chondroitin-sulfates and Hypertrophy

Physical medicine and rehabilitation aim to evaluate, diagnose and treat disability in haemophiliac patients, while preventing injury or deterioration. They also aim to maintain the greatest degree of functional capacity and independence in patients with haemophilia, or to return them to that state. Rehabilitation, together with clotting factor replacement therapy, has revolutionized the management of these patients in developed countries and reduced their morbidity/mortality rates. A knowledge of the musculoskeletal signs and symptoms of haemophilia is essential for providing a treatment which is suitable and customized. Physical medicine and rehabilitation techniques, which are based on physical means, are intended to reduce the impact which these injuries and their consequences or sequelae can have on the quality of life of patients with haemophilia. Under ideal haemostatic control conditions (primary prophylaxis), people with haemophilia could achieve good physical condition which will allow them to enjoy both physical activity and a daily life without limitations. Currently, children undergoing primary prophylaxis are quite close to this ideal situation. For these physical activities to be carried out, the safest possible situations must be sought.

Topics: Bone Cysts; Cartilage Diseases; Cartilage, Articular; Chondroitin Sulfates; Combined Modality Therapy; Electric Stimulation Therapy; Exercise Therapy; Factor IX; Factor VIII; Glucosamine; Hemarthrosis; Hemophilia A; Hemorrhage; Humans; Hyaluronic Acid; Hypertrophy; Motor Activity; Musculoskeletal Diseases; Physical and Rehabilitation Medicine; Synovectomy; Synovial Membrane; Synovitis; Transcutaneous Electric Nerve Stimulation

TMEM165 deficiency leads to skeletal disorder characterized by major skeletal dysplasia and pronounced dwarfism. However, the molecular mechanisms involved have not been fully understood. Here, we uncover that TMEM165 deficiency impairs the synthesis of proteoglycans by producing a blockage in the elongation of chondroitin-and heparan-sulfate glycosaminoglycan chains leading to the synthesis of proteoglycans with shorter glycosaminoglycan chains. We demonstrated that the blockage in elongation of glycosaminoglycan chains is not due to defect in the Golgi elongating enzymes but rather to availability of the co-factor Mn

Topics: Animals; Antiporters; Case-Control Studies; Cation Transport Proteins; Cell Differentiation; Cell Line, Tumor; Chondrocytes; Chondrogenesis; Chondroitin Sulfates; Dwarfism; Fibroblasts; Gene Knockout Techniques; Glycosylation; HEK293 Cells; Heparan Sulfate Proteoglycans; Humans; Hypertrophy; Mice; Signal Transduction; Transfection

Mesenchymal stem cells are a promising cell source for chondrogenic differentiation and have been widely used in several preclinical and clinical studies. However, they are prone to an unwanted differentiation process towards hypertrophy that limits their therapeutic efficacy. Matrix metallopeptidase 13 (MMP-13) is a well-known factor regulated during this undesirable event. MMP-13 is a collagen degrading enzyme, which is also highly expressed in the hypertrophic zone of the growth plate and in OA cartilage. Accordingly, we investigated the effect of MMP-13 inhibition on MSC hypertrophy.. In this study, 5-bromoindole-2-carboxylic acid (BICA) was used as an inhibitory agent for MMP-13 expression. After identifying its optimal concentration, BICA was mixed into a hydrogel and the release rate was studied. To prepare the ideal hydrogel, chondroitin sulfate (CS) and platelet lysate (PL) were mixed with sodium alginate (Alg) at concentrations selected based on synergistic mechanical and rheometric properties. Then, four hydrogels were prepared by combining alginate (1.5%w/v) and/or CS (1%w/v) and/or PL (20%v/v). The chondrogenic potential and progression to hypertrophy of human bone marrow-derived mesenchymal stem cell (hBM-MSC)-loaded hydrogels were investigated under free swelling and mechanical loading conditions, in the presence and absence of BICA.. Viability of hBM-MSCs seeded in the four hydrogels was similar. qRT-PCR revealed that BICA could successfully inhibit MMP-13 expression, which led to an inhibition of Coll X and induction of Coll-II, in both free swelling and loading conditions. The GAG deposition was higher in the group combining BICA and mechanical stimulation.. It is concluded that BICA inhibition of MMP-13 reduces MSC hypertrophy during chondrogenesis.

Topics: Alginates; Cell Differentiation; Cells, Cultured; Chondrocytes; Chondrogenesis; Chondroitin Sulfates; Humans; Hydrogels; Hypertrophy; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Mesenchymal Stem Cells

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in articular cartilage and the loss of CS-GAG occurs early in OA. As a major component of perichondral matrix interacting directly with chondrocytes, the active turnover of CS can affect to break the homeostasis of chondrocytes. Here we employ CS-based 3-dimensional (3D) hydrogel scaffold system to investigate how the degradation products of CS affect the catabolic phenotype of chondrocytes. The breakdown of CS-based ECM by the chondroitinase ABC (ChABC) resulted in a hypertrophy-like morphologic change in chondrocytes, which was accompanied by catabolic phenotypes, including increased MMP-13 and ADAMTS5 expression, nitric oxide (NO) production and oxidative stress. The inhibition of Toll-like receptor 2 (TLR2) or TLR4 with OxPAPC (TLR2 and TLR4 dual inhibitor) and LPS-RS (TLR4-MD2 inhibitor) ameliorated these catabolic phenotypes of chondrocytes by CS-ECM degradation, suggesting a role of CS breakdown products as damage-associated molecular patterns (DAMPs). As downstream signals of TLRs, MAP kinases, NF-kB, NO and STAT3-related signals were responsible for the catabolic phenotypes of chondrocytes associated with ECM degradation. NO in turn reinforced the activation of MAP kinases as well as NFkB signaling pathway. Thus, these results propose that the breakdown product of CS-GAG can recapitulate the catabolic phenotypes of OA.

Topics: ADAMTS5 Protein; Animals; Chondrocytes; Chondroitin Sulfates; Gene Expression Regulation; Hydrogels; Hypertrophy; Matrix Metalloproteinase 13; Mice; Signal Transduction

Fucosylated chondroitin sulfate from Isostichopus badionotus (fCS-Ib) is a kind of sulfated polysaccharides with well-repeated structure. In our former publications, fCS-Ib has been reported to be a functional food ingredient with hypoglycemic and antilipemic activities. However, there is no systematic study to investigate the effects of fCS-Ib on metabolic syndromes. In the present study, C57BL/6 mice fed on a high-fat and high sucrose diet (HFSD) for 6 weeks was used to cause metabolic syndromes. The final results showed that fCS-Ib alleviated obesity, hyperlipidemia, hyperglycemia, inflammation, liver steatosis, and adipocyte hypertrophy caused by HFSD. Meanwhile, fCS-Ib showed powerful effects on moderating gut microbiota dysbiosis in the HFSD-fed mice. Supplement of fCS-Ib could reduce ratio of Firmicutes to Bacteroidetes by decreasing abundance of Lachnospiraceae and Allobaculum while increasing abundance of Porphyromonadaceae, Barnesiella, and Bacteroides. Our results showed that fCS-Ib could be further developed as a potential pharmaceutical agent to prevent metabolic syndromes and gut microbiota dysbiosis.

Topics: Adipocytes; Animals; Chondroitin Sulfates; Diet, High-Fat; Dysbiosis; Fatty Liver; Fructose; Gastrointestinal Microbiome; Humans; Hyperglycemia; Hyperlipidemias; Hypertrophy; Inflammation; Metabolic Syndrome; Mice; Obesity; Sea Cucumbers

CXCR2 ligands contribute to chondrocyte hypertrophy and apoptosis, important determinants in cartilage pathophysiology. We unraveled the kinetics of signaling, biochemical, transcriptional, and morphological events triggered by GROalpha in human osteoarthritic chondrocytes kept in three-dimensional culture. p38 MAPK activation was assessed with a highly sensitive ELISA. Effector caspase activation was evaluated by cleavage of a fluorogenic substrate. Gene expression of key markers of hypertrophy (MMP-13, Runx-2) and matrix synthesis (aggrecan), and of cathepsin B isoform CB(-2,3) was evaluated by real time PCR. Occurrence of the morphological markers of apoptosis was investigated by transmission electron microscopy (TEM). GROalpha led to p38 MAPK activation in passaged chondrocytes cultured in micromass but not as a high-density monolayer. This caused the downstream triggering of chondrocyte hypertrophy (MMP-13 and Runx-2 upregulation, and calcium deposition) and apoptosis/anoikis following concurrence of matrix degrading activity, and inhibition of matrix synthesis which also involved the induction of CB(-2,3). These phenomena proved to be dependent on the co-receptor role of sulfated glycosaminoglycans (sGAG) and the activation of p38 MAPK, since they were abrogated either by preincubation with soluble chondroitin-4 sulfate or p38 MAPK inhibitors. The co-receptor role of sGAG was further demonstrated by colocalization experiments of these molecules with GROalpha in the stimulated micromasses. These findings suggest that extracellular matrix exerts a regulatory role in chondrocytes differentiation, and that meaningful investigation of the effects of chemokines on chondrocyte biology requires culture conditions respectful of both the differentiated status of the chondrocytes and of their three-dimensional interaction with the extracellular matrix.

Topics: Adult; Aged; Aged, 80 and over; Alternative Splicing; Apoptosis; Cartilage; Cathepsin B; Cell Differentiation; Cells, Cultured; Chemokine CXCL1; Chemokines, CXC; Chondrocytes; Chondroitin Sulfates; Core Binding Factor Alpha 1 Subunit; Enzyme Activation; Extracellular Matrix; Glycosaminoglycans; Humans; Hypertrophy; Matrix Metalloproteinase 13; Middle Aged; Mitochondrial Proteins; p38 Mitogen-Activated Protein Kinases; Protein Isoforms; Up-Regulation

Following neurulation, the anterior end of the neural tube undergoes a dramatic increase in size due mainly to the enlarging of the brain cavity. This cavity is filled with so-called neural tube fluid (NTF), whose positive pressure has been shown to play a key role in brain morphogenesis. This fluid contains a water-soluble matrix, rich in chondroitin sulfate (CS), which has been proposed as an osmotic regulator of NTF pressure genesis. The purpose of the present study is to observe the influence of CS on NTF osmolality and its relation to NTF hydrostatic pressure and brain expansion. NTF was obtained by means of microaspiration from the mesencephalic cavity of chick embryos. The osmolality of NTF between H.H. stages 20 and 29 was measured on the basis of its cryoscopic point. CS synthesis was disrupted by using beta-D-xyloside and the induced variations in brain volume were measured by means of morphometry. We also measured the variations in NTF osmolality, hydrostatic pressure, and the concentration of CS and sodium induced by means of beta-D-xyloside. Our data reveal that, at the earliest stages of development analyzed, variations in NTF osmolality show a characteristic pattern that coincides with the developmental changes in the previously described fluid pressure. Chick embryos treated with beta-D-xyloside, a chemical that disrupts CS synthesis, displayed a notable increase in brain volume but no other apparent developmental alterations. Morphometric analysis revealed that this increase was due to hyperenlargement of the brain cavity. Beta-D-xyloside brings about specific changes in the biochemical composition of NTF, which entails a large increase in CS concentration, mainly in the form of free chains, and in that of sodium. As a result, the fluid's osmolality and brain intraluminal pressure increased, which could account for the increase in size of the brain anlage. These data support the hypothesis that the intraluminal pressure involved in embryonic brain enlargement is directly dependent on NTF osmolality, and that the concentrations of CS and its associated microions could play a key role in the regulation of this process.

Topics: Animals; Brain; Cerebrospinal Fluid; Chick Embryo; Chondroitin Sulfates; Glycosides; Hypertrophy; Morphogenesis; Neurons; Osmotic Pressure

Morphometrical and histochemical techniques were used to demonstrate changes to the cartilage layer of the rat temporomandibular joint condyle following chronic exposure to fluoride. An increase in thickness of the cartilage layer was noted in rats given 100 parts per million sodium fluoride in drinking water. No significant changes were observed with either control or low dose (10 parts per million) groups. The observed thickening was attributable to an increase in number and size of cells of the lower hypertrophic zone. Accumulations of glycogen were observed in these cells, which reflects the inhibitory effect of fluoride on glycolysis. Stimulation of chondrocytes by fluoride may have delayed the normal processes of capillary invasion, resulting in thickening of the cartilage layer. No changes to staining patterns of immature or mature types of collagen were observed, nor did the staining pattern of detectable glycosaminoglycans change due to fluoride.

Topics: Animals; Cartilage; Cell Nucleus; Chondroitin Sulfates; Collagen; Cytoplasm; Drug Administration Schedule; Glycogen; Hypertrophy; Inclusion Bodies; Keratan Sulfate; Mandibular Condyle; Microscopy, Electron; Rats; Rats, Inbred Strains; Sodium Fluoride

Parallel histological stains and immunohistological stains were made of hypertrophic scars and normal scars in order to identify the type of cells and associated proteoglycans present in perivascular cuffs in hypertropic scars. Tissue sections were treated with monoclonal antibodies which specifically recognize T-cells and unsulphated, 4-sulphated and 6-sulphated chondroitin proteoglycans. There was a striking association between the perivascular lymphocytic infiltration and chondroitin-4-sulphate, which may be an important contributory factor in the development of hypertrophic scars.

Topics: Adolescent; Chondroitin Sulfates; Cicatrix; Humans; Hypertrophy; Immunohistochemistry; Proteoglycans; Skin; T-Lymphocytes; Wound Healing

Chondro-osseous tissue from four patients with the Kniest dysplasia was studied histochemically using a new plastic embedding technique. Extensive vacuolar changes were observed p--1 throughout the endochondral growth plate and adjacent resting cartilage. These changes occurred within the cartilage matrix and also in the lacunae of degenerating chrondrocytes. The septa of the lesions contained chondroitin sulfate, but little keratan sulfate or collagen. Resting cartilage not adjacent to the growth plate stained irregularly and showed few of the vacuolar lesions, and chondrocytes were enlarged and contained cytoplasic inclusions, but no vacuolar material. Thus, there appears to be a sequence of events initiated by cellular accumulation of a substance and progressing to cellular and matrix degeneration.

Topics: Adolescent; Adult; Bone and Bones; Bone Diseases, Developmental; Cartilage; Cartilage Diseases; Child; Chondroitin Sulfates; Collagen; Female; Humans; Hypertrophy; Keratan Sulfate; Proteoglycans; Syndrome

The collagen fibers of the nodules and whorl-like figures in hypertrophic scars are "coated" with proteoglycans, mainly chondroitin-4-sulfate. The latter was shown to prevent collagenase from breaking down collagen. This suggests that the presence of great amounts of chondroitin-4-sulfate in hypertrophic scars may contribute to the overabundance of collagen deposition which is characteristic of this abnormal healing process.

Topics: Child; Child, Preschool; Chondroitin Sulfates; Cicatrix; Collagen; Humans; Hypertrophy; Microbial Collagenase; Proteoglycans