves regeneration in repeatedly injured muscle and in dystrophic mice, accompanied by the persistence of sublaminar and interstitial, proliferating myoblasts. Additionally, muscle aging is improved in syndecan-3 null mice. Since syndecan-3 null myofiber-associated satellite cells downregulate Pax7 and migrate away from the niche more readily than wild type cells, syxndecan-3 appears to regulate satellite cell homeostasis and satellite cell homing to the niche., Conclusions: Manipulating syndecan-3 provides a promising target for development of therapies to enhance muscle regeneration in muscular dystrophies and in aged muscle.

Identification of the genes and polymorphisms underlying quantitative traits, and understanding these genes and polymorphisms affect economic growth traits, are important for successful marker-assisted selection and more efficient management strategies in commercial cattle (Bos taurus) population. Syndecan-3 (SDC3), a member of the syndecan family of type I transmembrane heparan sulfate proteoglycans is a novel regulator of feeding behavior and body weight. The aim of this study is to examine the association of the SDC3 polymorphism with growth traits in Chinese Jiaxian and Qinchuan cattle breeds (). Four single nucleotide polymorphisms (SNPs: 1-4) were detected in 555 cows from three Chinese native cattle breeds by means of sequencing pooled DNA samples and polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) methods. We found one SNP (g.28362A > G) in intron and three SNPs (g.30742T > G, g.30821C > T and 33418 A > G) in exons. The statistical analyses indicated that these SNPs of SDC3 gene were associated with bovine body height, body length, chest circumference, and circumference of cannon bone (P < 0.05). The mutant-type variant was superior for growth traits; the heterozygote was associated with higher growth traits compared to wild-type homozygote. Our result confirms the polymorphisms in the SDC3 gene are associated with growth traits that may be used for marker-assisted selection in beef cattle breeding programs.

Background: Tissue factor (TF) pathway inhibitor (TFPI) exists in two isoforms; TFPIα and TFPIβ. Both isoforms are cell surface attached mainly through glycosylphosphatidylinositol (GPI) anchors. TFPIα has also been proposed to bind other surface molecules, like glycosaminoglycans (GAGs). Cell surface TFPIβ has been shown to exert higher anticoagulant activity than TFPIα, suggesting alternative functions for TFPIα. Further characterization and search for novel TFPI binding partners is crucial to completely understand the biological functions of cell associated TFPI., Methods and Results: Potential association of TFPI to heparan sulphate (HS) proteoglycans in the syndecan family were evaluated by knock down studies and flow cytometry analysis. Cell surface colocalization was assessed by confocal microscopy, and native PAGE or immunoprecipitation followed by Western blotting was used to test for protein interaction. Heparanase was used to enzymatically degrade cell surface HS GAGs. Anticoagulant potential was evaluated using a factor Xa (FXa) activity assay. Knock down of syndecan-3 in endothelial,- smooth muscle- and breast cancer cells reduced the TFPI surface levels by 20-50%, and an association of TFPIα to syndecan-3 on the cell surface was demonstrated. Western blotting indicated that TFPIα was found in complex with syndecan-3. The TFPI bound to syndecan-3 did not inhibit the FXa generation. Removal of HS GAGs did not release TFPI antigen from the cells., Conclusions: We demonstrated an association between TFPIα and syndecan-3 in vascular cells and in cancer cells, which did not appear to depend on HS GAGs. No anticoagulant activity was detected for the TFPI associated with syndecan-3, which may indicate coagulation independent functions for this cell associated TFPI pool. This will, however, require further investigation.

Because intrinsically disordered proteins are incapable of forming unique tertiary structures in isolation, their interaction with partner structures enables them to play important roles in many different biological functions. Therefore, such proteins are usually multifunctional, and their ability to perform their major function, as well as accessory functions, depends on the characteristics of a given interaction. The present paper demonstrates, using predictions from two programs, that the transmembrane proteoglycans syndecans are natively disordered because of their diverse functions and large number of interaction partners. Syndecans perform multiple functions during development, damage repair, tumor growth, angiogenesis, and neurogenesis. By mediating the binding of a large number of extracellular ligands to their receptors, these proteoglycans trigger a cascade of reactions that subsequently regulate various cell processes: cytoskeleton formation, proliferation, differentiation, adhesion, and migration. The occurrences of 20 amino acids in syndecans 1-4 from 25 animals were compared with those in 17 animal proteomes. Gly + Ala, Thr, Glu, and Pro were observed to predominate in the syndecans, contributing to the lack of an ordered structure. In contrast, there were many fewer amino acids in syndecans that promote an ordered structure, such as Cys, Trp, Asn, and His. In addition, a region rich in Asp has been identified between two heparan sulfate-binding sites in the ectodomains, and a region rich in Lys has been identified in the conserved C1 site of the cytoplasmic domain. These particular regions play an essential role in the various functions of syndecans due to their lack of structure.

The survival promoting peptide Y-P30 has documented neuroprotective effects as well as cell survival and neurite outgrowth promoting activity in vitro and in vivo. Previous work has shown that multimerization of the peptide with pleiotrophin (PTN) and subsequent binding to syndecan (SDC) -2 and -3 is involved in its neuritogenic effects. In this study we show that Y-P30 application regulates the nuclear localization of the SDC binding partner Calcium/calmodulin-dependent serine kinase (CASK) in neuronal primary cultures during development. In early development at day in vitro (DIV) 8 when mainly SDC-3 is expressed supplementation of the culture medium with Y-P30 reduces nuclear CASK levels whereas it has the opposite effect at DIV 18 when SDC-2 is the dominant isoform. In the nucleus CASK regulates gene expression via its association with the T-box transcription factor T-brain-1 (Tbr-1) and we indeed found that gene expression of downstream targets of this complex, like the GluN2B NMDA-receptor, exhibits a corresponding down- or up-regulation at the mRNA level. The differential effect of Y-P30 on the nuclear localization of CASK correlates with its ability to induce shedding of the ectodomain of SDC-2 but not -3. shRNA knockdown of SDC-2 at DIV 18 and SDC-3 at DIV 8 completely abolished the effect of Y-P30 supplementation on nuclear CASK levels. During early development a protein knockdown of SDC-3 also attenuated the effect of Y-P30 on axon outgrowth. Taken together these data suggest that Y-P30 can control the nuclear localization of CASK in a SDC-dependent manner.

Axon pathfinding in the neuroepithelium of embryonic brain is dependent on a variety of short and long range guidance cues. Heparan sulfate proteoglycans such as syndecans act as modulators of these cues and their importance in neural development is highlighted by their phylogenetic conservation. In Drosophilia, a single syndecan is present on the surface of axon growth cones and is required for chemorepulsive signalling during midline crossing. Understanding the role of syndecans in the vertebrate nervous system is challenging given that there are four homologous genes, syndecans 1-4. We show here that syndecans 2-4 are expressed in the zebrafish embryonic brain during the major period of axon growth. These genes show differing expression patterns in the brain which provides putative insights into their functional specificity., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Artemin (ARTN) has been implicated in promoting oncogenicity, tumor growth and invasiveness in diverse human malignancies. However, the clinical and prognostic significance of upstream ligand binding components, potentially mediating ARTN oncogenicity, largely remain to be determined., Methods: We determined the mRNA and protein expression of three proteins demonstrated to bind ARTN, namely GFRα1, GFRα3 and syndecan-3 (SDC3), in benign breast disease and mammary carcinoma by in situ hybridization and immunohistochemistry, respectively. Their prognostic significance combined with ARTN expression was also investigated in mammary carcinoma., Results: The expression of GFRα1 and GFRα3, but not SDC3, was significantly increased in mammary carcinoma and positively associated with tumor lymph node metastases, higher clinical stage and HER-2 positivity. Moreover, both GFRα1 and GFRα3 expression were significantly associated with survival outcome of patients with mammary carcinoma by univariate and multivariate analyses, whereas expression of SDC3 was not. Co-expression of ARTN with either GFRα1 or GFRα3, but not SDC3, produced synergistic increases in the odds ratio for both relapse-free and overall survival in patients with mammary carcinoma. Furthermore, significant association of GFRα1 and GFRα3 expression with survival outcome observed herein were restricted to ER negative or HER-2 negative mammary carcinoma., Conclusions: The expression of GFRα1 and/or GFRα3, especially when combined with ARTN expression, may be useful predictors of disease progression and outcome in specific subtypes of mammary carcinoma.

Skeletal muscle postnatal growth and repair depend on satellite cells and are regulated by molecular signals within the satellite cell niche. We investigated the molecular and cellular events that lead to altered myogenesis upon genetic ablation of Syndecan-3, a component of the satellite cell niche. In the absence of Syndecan-3, satellite cells stall in S phase, leading to reduced proliferation, increased cell death, delayed onset of differentiation, and markedly reduced numbers of Pax7(+) satellite cells accompanied by myofiber hypertrophy and an increased number of centrally nucleated myofibers. We show that the aberrant cell cycle and impaired self-renewal of explanted Syndecan-3-null satellite cells are rescued by ectopic expression of the constitutively active Notch intracellular domain. Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size.

The heparan sulfate proteoglycan syndecan-3 (SDC3) is a novel regulator of feeding behavior and body weight. Recently, an association of SDC3 polymorphisms with obesity has been observed in Koreans. As female obesity is associated with hyperandrogenism and infertility, we studied the role of SDC3 polymorphisms in female individuals undergoing diagnostics prior to infertility treatment. For this purpose, endocrine parameters and body mass index of 249 women were assessed. Genotyping of V208I, D303N, and T329I was performed with TaqMan technology using lymphocyte-derived DNA and allelic discrimination polymerase chain reaction. Chi-square test, Student's t test, and one-way analysis of variance were used for statistical analysis. We find that an infrequent genotype and allele variation of T329I correlated with obesity (p = 0.028). Genotype and alleles of V208I were associated with luteinizing hormone (p = 0.007 and p = 0.001, respectively), luteinizing hormone/follicle-stimulating hormone (p = 0.002 and p < 0.005, respectively), 17 hydroxyprogesterone (p = 0.007 and p = 0.001, respectively), androstenedione (p = 0.046 and p = 0.013, respectively), and sex hormone-binding globulin (p = 0.021). We conclude that marked ethnic differences of the SDC3 SNP distribution in our European population could account for correlations less predominant compared to Koreans. While infrequent variations of T329I correlated with obesity, V208I was associated with endocrine parameters related to hyperandrogenism. These findings indicate that SDC3 polymorphisms could contribute to the link between female hyperandrogenism and obesity and suggest a novel potential role for SDC3 as a modulator of gonadal steroid function.

Dendritic cells (DCs) efficiently capture HIV-1 and mediate transmission to T cells, but the underlying molecular mechanism is still being debated. The C-type lectin DC-SIGN is important in HIV-1 transmission by DCs. However, various studies strongly suggest that another HIV-1 receptor on DCs is involved in the capture of HIV-1. Here we have identified syndecan-3 as a major HIV-1 attachment receptor on DCs. Syndecan-3 is a DC-specific heparan sulfate (HS) proteoglycan that captures HIV-1 through interaction with the HIV-1 envelope glycoprotein gp120. Syndecan-3 stabilizes the captured virus, enhances DC infection in cis, and promotes transmission to T cells. Removal of the HSs from the cell surface by heparinase III or by silencing syndecan-3 by siRNA partially inhibited HIV-1 transmission by immature DCs, whereas neutralizing both syndecan-3 and DC-SIGN completely abrogated HIV-1 capture and subsequent transmission. Thus, HIV-1 exploits both syndecan-3 and DC-SIGN to mediate HIV-1 transmission, and an effective microbicide should target both syndecan-3 and DC-SIGN on DCs to prevent transmission.

Context: Very recently the unforeseen role of syndecan 3 (SDC3), a family of membrane-bound heparin sulfate proteoglycans, in the regulation of energy balance has been discovered in the Sdc3 null female mice., Objective: The objective of the study was to test the hypothesis that single nucleotide polymorphisms (SNPs) in SDC3 are associated with obesity in the Korean population., Design/setting/subjects: We conducted a population-based cohort study consisting of 229 control and 245 study subjects and a second independent study consisting of 192 control and 115 study subjects., Main Outcome Measurement: Body mass index (BMI) was measured., Results: First, Sdc3 mRNA expression in the brain of ob/ob mice was profoundly increased, compared with control mice. Next, all three nonsynonymous SNPs [T271I (rs2282440, C>T), D245N (rs4949184, C>T), and V150I (rs2491132, C>T)] in the SDC3 gene in control female subjects (BMI < 23, n = 229) and obese female subjects (BMI > 30, n = 245) were genotyped. We demonstrated the presence of clear ethnic differences in three nonsynonymous SDC3 SNPs among African-Americans, Chinese, Europeans, and Koreans. Of three SNPs in SDC3, rs4949184 was not associated with obesity and the other two SNPs (rs2282440 and rs2491132) were strongly associated with obesity (P < 0.0001), and the results were confirmed in the second independent study group. Haplotype analysis also revealed strong association with obesity (chi2 = 76.92, P < 0.000001)., Conclusions: There are ethnic differences in the SDC3 polymorphisms, and the polymorphisms are strongly associated with obesity.