Glycosaminoglycans In Tissues Research Articles

Widespread Vascularization and Correlation of Glycosaminoglycan Accumulation to Tendon Pain in Human Plantar Fascia Tendinopathy

Background: Plantar fasciitis is a painful tendinous condition (tendinopathy) with a high prevalence in athletes. While a healthy tendon has limited blood flow, ultrasound has indicated elevated blood flow in tendinopathy, but it is unknown if this is related to a de facto increase in the tendon vasculature. Likewise, an accumulation of glycosaminoglycans (GAGs) is observed in tendinopathy, but its relationship to clinical pain is unknown. Purpose: To explore to what extent vascularization, inflammation, and fat infiltration were present in patients with plantar fasciitis and if they were related to clinical symptoms. Study Design: Descriptive laboratory study. Methods: Biopsy specimens from tendinopathic plantar fascia tissue were obtained per-operatively from both the primary site of tendon pain and tissue swelling (“proximal”) and a region that appeared macroscopically healthy at 1 to 2 cm away from the primary site (“distal”) in 22 patients. Biopsy specimens were examined with immunofluorescence for markers of blood vessels, tissue cell density, fat infiltration, and macrophage level. In addition, pain during the first step in the morning (registered during an earlier study) was correlated with the content of collagen and GAGs in tissue. Results: High vascularization (and cellularity) was present in both the proximal (0.89%) and the distal (0.96%) plantar fascia samples, whereas inconsistent but not significantly different fat infiltration and macrophage levels were observed. The collagen content was similar in the 2 plantar fascia regions, whereas the GAG content was higher in the proximal region (3.2% in proximal and 2.8% in distal; P = .027). The GAG content in the proximal region was positively correlated with the subjective morning pain score in the patients with tendinopathy (n = 17). Conclusion: In patients with plantar fasciitis, marked tissue vascularization was present in both the painful focal region and a neighboring nonsymptomatic area. In contrast, the accumulation of hydrophilic GAGs was greater in the symptomatic region and was positively correlated with increased clinical pain levels in daily life. Clinical Relevance: The accumulation of GAGs in tissue rather than the extent of vascularization appears to be linked with the clinical degree of pain symptoms of the disease.

Disturbances in mitochondrial bioenergetics and control quality and unbalanced redox homeostasis in the liver of a mouse model of mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a lysosomal storage disease caused by mutations in the gene encoding the enzyme iduronate 2-sulfatase (IDS) and biochemically characterized by the accumulation of glycosaminoglycans (GAGs) in different tissues. It is a multisystemic disorder that presents liver abnormalities, the pathophysiology of which is not yet established. In the present study, we evaluated bioenergetics, redox homeostasis, and mitochondrial dynamics in the liver of 6-month-old MPS II mice (IDS-). Our findings show a decrease in the activity of α-ketoglutarate dehydrogenase and an increase in the activities of succinate dehydrogenase and malate dehydrogenase. The activity of mitochondrial complex I was also increased whereas the other complex activities were not affected. In contrast, mitochondrial respiration, membrane potential, ATP production, and calcium retention capacity were not altered. Furthermore, malondialdehyde levels and 2',7'-dichlorofluorescein oxidation were increased in the liver of MPS II mice, indicating lipid peroxidation and increased ROS levels, respectively. Sulfhydryl and reduced glutathione levels, as well as glutathione S-transferase, glutathione peroxidase (GPx), superoxide dismutase, and catalase activities were also increased. Finally, the levels of proteins involved in mitochondrial mass and dynamics were decreased in knockout mice liver. Taken together, these data suggest that alterations in energy metabolism, redox homeostasis, and mitochondrial dynamics can be involved in the pathophysiology of liver abnormalities observed in MPS II.

Evaluation of tendon and ligament microstructure and mechanical properties in a canine model of mucopolysaccharidosis I.

Mucopolysaccharidosis (MPS) I is a lysosomal storage disorder characterized by deficient alpha-l-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a strong clinical need for improved treatment approaches that specifically target joint tissues; however, their development is hampered by poor understanding of underlying disease pathophysiology, including how pathological changes to component tissues contribute to overall joint dysfunction. Ligaments and tendons, in particular, have received very little attention, despite the critical roles of these tissues in joint stability and biomechanical function. The goal of this study was to leverage the naturally canine model to undertake functional and structural assessments of the anterior (cranial) cruciate ligament (CCL) and Achilles tendon in MPS I. Tissues were obtained postmortem from 12-month-old MPS I and control dogs and tested to failure in uniaxial tension. Both CCLs and Achilles tendons from MPS I animals exhibited significantly lower stiffness and failure properties compared to those from healthy controls. Histological examination revealed multiple pathological abnormalities, including collagen fiber disorganization, increased cellularity and vascularity, and elevated GAG content in both tissues. Clinically, animals exhibited mobility deficits, including abnormal gait, which was associated with hyperextensibility of the stifle and hock joints. These findings demonstrate that pathological changes to both ligaments and tendons contribute to abnormal joint function in MPS I, and suggest that effective clinical management of joint disease in patients should incorporate treatments targeting these tissues.

Identification of new variants in patients with mucopolysaccharidosis in consanguineous Iranian families.

Introduction: Mucopolysaccharidoses are a group of lysosomal storage disorders that include seven types that are classified based on the enzymes that are disrupted. Malfunction of these enzymes leads to the accumulation of glycosaminoglycans (GAGs) in various tissues. Due to genetic and clinical heterogeneity, diagnosing and distinguishing the different types is challenging. Genetic methods such as whole exome sequencing (WES) and Sanger sequencing are accurate methods for detecting pathogenic variants in patients. Methods: Thirty-two cases of mucopolysaccharidosis, predominantly from families with consanguineous marriages, were genetically examined. Out of these, fourteen cases underwent targeted sequencing, while the rest underwent WES. The results of WES were analyzed and the pathogenicity of the variants was examined using bioinformatics tools. In addition, a segregation analysis within families was carried out. Results: In most cases, a pathogenic or likely pathogenic variant was detected. Sixteen previously reported variants and six new variants were detected in the known IDS (c.458G>C, c.701del, c.920T>G), GNS (c.1430A>T), GALNS (c.1218_1221dup), and SGSH (c.149T>C) genes. Furthermore, we discovered a c.259G>C substitution in the NAGLU gene for the first time in three homozygous patients. This substitution was previously reported as heterozygous. Except for the variants related to the IDS gene, which were hemizygous, all the other variants were homozygous. Discussion: It appears that the high rate of consanguineous marriages in the families being studied has had a significant impact on the occurrence of this disease. Overall, these findings could expand the spectrum of pathogenic variants in mucopolysaccharidoses. Genetic methods, especially WES, are very accurate and can be used alone or in conjunction with other diagnostic methods for a more precise and rapid diagnosis of mucopolysaccharidoses. Additionally, they could be beneficial for family screening and disease prevention.

Capsular and retinaculum thickening in type II mucopolysaccharidosis: a novel MRI finding.

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by a deficiency of glycosaminoglycan (GAG) catalytic enzymes, resulting in an accumulation of unprocessed or partly degraded GAGs in different tissues, including bones and joints. Notably, skeletal and joint abnormalities may be the first complaint that prompts patients to seek medical attention, especially in the milder forms of the disease. To our knowledge, there are no prior imaging reports that have documented capsuloligamentous thickening in patients with MPS on MRI. In this study, we present four cases of patients with clinically and genetically confirmed diagnosis of type II MPS, encompassing seven MRI examination of different joints, including cervical spine, hip, wrist, knee, and shoulder. All of the patients were male, aged between 14 and 35years, and exhibited varying degrees of joint stiffness in the clinical examination and carpal tunnel syndrome in cases of the wrist joint was affected. None of the patients had a history of surgical procedures on the affected joint, other metabolic or deposit diseases, or sports activity practice. The MRI revealed significant capsuloligamentous and retinaculum thickening, up to eight times greater than the normal capsular thickness reported in the literature.

Reduction of lysosome abundance and GAG accumulation after odiparcil treatment in MPS I and MPS VI models

Deficiencies of lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAG) cause pathologies commonly known as the mucopolysaccharidoses (MPS). Each type of MPS is caused by a deficiency in a specific GAG-degrading enzyme and is characterized by an accumulation of disease-specific GAG species. Previously, we have shown the potential of the beta-D-xyloside, odiparcil, as an oral GAG clearance therapy for Maroteaux-Lamy syndrome (MPS VI), an MPS characterized by an accumulation of chondroitin sulphate (CS) and dermatan sulphate (DS). This work suggested that odiparcil acts via diverting the synthesis of CS and DS into odiparcil-bound excretable GAG. Here, we investigated the effect of odiparcil on lysosomal abundance in fibroblasts from patients with MPS I and MPS VI. In MPS VI fibroblasts, odiparcil reduced the accumulation of a lysosomal-specific lysotracker dye. Interestingly, a reduction of the lysotracker dye was also observed in odiparcil-treated fibroblasts from patients with MPS I, a disorder characterized by an accumulation of DS and heparan sulphate (HS). Furthermore, odiparcil was shown to be effective in reducing CS, DS, and HS concentrations in liver and eye, as representative organs, in MPS VI and MPS I mice treated with 3 doses of odiparcil over 3 and 9 months, respectively. In conclusion, our data demonstrates odiparcil efficiently reduced lysosome abundance and tissue GAG concentrations in in vitro and in vivo models of MPS VI and MPS I and has potential as a treatment for these disorders.

3D-Bioprinted Biomimetic Multilayer Implants Comprising Microfragmented Adipose Extracellular Matrix and Cells Improve Wound Healing in a Murine Model of Full-Thickness Skin Defects.

Repairing full-thickness skin defects is a major challenge in clinical practice. Three-dimensional (3D) bioprinting of living cells and biomaterials is a promising technique to resolve this challenge. However, the time-consuming preparation and limited sources of biomaterials are bottlenecks that must be addressed. Therefore, we developed a simple and fast method to directly process adipose tissue into a microfragmented adipose extracellular matrix (mFAECM) as the main component of bioink to fabricate 3D-bioprinted, biomimetic, multilayer implants. The mFAECM retained most of the collagen and sulfated glycosaminoglycans in the native tissue. In vitro, the mFAECM composite demonstrated biocompatibility, printability, and fidelity and could support cell adhesion. In a full-thickness skin defect model in nude mice, cells encapsulated in the implant survived and participated in wound repair after implantation. The basic structures of the implant were maintained throughout wound healing and gradually metabolized. The biomimetic multilayer implants fabricated via mFAECM composite bioinks and cells could accelerate wound healing by promoting the contraction of new tissue inside the wound, collagen secretion and remodeling, and neovascularization. This study provides an approach for improving the timeliness of fabricating 3D-bioprinted skin substitutes and may offer a useful tool for treating full-thickness skin defects.

Tissue Sodium Accumulation Induces Organ Inflammation and Injury in Chronic Kidney Disease.

High salt intake is a primary cause of over-hydration in chronic kidney disease (CKD) patients. Inflammatory markers are predictors of CKD mortality; however, the pathogenesis of inflammation remains unclear. Sodium storage in tissues has recently emerged as an issue of concern. The binding of sodium to tissue glycosaminoglycans and its subsequent release regulates local tonicity. Many cell types express tonicity-responsive enhancer-binding protein (TonEBP), which is activated in a tonicity-dependent or tonicity-independent manner. Macrophage infiltration was observed in the heart, peritoneal wall, and para-aortic tissues in salt-loading subtotal nephrectomized mice, whereas macrophages were not prominent in tap water-loaded subtotal nephrectomized mice. TonEBP was increased in the heart and peritoneal wall, leading to the upregulation of inflammatory mediators associated with cardiac fibrosis and peritoneal membrane dysfunction, respectively. Reducing salt loading by a diuretic treatment or changing to tap water attenuated macrophage infiltration, TonEBP expression, and inflammatory marker expression. The role of TonEBP may be crucial during the cardiac fibrosis and peritoneal deterioration processes induced by sodium overload. Anti-interleukin-6 therapy improved cardiac inflammation and fibrosis and peritoneal membrane dysfunction. Further studies are necessary to establish a strategy to regulate organ dysfunction induced by TonEBP activation in CKD patients.

Free-aldehyde neutralized and oligohyaluronan loaded bovine pericardium with improved anti-calcification and endothelialization for bioprosthetic heart valves.

The number of patients with valvular heart disease is increasing yearly, and valve replacement is the most effective treatment, during which bioprosthetic heart valves (BHVs) are the most widely used. Commercial BHVs are mainly prepared with glutaraldehyde (Glut) cross-linked bovine pericardial or porcine aortic valves, but the residual free aldehyde groups in these tissues can cause calcification and cytotoxicity. Moreover, insufficient glycosaminoglycans (GAGs) in tissues can further reduce biocompatibility and durability. However, the anti-calcification performance and biocompatibility might be improved by blocking the free aldehyde groups and increasing the GAGs content in Glut-crosslinked tissues. In our study, adipic dihydrazide (ADH) was used to neutralize the residual free aldehyde groups in tissues and provide sites to blind with oligohyaluronan (OHA) to increase the content of GAGs in tissues. The modified bovine pericardium was evaluated for its content of residual aldehyde groups, the amount of OHA loaded, physical/chemical characteristics, biomechanical properties, biocompatibility, and in vivo anticalcification assay and endothelialization effects in juvenile Sprague-Dawley rats. The results showed that ADH could completely neutralize the free aldehyde groups in the Glut-crosslinked bovine pericardium, the amount of OHA loaded increased and the cytotoxicity was reduced. Moreover, the in vivo results also showed that the level of calcification and inflammatory response in the modified pericardial tissue was significantly reduced in a rat subcutaneous implantation model, and the results from the rat abdominal aorta vascular patch repair model further demonstrated the improved capability of the modified pericardial tissues for endothelialization. Furthermore, more α-SMA+ smooth muscle cells and fewer CD68+ macrophages infiltrated in the neointima of the modified pericardial patch. In summary, blocking free-aldehydes and loading OHA improved the anti-calcification, anti-inflammation and endothelialization properties of Glut-crosslinked BHVs and in particularly, this modified strategy may be a promising candidate for the next-generation of BHVs.

Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS-/- NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.

A swelling-based biphasic analysis on the quasi-static biomechanical behaviors of healthy and degenerative intervertebral discs

Background and ObjectiveThe degeneration of intervertebral discs is significantly dependent of the changes in tissue composition ratio and tissue structure. Up to the present, the effects of degeneration on the quasi-static biomechanical responses of discs have not been well understood. The goal of this study is to quantitatively analyze the quasi-static responses of healthy and degenerative discs. MethodsFour biphasic swelling-based finite element models are developed and quantitatively validated. Four quasi-static test protocols, including the free-swelling, slow-ramp, creep and stress-relaxation, are implemented. The double Voigt and double Maxwell models are further used to extract the immediate (or residual), short-term and long-term responses of these tests. ResultsSimulation results show that both the swelling-induced pressure in the nucleus pulposus and the initial modulus decrease with degeneration. In the free-swelling test of discs possessing healthy cartilage endplates, simulation results show that over 80% of the total strain is contributed by the short-term response. The long-term response is dominant for discs with degenerated permeability in cartilage endplates. For the creep test, over 50% of the deformation is contributed by the long-term response. In the stress-relaxation test, the long-term stress contribution occupies approximately 31% of total response and is independent of degeneration. Both the residual and short-term responses vary monotonically with degeneration. In addition, both the glycosaminoglycan content and permeability affect the engineering equilibrium time constants of the rheologic models, in which the determining factor is the permeability. ConclusionsThe content of glycosaminoglycan in intervertebral soft tissues and the permeability of cartilage endplates are two critical factors that affect the fluid-dependent viscoelastic responses of intervertebral discs. The component proportions of the fluid-dependent viscoelastic responses depend also strongly on test protocols. In the slow-ramp test, the glycosaminoglycan content is responsible for the changes of the initial modulus. Since existing computational models simulate disc degenerations only by altering disc height, boundary conditions and material stiffness, the current work highlights the significance of biochemical composition and cartilage endplates permeability in the biomechanical behaviors of degenerated discs.

Dexamethasone effects on the expression and content of glycosylated components of mouse brain tissue

Introduction. Glucocorticoids are actively used in the treatment of various diseases, however their long-term use leads to numerous negative side-effects, the molecular mechanisms of which remain poorly understood.Aim. Study of the short-term (1–10 days) effects of various doses of dexamethasone (Dex) (0,1–10 mg/kg) on the expression of the glucocorticoid receptor (GR, Nr3c1), core proteins of main proteoglycans and heparan sulfate metabolism-involved genes, as well as the content of carbohydrate macromolecules of glycosaminoglycans in the brain tissue of experimental animals.Materials and methods. In the study, C57Bl/6 mice were used. The expression of GR, proteoglycan core proteins and heparan sulfate metabolism-involved genes was determined by real-time polymerase chain reaction with reverse transcription. The content and localization of GR protein molecule were studied by Western blot and immunohistochemical analysis, and the glycosaminoglycan content was determined by dot-blot analysis and Alcian Blue staining.Results. It was shown that a single Dex administration leads to fast (1–3 days) short-term activation of GR expression (+1.5 times, p <0.05), proteoglycan’s genes (syndecan-3, Sdc3; perlecan, Hspg2; phosphacan, Ptprz1; neurocan, Ncan; +2–3-fold; p <0.05) and heparan sulfate-metabolism-involved genes (Ndst1, Glce, Hs2st1, Hs6st1, Sulf1 / 2; +1.5–2-fold; p <0.05) in the mouse brain, with a return to control values by 7–10 days after Dex administration. At the same time, the effect of Dex on carbohydrate macromolecules of glycosaminoglycans was more delayed and stable, increasing the content of low-sulfated glycosaminoglycans in the brain tissue in a dose-dependent manner starting from day 1 after Dex administration. Highly-sulfated glycosaminoglycans showed more delayed response to Dex administration, and an increase in their content was observed only at higher doses (2.5 and 10 mg/kg) and only on 7–10 days after its administration, apparently, mainly due to an increase in heparan sulfate content.Conclusion. In general, the effect of a single injection of Dex on the transcriptional activity of GR, proteoglycan core proteins and heparan sulfate metabolism-involved genes were short-termed, and the genes expression quickly returned to the normal levels. However, even a single use of Dex significantly increased the content of total as well as highly sulfated glycosaminoglycans in the mouse brain tissue, which can lead to the changes in the composition and structure of the brain tissue, as well as its functional characteristics.

Gene therapy for cross-correction of somatic organs and the CNS in mucopolysaccharidosis II in rodents and non-human primates

Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by deficient activity of iduronate-2-sulfatase (I2S), leading to pathological accumulation of glycosaminoglycans (GAGs) in tissues. We used iduronate-2-sulfatase knockout (Ids KO) mice to investigate if liver-directed recombinant adeno-associated virus vectors (rAAV8-LSP-hIDSco) encoding human I2S (hI2S) could cross-correct I2S deficiency in Ids KO mouse tissues, and we then assessed the translation of mouse data to non-human primates (NHPs). Treated mice showed sustained hepatic hI2S production, accompanied by normalized GAG levels in somatic tissues (including critical tissues such as heart and lung), indicating systemic cross-correction from liver-secreted hI2S. Brain GAG levels in Ids KO mice were lowered but not normalized; higher doses were required to see improvements in brain histology and neurobehavioral testing. rAAV8-LSP-hIDSco administration in NHPs resulted in sustained hepatic hI2S production and therapeutic hI2S levels in cross-corrected somatic tissues but no hI2S exposure in the central nervous system, perhaps owing to lower levels of liver transduction in NHPs than in mice. Overall, we demonstrate the ability of rAAV8-LSP-hIDSco to cross-correct I2S deficiency in mouse somatic tissues and highlight the importance of showing translatability of gene therapy data from rodents to NHPs, which is critical for supporting translation to clinical development.

Anaesthetic challenges faced in a child with Morquio syndrome- An orphan disease

: Morquio syndrome is a progressive lysosomal storage disorder leading to accumulation of glycosaminoglycans in the soft tissue, cartilage, and bone causing skeletal dysplasia. : We present a four-year-old child diagnosed with right side inguinal hernia posted for herniotomy. He had a large head with short neck and kyphoscoliosis. Pre-operative MRI whole spine shows a hypoplastic dens causing canal stenosis, indenting the cord at C1 level. General Anesthesia was planned. With a video laryngoscope on standy by, patient was induced after stabilizing the neck with a custom neck collar and the airway was secured with a Proseal Laryngeal Mask Airway.: The airway management can be challenging because of accumulation of mucopolysaccharides in the soft tissue of upper airway and limited mouth opening due to involvement of temporo mandibular joints. A thorough pre-operative evaluation of airway must be done and a well planned anaesthetic technique must be executed.

Quantification of Glycosaminoglycans in Urine by Isotope‐Dilution Liquid Chromatography‐Electrospray Ionization Tandem Mass Spectrometry

Mucopolysaccharidoses (MPSs) are complex lysosomal storage disorders that result in the accumulation of glycosaminoglycans (GAGs) in urine, blood, and tissues. Lysosomal enzymes responsible for GAG degradation are defective in MPSs. GAGs including chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS) are disease-specific biomarkers for MPSs. This article describes a stable isotope dilution-tandem mass spectrometric method for quantifying CS, DS, and HS in urine samples. The GAGs are methanolyzed to uronic or iduronic acid-N-acetylhexosamine or iduronic acid-N-sulfo-glucosamine dimers and mixed with internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from HS, DS, and CS are separated by ultra-performance liquid chromatography (UPLC) and analyzed by electrospray ionization tandem mass spectrometry (MS/MS) using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. This UPLC-MS/MS GAG assay is useful for identifying patients with MPS types I, II, III, VI, and VII. © 2023 Wiley Periodicals LLC. Basic Protocol: Urinary GAG analysis by ESI-MS/MS Support Protocol 1: Prepare calibration samples Support Protocol 2: Preparation of stable isotope-labeled internal standards Support Protocol 3: Preparation of quality controls for GAG analysis in urine Support Protocol 4: Optimization of the methanolysis time Support Protocol 5: Measurement of the concentration of methanolic HCl.

Dental Considerations for the Treatment of Patients with Morquio Syndrome.

Morquio syndrome, also called Mucopolysaccharidosis IV (MPS IV), is a rare autosomal recessive metabolic lysosomal disorder that results in the deposition of glycosaminoglycans (GAGs) in various tissues and organs, resulting in an array of signs and symptoms. The aim of the study was to systematically record the clinical features with a special emphasis on oral manifestations of patients diagnosed with MPS IV and asses the dental treatment implications of the disease manifestations. A cross-sectional study was conducted on patients diagnosed with MPS IV (n = 26). A complete clinical and oral examination was done and the findings were systemically recorded. The study showed that the patients diagnosed with MPS IV have multiple treatment challenges owing to the range of disease manifestations. Furthermore, they have higher oral health care needs because of the anatomical and pathological changes. Dental professionals must be aware of the implications of the disease manifestation and their accompanying challenges while treating patients with MPS IV. The oral health needs are higher for these patients and regular dental evaluation and treatment must be incorporated into their health care regimen. Vinod A, Raj SN, Anand A, et al. Dental Considerations for the Treatment of Patients with Morquio Syndrome. Int J Clin Pediatr Dent 2022;15(6):707-710.

Paclitaxel-induced neuropathy induces changes in oral cavity organs of rats

The developmental mechanisms of pathological changes in the oral cavity organs, in particular, periodontal tissues and salivary glands, were elucidated in the model of paclitaxel-induced neuropathy. Experimental studies were performed on 41 white nonlinear rats of both sexes weighing 180–220 g. Toxic neuropathy was modeled by intraperitoneal injection of paclitaxel (Actavis Ltd; series 5GN5122) 2 mg/kg for 4 days (0, 2, 4 and 6). The presence of paclitaxel-induced peripheral neuropathy was confirmed by the Randall-Selitto tensoalgometric test to determine the threshold of pain sensitivity. The total proteolytic activity, total antitryptic activity, and the content of TBA-active products were determined in the homogenate of the rat submandibular and sublingual salivary glands and periodontal soft tissues, content of oxidatively modified proteins, content of average mass molecules and catalase activity; α-amylase activity was also determined in the salivary glands of animals, and the content of free fucose and glycosaminoglycans in periodontal tissues. Paclitaxel-induced neuropathy causes the development of pathological changes in the oral cavity, in particular in periodontal tissues and salivary glands of rats, as evidenced by impaired proteinase-inhibitory potential, intensification of carbonyl oxidative stress, inhibition of protein synthetic function in salivary glands and increased depolymerization of non-collagenous proteins in periodontal soft tissues.

Proteomics identifies novel biomarkers of synovial joint disease in a canine model of mucopolysaccharidosis I.

Mucopolysaccharidosis I is a lysosomal storage disorder characterized by deficient alpha-L-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a critical need for improved understanding of joint disease pathophysiology in MPS I, including specific biomarkers to predict and monitor joint disease progression, and response to treatment. The objective of this study was to leverage the naturally-occurring MPS I canine model and undertake an unbiased proteomic screen to identify systemic biomarkers predictive of local joint disease in MPS I. Synovial fluid and serum samples were collected from MPS I and healthy dogs at 12 months-of-age, and protein abundance characterized using liquid chromatography tandem mass spectrometry. Stifle joints were evaluated postmortem using magnetic resonance imaging (MRI) and histology. Proteomics identified 40 proteins for which abundance was significantly correlated between serum and synovial fluid, including markers of inflammatory joint disease and lysosomal dysfunction. Elevated expression of three biomarker candidates, matrix metalloproteinase 19, inter-alpha-trypsin inhibitor heavy-chain 3 and alpha-1-microglobulin, was confirmed in MPS I cartilage, and serum abundance of these molecules was found to correlate with MRI and histological degenerative grades. The candidate biomarkers identified have the potential to improve patient care by facilitating minimally-invasive, specific assessment of joint disease progression and response to therapeutic intervention.

Новые маркеры генитального пролапса

Pelvic organ prolapse (POP) is a very considerable problem not only due to its high prevalence, but also because of the significant decrease in the quality of life of women suffering from this disease. Given the high prevalence, pelvic floor disorders requiring plastic surgery are becoming an economic problem for public health. In recent decades, techniques for the treatment of pelvic floor dysfunction (PFD) have evolved rapidly. However, the pathophysiology of this disease is still poorly understood, which may be the reason for inadequate, untimely, and sometimes ineffective treatment of POP. One of the important findings when analyzing the results of morphological and morphometric studies of the levator ani muscle in PFD and clinical forms of POP became the detection of significant fibrous degradation of the pelvic floor muscular compartment in all the examined samples. Objective. To search for promising biomarkers of muscular and connective tissue remodeling and the interaction of the muscular and fascial compartments of the pelvic floor to predict pelvic organ prolapse. According to the literature, we found at least three candidate markers for assessing the condition of the muscular-fascial compartment of the pelvic floor: tenascin C, hyaluronic acid (HA), and myofibroblasts (MFB). Tenascin C is a non-structural component of the extracellular matrix of both muscular and connective tissue. Its role in the regulation of inflammation pathways has been discovered in recent studies, but in our study, this protein is of interest as a marker of tissue remodeling in case of tissue damage. Hyaluronic acid is one of the most abundant glycosaminoglycans in the connective tissue of vertebrates. HA is ubiquitous in fascial tissue, but its content is particularly high in loose connective tissue and between muscles and deep fascia. In the fascia, HA is not only a key structural component of the extracellular matrix, but also a functional one. The qualitative and quantitative analysis of HA content in pelvic floor fasciae is likely to help more accurately assess the tissue state, identify the nature of myofascial interaction during the formation of the hernia gate and may be the key to determining the treatment tactics for the initial signs of PFD. Myofibroblasts are connective tissue cells that represent an intermediate link between fibroblasts and smooth muscle cells. Their main task is to increase the basal tone and rigidity of the fascia and ensure proper muscular-skeletal dynamics. Normally, this tension is not enough for significant changes in musculature biomechanics, but persistent “hypertonicity” of the fascia quite quickly led to the formation of pathological contractures, which limited the motor activity of the underlying muscles. Thus, it can be assumed that myofibroblasts participate in the process of healing and remodeling of the fascial compartment. And the search for MFB in biopsy specimens of the levator ani muscle in patients with PFD can shed light on connective tissue dysplasia as the most controversial component of POP development. Conclusion. To date, the problem of pelvic organ prolapse remains unresolved in modern gynecology. When studying the literature, it became evident that determining the biochemical and biomechanical properties of the myofascial complex of the pelvic floor is necessary to gain a comprehensive picture of the disease. Although the significance of markers in predicting pelvic organ prolapse has not yet been investigated, we express optimistic expectations to find an ideal biomarker of the rate of PFD and POP development, improving knowledge about the pathogenesis of the disease. Key words: biomarkers, hyaluronic acid, myofibroblasts, pelvic organ prolapse, connective tissue, tenascin C

Characteristics of sulfated glycosaminoglycans in the cartilage tissue of skate and sturgeon

Sulfated glycosaminoglycans (GAGs) or chondroitin sulfates were obtained from the cartilage tissue of skate (indefinite species) and sturgeon (kaluga) under the processes of hydrothermal treatment of raw materials at 50 о C, then hydrolysis with proteolytic enzyme in 4 hours under temperature 45 о C (hydromodulus 1 : 1), then sequential precipitation of GAGs in 2–3 volumes of 96 о ethyl alcohol and salting out with 2 % sodium chloride solution. The content of hexosamines and sulfated GAGs was determined in the extracted samples. GAGs of both skate and sturgeon have a high content of sulfated forms, comparable to commercial preparations, that opens up prospects for development of technology for production of monocomponent biologically active additives of chondroprotective action from the wastes of skates and sturgeons processing.