Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.6.1 (sulfatase)
3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The levels of six lysosomal enzymes (acid phosphatase, beta-acetylglucosaminidase, cathepsin D, beta-galactosidase, arylsulfatase A, and beta-glucuronidase) and four neutral and alkaline hydrolases (esterase, inorganic phyrophosphatase, alkaline phosphatase, and 5'-nucleotidase) were measured in osteoarthritic, rheumatoid and control synovia. All enzyme levels in diseased synovium except esterase values in osteoarthritis were significantly elevated compared with controls. The mean values of the group of acid hydrolases and the group of neutral and alkaline hydrolases in osteoarthritic synovia were 1.9- and 2.0-fold greater than those of control specimens. In rheumatoid synovia, the values were 4.2- and 4.5 fold greater than control for the same enzymes. Levels in rheumatoid synovia were significantly higher than those in osteoarthritic synovia with the exception of 5'-nucleotidase. Only a limited correlation between the extents of inflammation present in the synovia and the levels of a lysosomal marker enzyme (cathepsin D) was observed. These results demonstrate that whatever the mechanism, increased levels of acid hydrolases as well as certain neutral and alkaline hydrolases are present in osteoarthritic and rheumatoid synovia, and these enzymes are probably contained in the synovial lining cells.
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PMID:Acid, neutral, and alkaline hydrolases in arthritic synovium. 0 9

We studied the light microscopic, ultrastructural, and cytochemical characteristics of the temporomandibular joints of male ICR mice, from early neonatal life until they reached senescence, when spontaneous osteoarthritis is a common phenomenon. Aging of mandibular condylar cartilage was accompanied by decreasing total proteoglycan content and by an unmasking of collagen fibers, with no shift in collagen type. Fibronectin was also commonly present on the articular surface of specimens from old animals. Chondrocytes of aged mice contained an increased number of lysosomes, and their adjacent matrix vesicles reacted positively for acid phosphatase and arylsulfatase, but not for alkaline phosphatase. Such vesicles were also found to be devoid of calcium complexes and, thus, did not appear to be involved in the mineralization process. Similar age-related changes have been described in human mandibular condyles; hence, the male ICR mouse could serve as a useful model for studies of spontaneous osteoarthritis in the human mandibular joint.
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PMID:Morphologic and cytochemical changes in maturing and osteoarthritic articular cartilage in the temporomandibular joint of mice. 403 56

Severance of the anterior cruciate ligament in the knees of mature beagles caused instability and resulted in the slow onset of changes comparable to those present in human osteoarthritis (OA). Heightened cellular activities were reflected in increased levels of arylsulfatase, acid phosphatase, and beta-glucuronidase in the articular cartilage. Similar increases in these lysosomal enzyme activities were found in the synovial fluid of the operated joints. Dietary supplementation with vitamin C resulted in increased serum protein content and increased cartilage formation, although ascorbate had no effect on enzyme activities. The early stages of OA in mature beagles, therefore, were characterized by interference with normal chondrocyte metabolism which resulted in staggered elevation of different lysosomal enzymes.
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PMID:Metabolic response during early stages of surgically-induced osteoarthritis in mature beagles. 720 21

Developing osteoarthritis, surgically induced in the right hind knee joint of guinea pigs by different procedures (A or B), was studied in animals maintained on either minimal or supplemented levels of dietary vitamin C. Procedure A, consisting of transecting the anterior cruciate and major portion of the medial collateral ligaments, resulted in a slower developing and less severe form of the disease than procedure B which also included a partial menisectomy. Regardless of the surgical procedure used, animals on minimal levels of ascorbate always exhibited more severe pathology than those on high levels. When compared with controls, a significant enhancement of acid phosphatase characterized arthritic cartilage in both supplemented and minimal diet groups, although the increase was 2-fold greater in the latter. In addition, a significant elevation of arylsulfatase A and B activities was observed only in the minimal diet group. Early stages of pathology in both diet groups were characterized by formation of repair cartilage which stained strongly with Safranin O on histologic sections. As the disease progressed, pitting, ulcerations, and eburnation occurred in the minimal diet group. Cartilage weight in normal joints was greater for guinea pigs kept on high levels of vitamin C. It is likely that this stimulated synthesis of cartilage in the supplemented animals protected against the erosion of the articular cartilage which characterized the more severe disease process in the guinea pigs on minimal levels of ascorbate.
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PMID:Experimentally induced osteoarthritis in guinea pigs: metabolic responses in articular cartilage to developing pathology. 731 12

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-4-sulfatase (4S). A feline MPS VI model used to demonstrate efficacy of enzyme replacement therapy is due to the homozygous presence of an L476P mutation in 4-sulfatase. An additional mutation, D520N, inherited independently from L476P and recently identified in the same family of cats, has resulted in three clinical phenotypes. L476P homozygotes exhibit dwarfism and facial dysmorphia due to epiphyseal dysplasia, abnormally low leukocyte 4S/betahexosaminidase ratios, dermatan sulfaturia, lysosomal inclusions in most tissues including chondrocytes, corneal clouding, degenerative joint disease, and abnormal leukocyte inclusions. Similarly, D520N/D520N and L476P/D520N cats have abnormally low leukocyte 4S/betahexosaminidase ratios, mild dermatan sulfaturia, lysosomal inclusions in some chondrocytes, and abnormal leukocyte inclusions. However, both have normal growth and appearance. In addition, L476P/D520N cats have a high incidence of degenerative joint disease. We conclude that L476P/D520N cats have a very mild MPS VI phenotype not previously described in MPS VI humans. The study of L476P/D520N and D520N/ D520N genotypes will improve understanding of genotype to phenotype correlations and the pathogenesis of skeletal dysplasia and joint disease in MPS VI, and will assist in development of therapies to prevent lysosomal storage in chondrocytes.
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PMID:Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes. 942 72

Mucopolysaccharidosis (MPS) Type VI (Maroteaux-Lamy Disease) is the lysosomal storage disease characterized by deficient arylsulfatase B activity and the resultant accumulation of dermatan sulfate-containing glycosaminoglycans (GAGs). A major feature of this and other MPS disorders is abnormal cartilage and bone development leading to short stature, dysostosis multiplex, and degenerative joint disease. To investigate the underlying cause(s) of degenerative joint disease in the MPS disorders, articular cartilage and cultured articular chondrocytes were examined from rats and cats with MPS VI. An age-progressive increase in the number of apoptotic chondrocytes was identified in the MPS animals by terminal transferase nick-end translation (TUNEL) staining and by immunohistochemical staining with anti-poly (ADP-ribose) polymerase (PARP) antibodies. Articular chondrocytes grown from these animals also released more nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) into the culture media than did control chondrocytes. Notably, dermatan sulfate, the GAG that accumulates in MPS VI cells, induced NO release from normal chondrocytes, suggesting that GAG accumulation was responsible, in part, for the enhanced cell death in the MPS cells. Coculture of normal chondrocytes with MPS VI cells reduced the amount of NO release, presumably because of the release of arylsulfatase B by the normal cells and reuptake by the mutant cells. As a result of the enhanced chondrocyte death, marked proteoglycan and collagen depletion was observed in the MPS articular cartilage matrix. These results demonstrate that MPS VI articular chondrocytes undergo cell death at a higher rate than normal cells, because of either increased levels of dermatan sulfate and/or the presence of inflammatory cytokines in the MPS joints. In turn, this leads to abnormal cartilage matrix homeostasis in the MPS individuals, which further exacerbates the joint deformities characteristic of these disorders.
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PMID:Articular chondrocytes from animals with a dermatan sulfate storage disease undergo a high rate of apoptosis and release nitric oxide and inflammatory cytokines: a possible mechanism underlying degenerative joint disease in the mucopolysaccharidoses. 1155 79

The incidence of autoimmune diseases is higher in females than in males. In both sexes, adrenal hormones, that is, glucocorticoids, dehydroepiandrosterone (DHEA), and androgens, are inadequately low in patients when compared to healthy controls. Hormonally active androgens are anti-inflammatory, whereas estrogens are pro-inflammatory. Therefore, the mechanisms responsible for the alterations of steroid profiles in inflammation are of major interest. The local metabolism of androgens and estrogens may determine whether a given steroid profile found in a subject's blood results in suppression or promotion of inflammation. The steroid metabolism in mixed synovial cells, fibroblasts, macrophages, and monocytes was assessed. Major focus was on cells from patients with rheumatoid arthritis (RA), while cells from patients with osteoarthritis served as controls. Enzymes directly or indirectly involved in local sex steroid metabolism in RA are: DHEA-sulfatase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and aromatase (CYP19), which are required for the synthesis of sex steroids from precursors, 5alpha-reductase and 16alpha-hydroxylase, which can be involved either in the generation of more active steroids or in the pathways leading to depletion of active hormones, and 3alpha-reductase and 7alpha-hydroxylase (CYP7B), which unidirectionally are involved in the depletion of active hormones. Androgens inhibit aromatization in synovial cells when their concentration is sufficiently high. As large amounts of estrogens are formed in synovial tissue, there may be a relative lack of androgens. Production of 5alpha-reduced androgens should increase the local anti-inflammatory activity; however, it also opens a pathway for the inactivation of androgens. The data discussed here suggest that therapy of RA patients may benefit from the use of nonaromatizable androgens and/or the use of aromatase inhibitors.
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PMID:Inflammation and sex hormone metabolism. 1685 50

Degenerative joint disease (DJD) is one aspect of mucopolysaccharidosis VI (MPS VI) pathology that has proven resistant to systemic enzyme replacement therapy (ERT). In this study the effect of repeated intra-articular injections (IA INJ) of recombinant human acetylgalactosamine-4-sulfatase (rh4S) on DJD was examined. Four MPS VI cats received i.v. ERT weekly from birth plus IA INJ (0 or 500 microg of rh4S per joint; monthly or every three months) while three MPS VI cats received IA INJ only. After 10 months, shoulders, elbows and knees were compared. Taken individually, an improvement in joint appearance was observed between the joints that received rh4S monthly or every three months compared with the contralateral joints treated with buffer or at lower frequency. Within articular cartilage of joints treated more frequently, the depth of clearance of lysosomal storage tended to be greater and uronic acid content was reduced reflecting the removal of glycosaminoglycans. Synovium in treated joints also showed less storage. No abnormal clinical signs were observed after the IA INJ and negligible antibody titres were measured throughout the study. No clear benefit was observed by combining IA INJ with weekly ERT and the most significant improvement in joint appearance resulted from increased IA INJ frequency. These data support the view that intra-articular therapy may be a good option for preventing the development of the severe articular pathology in MPS VI.
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PMID:Long-term intra-articular administration of recombinant human N-acetylgalactosamine-4-sulfatase in feline mucopolysaccharidosis VI. 1754 10

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 microg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided.
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PMID:Mucopolysaccharidosis VI. 2038 7

Chondroitin sulfate (CS) has shown either ameliorating or aggravating effects on osteoarthritis (OA) in separately conducted clinical trials. Because CS is usually administered orally, it should be affected by or would impact on the individual gut microbiota. Evidence is accumulating that CS can nourish sulfatase-secreting bacteria (SSB) and sulfate-reducing bacteria (SRB). To decipher how can an individual gut microbiota determine the clinical values of CS for treatment on OA, we suggest here that CS would give distinct outcomes for OA treatment depending on Akkermansia muciniphila, a gut commensal probiotic bacterial species as optimal presence albeit also behaving as mucus-eroding bacteria (MEB) when abundant presence. Briefly, CS would ameliorate OA if A. muciniphila is present due to without overgrowth of SSB and SRB, whereas CS would aggravate OA if A. muciniphila is absent because of failure in or lack of competition with abundant SSB and SRB. By noting such a frequently ignored phenomenon, we urge the development of non-orally administering CS to minimize its side-effects and extend it to other medicinal applications.
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PMID:Akkermansia muciniphila May Determine Chondroitin Sulfate Ameliorating or Aggravating Osteoarthritis. 2906 8


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