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This review highlights the attributes of pentosan polysulfate (PPS) in the promotion of intervertebral disc (IVD) repair processes. PPS has been classified as a disease-modifying osteoarthritic drug (DMOAD) and many studies have demonstrated its positive attributes in the countering of degenerative changes occurring in cartilaginous tissues during the development of osteoarthritis (OA). Degenerative changes in the IVD also involve inflammatory cytokines, degradative proteases, and cell signaling pathways similar to those operative in the development of OA in articular cartilage. PPS acts as a heparan sulfate (HS) mimetic to effect its beneficial effects in cartilage. The IVD contains small cell membrane HS proteoglycans (HSPGs) such as syndecan, and glypican and a large multifunctional HS/chondroitin sulfate (CS) hybrid proteoglycan (HSPG2/perlecan), that have important matrix-stabilizing properties and sequester, control, and present growth factors from the FGF, VEGF, PDGF, and BMP families to cellular receptors to promote cell proliferation, differentiation, and matrix synthesis. HSPG2 also has chondrogenic properties and stimulates the synthesis of extracellular matrix (ECM) components and expansion of cartilaginous rudiments, and has roles in matrix stabilization and repair. Perlecan is a perinuclear and nuclear proteoglycan (PG) in IVD cells with roles in chromatin organization and control of transcription factor activity, immunolocalizes to stem cell niches in cartilage, promotes escape of stem cells from quiescent recycling, differentiation and attainment of pluripotency and migratory properties. These participate in tissue development and morphogenesis, ECM remodeling and repair. PPS also localizes in the nucleus of stromal stem cells, promotes development of chondroprogenitor cell lineages, ECM synthesis and repair and discal repair by resident disc cells. The availability of recombinant perlecan and PPS offers new opportunities in repair biology. These multifunctional agents offer welcome new developments in repair strategies for the IVD.

Chondroitin sulfate (CS) is a ubiquitous glycosaminoglycan covalently attached to the core proteins of cell surface, extracellular, and intracellular proteoglycans. The multistep and highly regulated biosynthesis of chondroitin sulfate and its degradation products give rise to a diverse species of molecules with functional regulatory properties in biological systems. This review will elucidate and expand on the most recent advances in understanding the role of chondroitin sulfate and its associate proteoglycans, in arthritis and Duchenne muscular dystrophy (DMD), two different and discrete pathologies. Highlighting not only the biodiverse nature of this family of molecules but also the utilization of CS proteoglycans, CS, and its catabolic fragments as biomarkers and potential therapeutic targets for disease pathologies.

The aim of this review was to highlight the unique biodiversity of the flowering plants and shrubs of Australia and their component chemicals that evolved during the separation of the Australian continent from Gondwanaland. The chemicals produced by these flowering plants provided protection ensuring the survival of the Australian flora which had to contend with often harsh Australian climatic conditions. The diversity of plant phytochemicals produced by these flowering plants reflects the unique diversity of the Australian Flora and these represent a Pharmacological goldmine. It was beyond the scope of this review to cover the full spectrum of these chemical compounds present in Australian plants instead we focused on the chalcones in this review. This compound has a special status in medicinal chemistry as a base intermediate for the synthesis of a large repertoire of polycyclic compounds that display anti-bacterial, antifungal, anti-viral and anti-tumour properties and these are thus of considerable interest in Biomedicine.

The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.

Disc degeneration and associated back and neck pain elicits a substantial burden on healthcare systems and the individuals affected, necessitating the development of novel therapeutic strategies. This goal can only be achieved by a better understanding of intervertebral disc development, homeostasis and pathogenesis. A number of genetic and in-bred murine models are reviewed to underscore the importance of the mouse as an animal model of choice for the assessment of intervertebral disc pathobiology. Appraisals of the differences between mouse and human musculoskeletal systems and proteoglycan structures are also included. A number of important target pathways and molecules have been identified, many of which are worthy of further examination, requiring that the activity of these be confirmed in large animal models and assessed in the context of therapeutic intervention.

Inter-α-trypsin inhibitor (IαI) family members are ancient and unique molecules that have evolved over several hundred million years of vertebrate evolution. IαI is a complex containing the proteoglycan bikunin to which heavy chain proteins are covalently attached to the chondroitin sulfate chain. Besides its matrix protective activity through protease inhibitory action, IαI family members interact with extracellular matrix molecules and most notably hyaluronan, inhibit complement, and provide cell regulatory functions. Recent evidence for the diverse roles of the IαI family in both biology and pathology is reviewed and gives insight into their pivotal roles in tissue homeostasis. In addition, the clinical uses of these molecules are explored, such as in the treatment of inflammatory conditions including sepsis and Kawasaki disease, which has recently been associated with severe acute respiratory syndrome coronavirus 2 infection in children

The aim of this study was to highlight the roles of perlecan in the regulation of the development of the rudiment developmental cartilages and growth plate cartilages, and also to show how perlecan maintains permanent articular cartilage homeostasis. Cartilage rudiments are transient developmental templates containing chondroprogenitor cells that undergo proliferation, matrix deposition, and hypertrophic differentiation. Growth plate cartilage also undergoes similar changes leading to endochondral bone formation, whereas permanent cartilage is maintained as an articular structure and does not undergo maturational changes. Pericellular and extracellular perlecan-HS chains interact with growth factors, morphogens, structural matrix glycoproteins, proteases, and inhibitors to promote matrix stabilization and cellular proliferation, ECM remodelling, and tissue expansion. Perlecan has mechanotransductive roles in cartilage that modulate chondrocyte responses in weight-bearing environments. Nuclear perlecan may modulate chromatin structure and transcription factor access to DNA and gene regulation. Snail-1, a mesenchymal marker and transcription factor, signals through FGFR-3 to promote chondrogenesis and maintain Acan and type II collagen levels in articular cartilage, but prevents further tissue expansion. Pre-hypertrophic growth plate chondrocytes also express high Snail-1 levels, leading to cessation of Acan and CoI2A1 synthesis and appearance of type X collagen. Perlecan differentially regulates FGF-2 and FGF-18 to maintain articular cartilage homeostasis, rudiment and growth plate cartilage growth, and maturational changes including mineralization, contributing to skeletal growth.

Heparan sulfate is a ubiquitous, variably sulfated interactive glycosaminoglycan that consists of repeating disaccharides of glucuronic acid and glucosamine that are subject to a number of modifications (acetylation, de-acetylation, epimerization, sulfation). Variable heparan sulfate chain lengths and sequences within the heparan sulfate chains provide structural diversity generating interactive oligosaccharide binding motifs with a diverse range of extracellular ligands and cellular receptors providing instructional cues over cellular behaviour and tissue homeostasis through the regulation of essential physiological processes in development, health, and disease. heparan sulfate and heparan sulfate-PGs are integral components of the specialized glycocalyx surrounding cells. Heparan sulfate is the most heterogeneous glycosaminoglycan, in terms of its sequence and biosynthetic modifications making it a difficult molecule to fully characterize, multiple ligands also make an elucidation of heparan sulfate functional properties complicated. Spatio-temporal presentation of heparan sulfate sulfate groups is an important functional determinant in tissue development and in cellular control of wound healing and extracellular remodelling in pathological tissues. The regulatory properties of heparan sulfate are mediated via interactions with chemokines, chemokine receptors, growth factors and morphogens in cell proliferation, differentiation, development, tissue remodelling, wound healing, immune regulation, inflammation, and tumour development. A greater understanding of these HS interactive processes will improve therapeutic procedures and prognoses. Advances in glycosaminoglycan synthesis and sequencing, computational analytical carbohydrate algorithms and advanced software for the evaluation of molecular docking of heparan sulfate with its molecular partners are now available. These advanced analytic techniques and artificial intelligence offer predictive capability in the elucidation of heparan sulfate conformational effects on heparan sulfate-ligand interactions significantly aiding heparan sulfate therapeutics development.

Purpose Proprioceptive deficits are common in low back pain. The multifidus muscle undergoes substantial structural change after back injury, but whether muscle spindles are affected is unclear. This study investigated whether muscle spindles of the multifidus muscle are changed by intervertebral disc (IVD) degeneration in a large animal model. Methods IVD degeneration was induced by partial thickness annulus fibrosus lesion to the L3-4 IVD in nine sheep. Multifidus muscle tissue at L4 was harvested at six months after lesion, and from six age-/sex-matched naïve control animals. Muscle spindles were identified in Van Gieson’s-stained sections by morphology. The number, location and cross-sectional area (CSA) of spindles, the number, type and CSA of intrafusal fibers, and thickness of the spindle capsule were measured. Immunofluorescence assays examined Collagen I and III expression. Results Multifidus muscle spindles were located centrally in the muscle and generally near connective tissue. There were no differences in the number or location of muscle spindles after IVD degeneration and only changes in the CSA of nuclear chain fibers. The thickness of connective tissue surrounding the muscle spindle was increased as was the expression of Collagen I and III. Conclusion Changes to the connective tissue and collagen expression of the muscle spindle capsule are likely to impact their mechanical properties. Changes in capsule stiffness may impact the transmission of length change to muscle spindles and thus transduction of sensory information. This change in muscle spindle structure may explain some of the proprioceptive deficits identified with low back pain.

Background. The extracellular matrix of the PNS/CNS is unusual in that it is dominated by glycosaminoglycans, especially hyaluronan, whose space filling and hydrating properties make essential contributions to the functional properties of this tissue. Hyaluronan has a relatively simple structure but its space-filling properties ensure micro-compartments are maintained in the brain ultrastructure, ensuring ionic niches and gradients are maintained for optimal cellular function. Hyaluronan has cell-instructive, anti-inflammatory properties and forms macro-molecular aggregates with the lectican CS-proteoglycans, forming dense protective perineuronal net structures that provide neural and synaptic plasticity and support cognitive learning. Aims. To highlight the central nervous system/peripheral nervous system (CNS/PNS) and its diverse extracellular and cell-associated proteoglycans that have cell-instructive properties regulating neural repair processes and functional recovery through interactions with cell adhesive molecules, receptors and neuroregulatory proteins. Despite a general lack of stabilising fibrillar collagenous and elastic structures in the CNS/PNS, a sophisticated dynamic extracellular matrix is nevertheless important in tissue form and function. Conclusions. This review provides examples of the sophistication of the CNS/PNS extracellular matrix, showing how it maintains homeostasis and regulates neural repair and regeneration.

The recent discovery of nuclear and perinuclear perlecan in annulus fibrosus and nucleus pulposus cells and its known matrix stabilizing properties in tissues introduces the possibility that perlecan may also have intracellular stabilizing or regulatory roles through interactions with nuclear envelope or cytoskeletal proteins or roles in nucleosomal-chromatin organization that may regulate transcriptional factors and modulate gene expression. The nucleus is a mechano-sensor organelle, and sophisticated dynamic mechanoresponsive cytoskeletal and nuclear envelope components support and protect the nucleus, allowing it to perceive and respond to mechano-stimulation. This review speculates on the potential roles of perlecan in the nucleus based on what is already known about nuclear heparan sulphate proteoglycans. Perlecan is frequently found in the nuclei of tumour cells; however, its specific role in these diseased tissues is largely unknown. The aim of this review is to highlight probable roles for this intriguing interactive regulatory proteoglycan in the nucleus of normal and malignant cell types.

In this study, we review mechanoregulatory roles for perlecan in load-bearing connective tissues. Perlecan facilitates the co-acervation of tropoelastin and assembly of elastic microfibrils in translamellar cross-bridges which, together with fibrillin and elastin stabilise the extracellular matrix of the intervertebral disc annulus fibrosus. Pericellular perlecan interacts with collagen VI and XI to define and stabilize this matrix compartment which has a strategic position facilitating two-way cell-matrix communication between the cell and its wider extracellular matrix. Cues from the extracellular matrix are fed through this pericellular matrix back to the chondrocyte, allowing it to perceive and respond to subtle microenvironmental changes to regulate tissue homeostasis. Thus perlecan plays a key regulatory role in chondrocyte metabolism, and in chondrocyte differentiation. Perlecan acts as a transport proteoglycan carrying poorly soluble, lipid-modified proteins such as the Wnt or Hedgehog families facilitating the establishment of morphogen gradients that drive tissue morphogenesis. Cell surface perlecan on endothelial cells or osteocytes acts as a flow sensor in blood and the lacunar canalicular fluid providing feedback cues to smooth muscle cells regulating vascular tone and blood pressure, and the regulation of bone metabolism by osteocytes highlighting perlecan’s multifaceted roles in load-bearing connective tissues.

The aim of this study was to illustrate recent developments in neural repair utilizing hyaluronan as a carrier of olfactory bulb stem cells and in new bioscaffolds to promote neural repair. Hyaluronan interacts with brain hyalectan proteoglycans in protective structures around neurons in perineuronal nets, which also have roles in the synaptic plasticity and development of neuronal cognitive properties. Specialist stem cell niches termed fractones located in the sub-ventricular and sub-granular regions of the dentate gyrus of the hippocampus migrate to the olfactory bulb, which acts as a reserve of neuroprogenitor cells in the adult brain. The extracellular matrix associated with the fractone stem cell niche contains hyaluronan, perlecan and laminin α5, which regulate the quiescent recycling of stem cells and also provide a means of escaping to undergo the proliferation and differentiation to a pluripotent migratory progenitor cell type that can participate in repair processes in neural tissues. Significant improvement in the repair of spinal cord injury and brain trauma has been reported using this approach. FGF-2 sequestered by perlecan in the neuroprogenitor niche environment aids in these processes. Therapeutic procedures have been developed using olfactory ensheathing stem cells and hyaluronan as a carrier to promote neural repair processes. Now that recombinant perlecan domain I and domain V are available, strategies may also be expected in the near future using these to further promote neural repair strategies.

Articular cartilage is considered to have limited regenerative capacity, which has led to the search for therapies to limit or halt the progression of its destruction. Perlecan, a multifunctional heparan sulphate (HS) proteoglycan, promotes embryonic cartilage development and stabilises the mature tissue. We investigated the immunolocalisation of perlecan and collagen between donor-matched biopsies of human articular cartilage defects (n = 10 &times, 2) that were repaired either naturally or using autologous cell therapy, and with age-matched normal cartilage. We explored how the removal of HS from perlecan affects human chondrocytes in vitro. Immunohistochemistry showed both a pericellular and diffuse matrix staining pattern for perlecan in both natural and cell therapy repaired cartilage, which related to whether the morphology of the newly formed tissue was hyaline cartilage or fibrocartilage. Immunostaining for perlecan was significantly greater in both these repair tissues compared to normal age-matched controls. The immunolocalisation of collagens type III and VI was also dependent on tissue morphology. Heparanase treatment of chondrocytes in vitro resulted in significantly increased proliferation, while the expression of key chondrogenic surface and genetic markers was unaffected. Perlecan was more prominent in chondrocyte clusters than in individual cells after heparanase treatment. Heparanase treatment could be a means of increasing chondrocyte responsiveness to cartilage injury and perhaps to improve repair of defects.

Chondroitin sulphate (CS) has essential roles to play in the stem cell niche with regard to stem cell differentiation and the attainment of pluripotency. The sulphation status of CS is an important determinant of its functional properties, and this parameter has been used in innovative bioscaffold design to direct the differentiation of stem cells in culture. The intrinsic charge properties of CS determine its interactive properties with extracellular matrix (ECM) components, growth factors, cytokines, and morphogens regulating the growth and differentiation of the resident stem cell populations. Stem cells express cell surface proteoglycans decorated with CS sulphation motifs identified by the monoclonal antibodies 4-C-3, 7-D-4 and 3-B-3(−). These CS sulphation motifs occur at many important centres/interfaces of growth and differentiation in tissue morphogenesis during the development of a wide range of connective tissues. The 3-B-3(−) sulphation epitope is a non-reducing terminal CS epitope generated by HYAL4 produced by mast cells. Stem cells also generate the 3-B-3(−) epitope. A greater understanding of the interactive properties of the aforementioned CS sulphation motifs with ECM components, growth factors and morphogenetic proteins will be insightful as to how stem cells control and interact with their tissue environment to regulate tissue development and tissue homeostasis.

Glycosaminoglycans (GAGs) are a family of diverse biomolecules that decorate proteoglycans in the glycocalyx and extracellular matrix of all cells. They exist as linear polysaccharide chains consisting of repeating disaccharide units that can be variably sulfated and carboxylated along their GAG chain length. These ionizable carboxyl and sulfate groups on GAGs create charged interactive motifs that convey cell regulatory properties important in tissue homeostasis and the maintenance of optimal tissue function. GAGs participate in a number of essential physiological processes including coagulation‐fibrinolysis, matrix assembly and stabilization, immune regulation, and the complement system. The high fixed charge density and the counter‐ions of GAGs is central to their role in the hydration of various connective tissues within the body. Charge transfer properties of GAGs make them amenable to electro‐stimulation and offers a potential mechanism for promoting or enhancing cellular tissue repair processes. This review is undertaken to illustrate these properties and to gain a better understanding of how these processes might be manipulated through electro‐stimulation to help improve tissue repair and the recovery of normal function in traumatized tissues. Weight‐bearing and tension‐bearing, collagen‐rich, avascular tissues have intrinsically poor repair properties and represent difficult clinical challenges. Electro‐stimulation represents a novel approach with significant potential in the stimulation of repair in these most intransigent of tissues.

Compared to the other classes of glycosaminoglycans (GAGs), that is, chondroitin/dermatan sulfate, heparin/heparan sulfate and hyaluronan, keratan sulfate (KS), have the least known of its interactive properties. In the human body, the cornea and the brain are the two most abundant tissue sources of KS. Embryonic KS is synthesized as a linear poly-N-acetyllactosamine chain of d-galactose-GlcNAc repeat disaccharides which become progressively sulfated with development, sulfation of GlcNAc is more predominant than galactose. KS contains multi-sulfated high-charge density, monosulfated and non-sulfated poly-N-acetyllactosamine regions and thus is a heterogeneous molecule in terms of chain length and charge distribution. A recent proteomics study on corneal KS demonstrated its interactivity with members of the Slit-Robbo and Ephrin-Ephrin receptor families and proteins which regulate Rho GTPase signaling and actin polymerization/depolymerization in neural development and differentiation. KS decorates a number of peripheral nervous system/CNS proteoglycan (PG) core proteins. The astrocyte KS-PG abakan defines functional margins of the brain and is up-regulated following trauma. The chondroitin sulfate/KS PG aggrecan forms perineuronal nets which are dynamic neuroprotective structures with anti-oxidant properties and roles in neural differentiation, development and synaptic plasticity. Brain phosphacan a chondroitin sulfate, KS, HNK-1 PG have roles in neural development and repair. The intracellular microtubule and synaptic vesicle KS-PGs MAP1B and SV2 have roles in metabolite transport, storage, and export of neurotransmitters and cytoskeletal assembly. MAP1B has binding sites for tubulin and actin through which it promotes cytoskeletal development in growth cones and is highly expressed during neurite extension. The interactive capability of KS with neuroregulatory ligands indicate varied roles for KS-PGs in development and regenerative neural processes.

Heparan sulfate (HS) regulates diverse cell signalling events in intervertebral disc development and homeostasis. The aim of the present study was to investigate the effect of ablation of perlecan HS/CS on murine intervertebral disc development. Genetic models carrying mutations in genes encoding HS biosynthetic enzymes have identified multiple roles for HS in tissue homeostasis. In the present study, we utilised an Hspg2 exon 3 null HS/CS-deficient mouse to assess the role of perlecan HS in disc cell regulation. HS makes many important contributions to growth factor sequestration, stabilisation/delivery, and activation of receptors directing cellular proliferation, differentiation, and assembly of extracellular matrix. Perlecan HS/CS-mediated interactions promote extracellular matrix assembly/stabilisation and tissue functional properties, and thus, removal of perlecan HS/CS should affect extracellular matrix function and homeostasis. Hspg2 exon 3 null intervertebral discs accumulated significantly greater glycosaminoglycan in the nucleus pulposus, annulus fibrosus, and vertebral growth plates than C57BL/6 wild-type (WT) I intervertebral discs. Proliferation of intervertebral disc progenitor cells was significantly higher in Hspg2 exon 3 null intervertebral discs, and these cells became hypertrophic by 12 weeks of age and were prominent in the vertebral growth plates but had a disorganised organisation. C57BL/6 WT vertebral growth plates contained regular columnar growth plate chondrocytes. Exostosis-like, ectopic bone formation occurred in Hspg2 exon 3 null intervertebral discs, and differences were evident in disc cell maturation and in matrix deposition in this genotype, indicating that perlecan HS/CS chains had cell and matrix interactive properties which repressively maintained tissue homeostasis in the adult intervertebral disc.

Keratan sulphate (KS) is a bioactive glycosaminoglycan (GAG) of some complexity composed of the repeat disaccharide D-galactose β1→4 glycosidically linked to N-acetyl glucosamine. During the biosynthesis of KS, a family of glycosyltransferase and sulphotransferase enzymes act sequentially and in a coordinated fashion to add D-galactose (D-Gal) then N-acetyl glucosamine (GlcNAc) to a GlcNAc acceptor residue at the reducing terminus of a nascent KS chain to effect chain elongation. D-Gal and GlcNAc can both undergo sulphation at C6 but this occurs more frequently on GlcNAc than D-Gal. Sulphation along the developing KS chain is not uniform and contains regions of variable length where no sulphation occurs, regions which are monosulphated mainly on GlcNAc and further regions of high sulphation where both of the repeat disaccharides are sulphated. Each of these respective regions in the KS chain can be of variable length leading to KS complexity in terms of chain length and charge localization along the KS chain. Like other GAGs, it is these variably sulphated regions in KS which define its interactive properties with ligands such as growth factors, morphogens and cytokines and which determine the functional properties of tissues containing KS. Further adding to KS complexity is the identification of three different linkage structures in KS to asparagine (N-linked) or to threonine or serine residues (O-linked) in proteoglycan core proteins which has allowed the categorization of KS into three types, namely KS-I (corneal KS, N-linked), KS-II (skeletal KS, O-linked) or KS-III (brain KS, O-linked). KS-I to -III are also subject to variable addition of L-fucose and sialic acid groups. Furthermore, the GlcNAc residues of some members of the mucin-like glycoprotein family can also act as acceptor molecules for the addition of D-Gal and GlcNAc residues which can also be sulphated leading to small low sulphation glycoforms of KS. These differ from the more heavily sulphated KS chains found on proteoglycans. Like other GAGs, KS has evolved molecular recognition and information transfer properties over hundreds of millions of years of vertebrate and invertebrate evolution which equips them with cell mediatory properties in normal cellular processes and in aberrant pathological situations such as in tumourogenesis. Two KS-proteoglycans in particular, podocalyxin and lumican, are cell membrane, intracellular or stromal tissue-associated components with roles in the promotion or regulation of tumour development, mucin-like KS glycoproteins may also contribute to tumourogenesis. A greater understanding of the biology of KS may allow better methodology to be developed to more effectively combat tumourogenic processes.

Perlecan, or heparan sulfate proteoglycan 2 (HSPG2), is a ubiquitous heparan sulfate proteoglycan that has major roles in tissue and organ development and wound healing by orchestrating the binding and signaling of mitogens and morphogens to cells in a temporal and dynamic fashion. In this review, its roles in fibrosis are reviewed by drawing upon evidence from tissue and organ systems that undergo fibrosis as a result of an uncontrolled response to either inflammation or traumatic cellular injury leading to an over production of a collagen-rich extracellular matrix. This review focuses on examples of fibrosis that occurs in lung, liver, kidney, skin, kidney, neural tissues and blood vessels and its link to the expression of perlecan in that particular organ system.

Chondroitin sulphate glycosaminoglycan chains on cell and ECM proteoglycans can no longer be regarded as merely hydrodynamic space fillers. Overwhelming evidence over recent years indicates that sulphation motif sequences within the chondroitin sulphate chain structure are a source of significant biological information to cells and their surrounding environment. Chondroitin sulphate sulphation motifs have been shown to interact with a wide variety of bioactive molecules e.g. cytokines, growth factors, chemokines, morphogenetic proteins, enzymes and enzyme inhibitors, as well as structural components within the extracellular milieu. They are therefore capable of modulating a panoply of signalling pathways thus controlling diverse cellular behaviours including proliferation, differentiation, migration and matrix synthesis. Consequently, through these motifs, chondroitin sulphate proteoglycans play significant roles in the maintenance of tissue homeostasis, morphogenesis, development, growth and disease. Here we review (i) the biodiversity of chondroitin sulphate proteoglycans and their sulphation motif sequences and (ii) the current understanding of the signalling roles they play in regulating cellular behaviour during tissue development, growth, disease and repair

The role of hyaluronan (HA) oligosaccharides in disc cell mediated matrix metalloproteinase (MMP) and anabolic gene expression in-vitro and annular repair in-vivo were examined in this study. Monolayer and alginate bead cultures of ovine intervertebral disc cells were stimulated with 10-12 mer hyaluronan oligosaccharides (HA-oligos). Annulus fibrosus (AF) monolayers were poorly responsive to the HA-oligos, proMMP-2 levels were marginally elevated and MMP-9 unaffected. ProMMP-2 displayed a strong dose dependant increase in the nucleus pulposus (NP) monolayers. In AF alginate bead cultures, proMMP-2 and active MMP-9 increased up to day 10, in NP cultures proMMP-2 was progressively converted to active MMP-2 over days 7-10 and active MMP-9 levels were elevated on day 10. A steady decline in MMP-2 and 9 activity was evident over days 2-10 in the non-stimulated NP cultures. Disc cell viabilities were ≥ 92 ± 5% in all cultures indicating that the HA-oligo was not cytotoxic. RT-PCR demonstrated an up-regulation in MMP1,13 and ADAMTS1 and the anabolic matrix repair genes ACAN, COL1A1 and COL2A1 in the NP by HA-oligos, AF MMP13, ADAMTS1, 4 and 5, ACAN and COL2A1 were down-regulated this differential regulation is expected to promote clearance of granulation/scar tissue from AF defects and matrix replenishment. AF defect sites contained enlarged annular lamellae in-vivo in response to the HA oligos consistent with an active repair response. Masson Trichrome and Picrosirius red histology and immunolocalisation of type I collagen supported active remodelling in the outer lesion zone by the HA oligo treatment but not the inner lesion.

The meniscal cartilages in the knee function to improve congruity of the medial and lateral femoro-tibial joints and play critical roles in load distribution and joint stability. Meniscal tears of various configurations are one of the most common conditions of the knee and are associated with an increased risk of developing osteoarthritis (OA). While this risk has been largely attributed to loss of the biomechanical functions of the menisci, there is accumulating evidence suggesting that other aspects of meniscal biology may play a role in determining the long-term consequences of meniscal damage for joint health. In this narrative review, we examine the existing literature and present some new data implicating synthesis and secretion of enzymes and other pro-catabolic mediators by injured and degenerate menisci, contributing to the pathological change in other knee joint tissues in OA.

Cancer metastasis is the dissemination of tumor cells to new sites, resulting in the formation of secondary tumors. This process is complex and is spatially and temporally regulated by intrinsic and extrinsic factors. One important extrinsic factor is the extracellular matrix, the non-cellular component of tissues. Heparan sulfate proteoglycans (HSPGs) are constituents of the extracellular matrix, and through their heparan sulfate chains and protein core, modulate multiple events that occur during the metastatic cascade. This review will provide an overview of the role of the extracellular matrix in the events that occur during cancer metastasis, primarily focusing on perlecan. Perlecan, a basement membrane HSPG is a key component of the vascular extracellular matrix and is commonly associated with events that occur during the metastatic cascade. Its contradictory role in these events will be discussed and we will highlight the recent advances in cancer therapies that target HSPGs and their modifying enzymes.

During acute energy deprivation, hunger signaling mechanisms support homeostasis by enhancing incentive for food. There is some evidence (primarily based on nonhuman experiments) that fasting heightens incentive signaling for nonfood reward as well. We hypothesized that, consistent with results from research in rodent and nonhuman primates, human participants would evidence increased incentive-related brain activity for nonfood rewards during fast (relative to satiety) and that this increase would be heightened when available rewards were immediate. To assess these possibilities, healthy participants with body mass index between 18 and 29 kg/m2 completed a task which engaged participants in opportunities to win immediate and delayed money (Monetary Incentive Delay Task) during 2 neuroimaging sessions (1 postprandial, 1 fasted). Analyses of participants (N = 18 included, body mass index 22.12± 2.72, age 21.39± 3.52) focused on brain activity during the incentive window of the task. Region of interest, as well as whole-brain analyses, supported the hypothesized increase in incentive signaling during fasting in regions that included caudate and putamen. No evidence of interaction was observed between fasting and the effect of reward immediacy or reward magnitude. Although provisional given the modest sample size, these results suggest that acute fasting can heighten incentive signaling for nonfood rewards.

The aim of this study is to review developments in glycosaminoglycan and proteoglycan research relevant to cartilage repair biology and in particular the treatment of osteoarthritis (OA). Glycosaminoglycans decorate a diverse range of extracellular matrix and cell associated proteoglycans conveying structural organization and physico‐chemical properties to tissues. They play key roles mediating cellular interactions with bioactive growth factors, cytokines, and morphogenetic proteins, and structural fibrillar collagens, cell interactive and extracellular matrix proteoglycans, and glycoproteins which define tissue function. Proteoglycan degradation detrimentally affects tissue functional properties. Therapeutic strategies have been developed to counter these degenerative changes. Neo‐proteoglycans prepared from chondroitin sulfate or hyaluronan and hyaluronan or collagen‐binding peptides emulate the interactive, water imbibing, weight bearing, and surface lubricative properties of native proteoglycans. Many neo‐proteoglycans outperform native proteoglycans in terms of water imbibition, matrix stabilization, and resistance to proteolytic degradation. The biospecificity of recombinant proteoglycans however, provides precise attachment to native target molecules. Visco‐supplements augmented with growth factors/therapeutic cells, hyaluronan, and lubricin (orthobiologicals) have the capacity to lubricate and protect cartilage, control inflammation, and promote cartilage repair and regeneration of early cartilage lesions and may represent a more effective therapeutic approach to the treatment of mild to moderate OA and deserve further study.

This study reviewed aspects of the biology of two members of the glucosinolate family, namely sinigrin and glucoraphanin and their potential biomedical therapeutic and industrial applications. Sinigrin and glucoraphanin are converted by the -sulphoglucosidase myrosinase or the gut microbiota into their bioactive forms, allyl isothiocyanate (AITC) and sulphoraphanin (SFN) which constitute part of a sophisticated defence mechanism plants have developed over several hundred million years of evolution to protect them from parasitic attack from aphids, ticks and nematodes. These compounds display biological activities in a number of mammalian physiological processes and potential biotherapeutic application. Glucosinolates may be useful in bio-fumigation and treatment of biofilms which occur on plant equipment and medical implants formed by problematic pathogenic bacteria such as Pseudomonas aeruginosa. AITC and SFN display similar antibiotic activity as Vancomycin in the treatment of bacteria listed by the World Health Organization as antibiotic-resistant "priority pathogens".AITC and SFN also display bioactivity in cancer chemoprevention through the induction of phase II antioxidant enzymes which inactivate potential carcinogens. The glucosinolates have found application in the prevention of bacterial and fungal spoilage of food substances during processing and in advanced food packaging formats which improve the shelf-life of food products.