Conformations, interactions and functions of intrinsically disordered syndecans.

Syndecans are transmembrane heparan sulfate proteoglycans present on most mammalian cell surfaces. They have a long evolutionary history, a single syndecan gene being expressed in bilaterian invertebrates. Syndecans have attracted interest because of their potential roles in development and disease, including vascular diseases, inflammation and various cancers. Recent structural data is providing important insights into their functions, which are complex, involving both intrinsic signaling through cytoplasmic binding partners and co-operative mechanisms where syndecans form a signaling nexus with other receptors such as integrins and tyrosine kinase growth factor receptors. While the cytoplasmic domain of syndecan-4 has a well-defined dimeric structure, the syndecan ectodomains are intrinsically disordered, which is linked to a capacity to interact with multiple partners. However, it remains to fully establish the impact of glycanation and partner proteins on syndecan core protein conformations. Genetic models indicate that a conserved property of syndecans links the cytoskeleton to calcium channels of the transient receptor potential class, compatible with roles as mechanosensors. In turn, syndecans influence actin cytoskeleton organization to impact motility, adhesion and the extracellular matrix environment. Syndecan clustering with other cell surface receptors into signaling microdomains has relevance to tissue differentiation in development, for example in stem cells, but also in disease where syndecan expression can be markedly up-regulated. Since syndecans have potential as diagnostic and prognostic markers as well as possible targets in some forms of cancer, it remains important to unravel structure/function relationships in the four mammalian syndecans.

Participation of selected soluble cell adhesion molecules and syndecans in formation and development of endometriosis.

OBJECTIVES: Concentrations of soluble ICAM-2, -3, -4 and syndecan-1 and -4 have not yet been marked in the peritoneal fluid of women with endometriosis. The aim of the study was to determine whether these molecules can participate in formation and development of endometriosis. MATERIAL AND METHODS: The study comprised of 80 women at the proliferative phase of the menstrual cycle, aged 21 to 49 years (mean age 31. 3 ± 6. 7 years) undergoing laparoscopy, to determine the causes of primary infertility and to confirm or exclude endometriosis. The study group consisted of 60 women with endometriosis in the pelvis as confirmed by laparoscopy and histopathology. The reference group consisted of 20 women in whom no endometriosis. Concentrations of selected sICAM and syndecans in the peritoneal fluid were determined with the use of ELISA method. RESULTS: Decreased concentrations of sICAM-2 and increased concentrations of sICAM-3, sICAM-4 and syndnecan-1 and -4 were observed in the peritoneal fluid of women with endometriosis and compared with concentrations of this parameter in the reference group (p < 0.0001). Additionally, negative correlation was found between the concentrations of sICAM-3 and sICAM-2 among women with endometriosis. There was no statistically significant correlation between the concentration of sICAM-2 and sICAM-4, sICAM-3 and sICAM-4 and syndecan-1 and syndecan-4 in the examined women. CONCLUSIONS: Changes in concentrations of all the evaluated molecules were observed in the peritoneal fluid in women suffering from endometriosis. Since they have a role in regulation of the immune response, in angiogenesis and apoptosis of the endometrial cells.

Syndecan receptors: pericellular regulators in development and inflammatory disease.

The syndecans are the major family of transmembrane proteoglycans, usually bearing multiple heparan sulfate chains. They are present on virtually all nucleated cells of vertebrates and are also present in invertebrates, indicative of a long evolutionary history. Genetic models in both vertebrates and invertebrates have shown that syndecans link to the actin cytoskeleton and can fine-tune cell adhesion, migration, junction formation, polarity and differentiation. Although often associated as co-receptors with other classes of receptors (e.g. integrins, growth factor and morphogen receptors), syndecans can nonetheless signal to the cytoplasm in discrete ways. Syndecan expression levels are upregulated in development, tissue repair and an array of human diseases, which has led to the increased appreciation that they may be important in pathogenesis not only as diagnostic or prognostic agents, but also as potential targets. Here, their functions in development and inflammatory diseases are summarized, including their potential roles as conduits for viral pathogen entry into cells.

Contribution of syndecans to cellular uptake and fibrillation of α-synuclein and tau.

Scientific evidence suggests that α-synuclein and tau have prion-like properties and that prion-like spreading and seeding of misfolded protein aggregates constitutes a central mechanism for neurodegeneration. Heparan sulfate proteoglycans (HSPGs) in the plasma membrane support this process by attaching misfolded protein fibrils. Despite of intense studies, contribution of specific HSPGs to seeding and spreading of α-synuclein and tau has not been explored yet. Here we report that members of the syndecan family of HSPGs mediate cellular uptake of α-synuclein and tau fibrils via a lipid-raft dependent and clathrin-independent endocytic route. Among syndecans, the neuron predominant syndecan-3 exhibits the highest affinity for both α-synuclein and tau. Syndecan-mediated internalization of α-synuclein and tau depends heavily on conformation as uptake via syndecans start to dominate once fibrils are formed. Overexpression of syndecans, on the other hand, reduces cellular uptake of monomeric α-synuclein and tau, yet exerts a fibril forming effect on both proteins. Data obtained from syndecan overexpressing cellular models presents syndecans, especially the neuron predominant syndecan-3, as important mediators of seeding and spreading of α-synuclein and tau and reveal how syndecans contribute to fundamental molecular events of α-synuclein and tau pathology.

New SDC function prediction based on protein-protein interaction using bioinformatics tools.

The precise roles for SDC have been complex to specify. Assigning and reanalyzing protein and peptide identification to novel protein functions is one of the most important challenges in postgenomic era. Here, we provide SDC molecular description to support, contextualize and reanalyze the corresponding protein-protein interaction (PPI). From SDC-1 data mining, we discuss the potential of bioinformatics tools to predict new biological rules of SDC. Using these methods, we have assembled new possibilities for SDC biology from PPI data, once, the understanding of biology complexity cannot be capture from one simple question.

Structures and interactions of syndecans.

The four syndecans identified in mammals are membrane proteoglycans that play major roles in regulating cell behavior, cell signaling, and cell-matrix interactions. The membrane forms of these syndecans function as receptors and co-receptors. Their ectodomains, which are proteolytically released in the extracellular matrix by shedding, also regulate various biological processes. Apart from the cytoplasmic domain of syndecan-4, the 3D structures of syndecans are poorly characterized, which hinders our understanding of the molecular mechanisms underlying syndecan functions that are mediated by numerous interactions. This mini-review summarizes the structural data that are available for syndecans and provides a comprehensive syndecan interactome, which comprises three hundred and fifty-one partners, including those identified by the high-throughput method affinity purification-mass spectrometry. It also gives a perspective on future studies of syndecan structures and interactions, which are required to further elucidate the molecular recognition processes that mediate the biological roles of the membrane and shed forms of syndecans.

Contribution of syndecans to cellular internalization and fibrillation of amyloid-ß(1-42).

Intraneuronal accumulation of amyloid-ß(1-42) (Aß1-42) is one of the earliest signs of Alzheimer's disease (AD). Cell surface heparan sulfate proteoglycans (HSPGs) have profound influence on the cellular uptake of Aß1-42 by mediating its attachment and subsequent internalization into the cells. Colocalization of amyloid plaques with members of the syndecan family of HSPGs, along with the increased expression of syndecan-3 and -4 have already been reported in postmortem AD brains. Considering the growing evidence on the involvement of syndecans in the pathogenesis of AD, we analyzed the contribution of syndecans to cellular uptake and fibrillation of Aß1-42. Among syndecans, the neuron specific syndecan-3 isoform increased cellular uptake of Aß1-42 the most. Kinetics of Aß1-42 uptake also proved to be fairly different among SDC family members: syndecan-3 increased Aß1-42 uptake from the earliest time points, while other syndecans facilitated Aß1-42 internalization at a slower pace. Internalized Aß1-42 colocalized with syndecans and flotillins, highlighting the role of lipid-rafts in syndecan-mediated uptake. Syndecan-3 and 4 also triggered fibrillation of Aß1-42, further emphasizing the pathophysiological relevance of syndecans in plaque formation. Overall our data highlight syndecans, especially the neuron-specific syndecan-3 isoform, as important players in amyloid pathology and show that syndecans, regardless of cell type, facilitate key molecular events in neurodegeneration.

Multifunctionalization of Cells with a Self-Assembling Molecule to Enhance Cell Engraftment.

Cell-based therapy is a promising approach to restoring lost functions to compromised organs. However, the issue of inefficient cell engraftment remains to be resolved. Herein, we take a chemical approach to facilitate cell engraftment by using self-assembling molecules which modify two cellular traits: cell survival and invasiveness. In this system, the self-assembling molecule induces syndecan-4 clusters on the cellular surface, leading to enhanced cell viability. Further integration with Halo-tag technology provided this self-assembly structure with matrix metalloproteinase-2 to functionalize cells with cell-invasion activity. In vivo experiments showed that the pretreated cells were able to survive injection and then penetrate and engraft into the host tissue, demonstrating that the system enhances cell engraftment. Therefore, cell-surface modification via an alliance between self-assembling molecules and ligation technologies may prove to be a promising method for cell engraftment.

Syndecan transmembrane domain modulates intracellular signaling by regulating the oligomeric status of the cytoplasmic domain.

Cell surface receptors must specifically recognize an extracellular ligand and then trigger an appropriate response within the cell. Their general structure enables this, as it comprises an extracellular domain that can bind an extracellular ligand, a cytoplasmic domain that can transduce a signal inside the cell to produce an appropriate response, and a transmembrane domain that links the two and is responsible for accurately delivering specific information on a binding event from the extracellular domain to the cytoplasmic domain, to trigger the proper response. A vast body of research has focused on elucidating the specific mechanisms responsible for regulating extracellular binding events and the subsequent interactions of the cytoplasmic domain with intracellular signaling. In contrast, far less work has focused on examining how the transmembrane domain links these domains and delivers the necessary information. In this review, we propose the importance of the transmembrane domain as a signal regulator. We highlight the cell adhesion receptor, syndecan, as a special case, and propose that the transmembrane domain-mediated oligomerization of the syndecan cytoplasmic domain is a unique regulatory mechanism in syndecan signaling.

Isolation and functional analysis of syndecans.

Syndecans comprise a major family of cell surface heparan sulfate proteoglycans (HSPGs). Syndecans are composed of sulfated glycosaminoglycans (GAGs), heparan sulfate (HS) or both HS and chondroitin sulfate (CS), attached covalently to core proteins. Syndecans regulate many cellular processes, such as adhesion, proliferation, and migration. Syndecans bind and regulate molecules primarily through their HS chains, but do not bind to all HS/heparin-binding molecules. Furthermore, mice ablated for the syndecan-1 or -4 gene do not show major developmental abnormalities, but they do show striking pathological phenotypes when challenged with infectious or inflammatory stimuli and conditions, suggesting that certain functions of syndecans are specific and cannot be compensated for by other syndecans or other HSPGs. These observations underscore the physiological importance of syndecans and indicate a need to study the activities of isolated native syndecans to define their molecular and cellular functions, and to establish their biological significance. Here we describe methods to isolate syndecans and several assays to analyze their functions.

Proteoglycans, ion channels and cell-matrix adhesion.

Cell surface proteoglycans comprise a transmembrane or membrane-associated core protein to which one or more glycosaminoglycan chains are covalently attached. They are ubiquitous receptors on nearly all animal cell surfaces. In mammals, the cell surface proteoglycans include the six glypicans, CD44, NG2 (CSPG4), neuropilin-1 and four syndecans. A single syndecan is present in invertebrates such as nematodes and insects. Uniquely, syndecans are receptors for many classes of proteins that can bind to the heparan sulphate chains present on syndecan core proteins. These range from cytokines, chemokines, growth factors and morphogens to enzymes and extracellular matrix (ECM) glycoproteins and collagens. Extracellular interactions with other receptors, such as some integrins, are mediated by the core protein. This places syndecans at the nexus of many cellular responses to extracellular cues in development, maintenance, repair and disease. The cytoplasmic domains of syndecans, while having no intrinsic kinase activity, can nevertheless signal through binding proteins. All syndecans appear to be connected to the actin cytoskeleton and can therefore contribute to cell adhesion, notably to the ECM and migration. Recent data now suggest that syndecans can regulate stretch-activated ion channels. The structure and function of the syndecans and the ion channels are reviewed here, along with an analysis of ion channel functions in cell-matrix adhesion. This area sheds new light on the syndecans, not least since evidence suggests that this is an evolutionarily conserved relationship that is also potentially important in the progression of some common diseases where syndecans are implicated.

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans.

The transmembrane domain (TMD) of the syndecans, a family of transmembrane heparin sulfate proteoglycans, is involved in forming homo- and heterodimers and oligomers that transmit signaling events. Recently, we reported that the unique phenylalanine in TMD positively regulates intramolecular interactions of syndecan-2. Besides the unique phenylalanine, syndecan-2 contains a conserved phenylalanine (SDC2-Phe-169) that is present in all syndecan TMDs, but its function has not been determined. We therefore investigated the structural role of SDC2-Phe-169 in syndecan TMDs. Replacement of SDC2-Phe-169 by tyrosine (S2F169Y) did not affect SDS-resistant homodimer formation but significantly reduced SDS-resistant heterodimer formation between syndecan-2 and -4, suggesting that SDC2-Phe-169 is involved in the heterodimerization/oligomerization of syndecans. Similarly, in an in vitro binding assay, a syndecan-2 mutant (S2(F169Y)) showed a significantly reduced interaction with syndecan-4. FRET assays showed that heteromolecular interactions between syndecan-2 and -4 were reduced in HEK293T cells transfected with S2(F169Y) compared with syndecan-2. Moreover, S2(F169Y) reduced downstream reactions mediated by the heterodimerization of syndecan-2 and -4, including Rac activity, cell migration, membrane localization of PKCα, and focal adhesion formation. The conserved phenylalanine in syndecan-1 and -3 also showed heterodimeric interaction with syndecan-2 and -4. Taken together, these findings suggest that the conserved phenylalanine in the TMD of syndecans is crucial in regulating heteromeric interactions of syndecans.

Wnt Signaling Cascades and the Roles of Syndecan Proteoglycans.

Wnt signaling comprises a group of pathways emanating from the extracellular environment through cell-surface receptors into the intracellular milieu. Wnt signaling cascades can be divided into two main branches, the canonical/ß-catenin pathway and the non-canonical pathways containing the Wnt/planar cell polarity and Wnt/calcium signaling. Syndecans are type I transmembrane proteoglycans with a long evolutionary history, being expressed in all Bilateria and in almost all cell types. Both Wnt pathways have been extensively studied over the past 30 years and shown to have roles during development and in a multitude of diseases. Although the first evidence for interactions between syndecans and Wnts dates back to 1997, the number of studies connecting these pathways is low, and many open questions remained unanswered. In this review, syndecan's involvement in Wnt signaling pathways as well as some of the pathologies resulting from dysregulation of the components of these pathways are summarized.

Fell-Muir Lecture: Syndecans: from peripheral coreceptors to mainstream regulators of cell behaviour.

In the 25 years, as the first of the syndecan family was cloned, interest in these transmembrane proteoglycans has steadily increased. While four distinct members are present in mammals, one is present in invertebrates, including C. elegans that is such a powerful genetic model. The syndecans, therefore, have a long evolutionary history, indicative of important roles. However, these roles have been elusive. The knockout in the worm has a developmental neuronal phenotype, while knockouts of the syndecans in the mouse are mild and mostly limited to post-natal rather than developmental effects. Moreover, their association with high-affinity receptors, such as integrins, growth factor receptors, frizzled and slit/robo, have led to the notion that syndecans are coreceptors, with minor roles. Given that their heparan sulphate chains can gather many different protein ligands, this gave credence to views that the importance of syndecans lay with their ability to concentrate ligands and that only the extracellular polysaccharide was of significance. Syndecans are increasingly identified with roles in the pathogenesis of many diseases, including tumour progression, vascular disease, arthritis and inflammation. This has provided impetus to understanding syndecan roles in more detail. It emerges that while the cytoplasmic domains of syndecans are small, they have clear interactive capabilities, most notably with the actin cytoskeleton. Moreover, through the binding and activation of signalling molecules, it is likely that syndecans are important receptors in their own right. Here, an overview of syndecan structure and function is provided, with some prospects for the future.

Anionic biopolyelectrolytes of the syndecan/perlecan superfamily: physicochemical properties and medical significance.

In the review article presented here, we demonstrate that the connective tissue is more than just a matrix for cells and a passive scaffold to provide physical support. The extracellular matrix can be subdivided into proteins (collagen, elastin), glycoconjugates (structural glycoproteins, proteoglycans) and glycosaminoglycans (hyaluronan). Our main focus rests on the anionic biopolyelectrolytes of the perlecan/syndecan superfamily which belongs to extracellular matrix and cell membrane integral proteoglycans. Though the extracellular domain of the syndecans may well be performing a structural role within the extracellular matrix, a key function of this class of membrane intercalated proteoglycans may be to act as signal transducers across the plasma membrane and thus be more appropriately included in the group of cell surface receptors. Nevertheless, there is a continuum in functions of syndecans and perlecans, especially with respect to their structural role and biomedical significance. HS/CS proteoglycans are receptor sites for lipoprotein binding thus intervening directly in lipid metabolism. We could show that among all lipoproteins, HDL has the highest affinity to these proteoglycans and thus instals a feedforward forechecking loop against atherogenic apoB100 lipoprotein deposition on surface membranes and in subendothelial spaces. Therefore, HDL is not only responsible for VLDL/IDL/LDL cholesterol exit but also controls thoroughly the entry. This way, it inhibits arteriosclerotic nanoplaque formation. The ternary complex 'lipoprotein receptor (HS/CS-PG) - lipoprotein (LDL, oxLDL, Lp(a)) - calcium' may be interpreted as arteriosclerotic nanoplaque build-up on the molecular level before any cellular reactivity, possibly representing the arteriosclerotic primary lesion combined with endothelial dysfunction. With laser-based ellipsometry we could demonstrate that nanoplaque formation is a Ca(2+)-driven process. In an in vitro biosensor application of HS-PG coated silica surfaces we tested nanoplaque formation and size in clinical trials with cardiovascular high-risk patients who underwent treatment with ginkgo or fluvastatin. While ginkgo reduced nanoplaque formation (size) by 14.3% (23.4%) in the isolated apoB100 lipid fraction at a normal blood Ca(2+) concentration, the effect of the statin with a reduction of 44.1% (25.4%) was more pronounced. In addition, ginkgo showed beneficial effects on several biomarkers of oxidative stress and inflammation. Besides acting as peripheral lipoprotein binding receptor, HS/CS-PG is crucially implicated in blood flow sensing. A sensor molecule has to fulfil certain mechanochemical and mechanoelectrical requirements. It should possess viscoelastic and cation binding properties capable of undergoing conformational changes caused both mechanically and electrostatically. Moreover, the latter should be ion-specific. Under no-flow conditions, the viscoelastic polyelectrolyte at the endothelium - blood interface assumes a random coil form. Blood flow causes a conformational change from the random coil state to the directed filament structure state. This conformational transition effects a protein unfurling and molecular elongation of the GAG side chains like in a 'stretched' spring. This configuration is therefore combined with an increase in binding sites for Na(+) ions. Counterion migration of Na(+) along the polysaccharide chain is followed by transmembrane Na(+) influx into the endothelial cell and by endothelial cell membrane depolarization. The simultaneous Ca(2+) influx releases NO and PGI2, vasodilatation is the consequence. Decrease in flow reverses the process. Binding of Ca(2+) and/or apoB100 lipoproteins (nanoplaque formation) impairs the flow sensor function. The physicochemical and functional properties of proteoglycans are due to their amphiphilicity and anionic polyelectrolyte character. Thus, they potently interact with cations, albeit in a rather complex manner. Utilizing (23)Na(+) and (39)K(+) NMR techniques, we could show that, both in HS-PG solutions and in native vascular connective tissue, the mode of interaction for monovalent cations is competition. Mg(2+) and Ca(2+) ions, however, induced a conformational change leading to an increased allosteric, cooperative K(+) and Na(+) binding, respectively. Since extracellular matrices and basement membranes form a tight-fitting sheath around the cell membrane of muscle and Schwann cells, in particular around sinus node cells of the heart, and underlie all epithelial and endothelial cell sheets and tubes, a release of cations from or an adsorption to these polyanionic macromolecules can transiently lead to fast and drastic activity changes in these tiny extracellular tissue compartments. The ionic currents underlying pacemaker and action potential of sinus node cells are fundamentally modulated. Therefore, these polyelectrolytic ion binding characteristics directly contribute to and intervene into heart rhythm.

Structure and functions of syndecans in vertebrates.

Syndecans constitute a family of transmembrane proteoglycans that perform multiple functions during development, damage repair, tumor growth, angiogenesis, and neurogenesis. Through mediating binding of a great number of extracellular ligands to their receptors, these proteoglycans trigger a cascade of reactions regulating, thereby, various processes in a cell: cytoskeleton formation, proliferation, differentiation, adhesion, and migration. In fibroblasts, syndecans are responsible for cell adhesion by modulating functions of integrins through interaction with fibronectin at the external side of a cell and with cytoskeleton and signaling molecules inside the cell. The extracellular domain of syndecans is subjected to periodic shedding from the cell membrane. This process may be stimulated in response to inflammation, tissue damage, and other pathological manifestations. Cleaved domain may act as either competitive inhibitor or activator of signaling cascades. This review summarizes and analyzes the available data regarding structure, main biochemical properties, and functions of syndecans in vertebrates.

Small-molecule-induced clustering of heparan sulfate promotes cell adhesion.

Adhesamine is an organic small molecule that promotes adhesion and growth of cultured human cells by binding selectively to heparan sulfate on the cell surface. The present study combined chemical, physicochemical, and cell biological experiments, using adhesamine and its analogues, to examine the mechanism by which this dumbbell-shaped, non-peptidic molecule induces physiologically relevant cell adhesion. The results suggest that multiple adhesamine molecules cooperatively bind to heparan sulfate and induce its assembly, promoting clustering of heparan sulfate-bound syndecan-4 on the cell surface. A pilot study showed that adhesamine improved the viability and attachment of transplanted cells in mice. Further studies of adhesamine and other small molecules could lead to the design of assembly-inducing molecules for use in cell biology and cell therapy.

Contribution of syndecans to lipoplex-mediated gene delivery.

The long awaited breakthrough of gene therapy significantly depends on the in vivo efficiency of targeted intracellular delivery. Hidden details of cellular uptake present a great hurdle for non-viral gene delivery with liposomes. Growing scientific evidence supports the involvement of polyanionic cell surface carbohydrates in cellular internalization of cationic liposomes. Syndecans, a highly conserved family of transmembrane heparan sulfate proteoglycans serve attachment sites for great variety of cationic ligands including growth factors, cytokines and even parasites. In the present study we quantitatively measured the contribution of various syndecan isoforms to liposome-mediated gene transfer. The obtained data show the superiority of syndecan-4, the ubiquitously expressed isoform of the syndecan family, in cellular uptake of liposomes. Applied mutational analysis demonstrated that gene delivery could be abolished by mutating the glycosaminoglycan attachment site of syndecans, highlighting the importance of polyanionic heparan sulfate side chains in the attachment of cationic liposomes. Blocking sulfation of syndecans also diminished gene delivery, a finding that confirms the essential role of polyanionic charges in binding cationic liposomes. Mutating other parts of the syndecan extracellular domain, including the cell-binding domain, had clearly smaller effect on liposome internalization. Mutational analyses also revealed that superiority of syndecan-4 in liposome-mediated gene delivery is significantly influenced by its cytoplasmic domain that orchestrates signaling pathways leading to macropinocytosis. In summary our study present a mechanistic insight into syndecan-mediated macropinocytic uptake of lipoplexes and highlights syndecan-4 as a superior target for cationic liposomes.

Novel insight into the biological functions of syndecan ectodomain core proteins.

Syndecans are a four member family of multifunctional transmembrane heparan sulphate bearing cell surface receptors. Each family member has common molecular architecture but a distinct expression profile. Numerous molecular interactions between syndecan heparan sulphate chains, growth factors, cytokines, and extracellular matrix molecules have been reported and syndecans are intimately associated with cell adhesion and migration. Here, we describe the important emerging concept that contained within syndecan extracellular core proteins are "adhesion regulatory domains." Cell adhesion is driven by the integrins and syndecan ectodomain adhesion regulatory domains can alter integrin driven cellular responses. Cell adhesion and migration is central to numerous pathologies and an understanding of how syndecan ectodomains influence integrins will lead to novel therapeutic strategies.

Syndecans in cartilage breakdown and synovial inflammation.

Syndecans are transmembrane heparan sulphate proteoglycans (HSPGs) that have gained increasing interest as regulators of a variety of tissue responses, including cartilage development and remodelling. These proteoglycans are composed of a core protein to which extracellular glycosaminoglycan (GAG) chains are attached. Through these GAG chains, syndecans can interact with a variety of extracellular matrix molecules and bind to a number of soluble mediators including morphogens, growth factors, chemokines and cytokines. The structure and post-translational modification of syndecan GAG chains seem to differ not only from cell to cell, but also during different stages of cellular differentiation, leading to a complexity of syndecan function that is unique among membrane-bound HSPGs. Unlike other membrane-bound HSPGs, syndecans contain intracellular signalling motifs that can initiate signalling mainly through protein kinase C. This Review summarizes our knowledge of the biology of syndecans and the mechanisms by which binding of molecules to syndecans exert different biological effects, particularly in the joints. On the basis of the structural and functional peculiarities of syndecans, we discuss the regulation of syndecans and their roles in the developing joint as well as during degenerative and inflammatory cartilage remodelling as understood from expression studies and functional analyses involving syndecan-deficient mice.