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  • 1
    Keywords: ANGIOGENESIS ; EXPRESSION ; GROWTH ; SURVIVAL ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; human ; IN-VIVO ; VIVO ; SUPPORT ; DEATH ; GENE ; COMPONENTS ; MOLECULES ; MICE ; recombination ; MOLECULE ; knockout ; MOUSE ; CELL-DEATH ; AGE ; MUTATION ; COMPONENT ; inactivation ; EXTRACELLULAR-MATRIX ; PHENOTYPE ; DEGRADATION ; RECRUITMENT ; BONE-FORMATION ; SKELETAL DEVELOPMENT ; HOMOLOGOUS RECOMBINATION ; LACKING ; MMP ; MATRIX ; DEFICIENCY ; PROGRAM ; VARIANT ; collagen ; MICE LACKING ; II COLLAGEN ; aggrecan ; chondrocyte ; collagenase ; COLLAGENASE CLEAVAGE SITE ; DEVELOPING LONG BONES ; hypertrophic cartilage ; HYPERTROPHIC CHONDROCYTES ; OSTEOARTHRITIC CARTILAGE ; PARATHYROID-HORMONE ; SPONDYLOEPIMETAPHYSEAL DYSPLASIA ; trabecular bone
    Abstract: The assembly and degradation of extracellular matrix (ECM) molecules are crucial processes during bone development. In this study, we show that ECM remodeling is a critical rate-limiting step in endochondral bone formation. Matrix metalloproteinase (MMP) 13 (collagenase 3) is poised to play a crucial role in bone formation and remodeling because of its expression both in terminal hypertrophic chondrocytes in the growth plate. p and in osteoblasts. Moreover, a mutation in the human MMP13 gene causes the Missouri variant of spondyloepimetaphyseal dysplasia. Inactivation of Mmp13 in mice through homologous recombination led to abnormal skeletal growth plate development. Chondrocytes differentiated normally but their exit from the growth plate was delayed. The severity of the Mmp13-null growth plate phenotype increased until about 5 weeks and completely resolved by 12 weeks of age. Mmp13-null mice had increased trabecular bone, which persisted for months. Conditional inactivation of Mmp13 in chondrocytes and osteoblasts showed that increases in trabecular bone occur independently of the improper cartilage ECM degradation caused by Mmp13 deficiency in late hypertrophic chondrocytes. Our studies identified the two major components of the cartilage ECM, collagen type II and aggrecan, as in vivo substrates for MMP13. We found that degradation of cartilage collagen and aggrecan is a coordinated process in which MMP13 works synergistically with MMP9. Mice lacking both MMP13 and MMP9 had severely impaired endochondral bone, characterized by diminished ECM remodeling, prolonged chondrocyte survival, delayed vascular recruitment and defective trabecular bone formation (resulting in drastically shortened bones). These data support the hypothesis that proper ECM remodeling is the dominant rate-limiting process for programmed cell death, angiogenesis and osteoblast recruitment during normal skeletal morphogenesis
    Type of Publication: Journal article published
    PubMed ID: 15539485
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  • 2
    ISSN: 1432-0428
    Keywords: Key words: Hyaluronan ; prostaglandin ; sulphated proteoglycan ; glycosaminoglycan ; mesangial cell.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Exposure in vivo or in vitro to elevated glucose increases production of vasoactive prostaglandins by glomeruli and mesangial cells. This study aimed to determine whether this increased prostaglandin production could provide a link with later structural changes in diabetic nephropathy. Glomerular cores were prepared from control rats and streptozotocin-diabetic rats (3 weeks' duration). Over 24 h in culture hyaluronan production from diabetic glomerular cores was higher than production from control glomerular cores whether maintained in 5.6 mmol/l glucose (105.6 ± 15.5 vs 53.6 ± 8.5 ng hyaluronan per 250 glomerular cores, p 〈 0.001); in 25 mmol/l glucose (149.3 ± 34.8 vs 62.7 ± 7.8 ng hyaluronan per 250 glomerular cores, p 〈 0.01); or in 45 mmol/l glucose (176.8 ± 23.3 vs 102.0 ± 17.9 ng hyaluronan per 250 glomerular cores, p 〈 0.01). At 5.6 mmol/l glucose, exposure in vitro to prostaglandin E2 caused an increase in hyaluronan production [maximal at 10 − 9 mol/l prostaglandin E2, 237 ± 19 vs 42 ± 4, ng hyaluronan per 250 glomerular cores, p 〈 0.001 (control) and 195 ± 7 vs 103 ± 5, ng hyaluronan per 250 glomerular cores, p 〈 0.001 (diabetic) ]. In both control and diabetic glomerular cores hyaluronan production was reduced significantly by the cyclooxygenase inhibitor indomethacin (10−5 mol/l) [24.7 ± 3.33 vs 40.25 ± 4.11 ng hyaluronan per 250 glomerular cores, p 〈 0.05 (control) and 36.5 ± 6.25 vs 118.0 ± 22.6, p 〈 0.01 (diabetic) ]. A direct spectrophotometric microassay was used to determine the concentration of sulphated glycosaminoglycans derived from papain-digested glomerular core proteoglycans. Release of sulphated glycosaminoglycans from diabetic glomerular cores maintained at 5.6 mmol/l glucose was decreased [41.9 ± 1.1 vs 54.0 ± 1.0 μg of sulphated glycosaminoglycans (chondroitin sulphate) per 250 glomerular cores p 〈 0.01]. A decrease in sulphated glycosaminoglycans was also shown from control glomerular cores maintained at 25 mmol/l glucose. At this glucose concentration, addition of exogenous hyaluronan or prostaglandin E2 significantly reduced sulphated glycosaminoglycans from control and diabetic glomerular cores. It is concluded that increased prostaglandin production secondary to high glucose environment can lead to an increased glomerular hyaluronan synthesis. This can substantially affect the levels of sulphated glycosaminoglycans in the extracellular matrix. We propose that these effects provide a possible link between the initial biochemical consequences of hyperglycaemia and later structural changes seen in the glomerulus in diabetes. [Diabetologia (1995) 38: 298–305]
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Hyaluronan ; prostaglandin ; sulphated proteoglycan ; glycosaminoglycan ; mesangial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Exposure in vivo or in vitro to elevated glucose increases production of vasoactive prostaglandins by glomeruli and mesangial cells. This study aimed to determine whether this increased prostaglandin production could provide a link with later structural changes in diabetic nephropathy. Glomerular cores were prepared from control rats and streptozotocin-diabetic rats (3 weeks' duration). Over 24 h in culture hyaluronan production from diabetic glomerular cores was higher than production from control glomerular cores whether maintained in 5.6 mmol/l glucose (105.6±15.5 vs 53.6±8.5 ng hyaluronan per 250 glomerular cores, p〈0.001); in 25 mmol/l glucose (149.3±34.8 vs 62.7±7.8 ng hyaluronan per 250 glomerular cores, p〈0.01); or in 45 mmol/l glucose (176.8±23.3 vs 102.0±17.9 ng hyaluronan per 250 glomerular cores, p〈0.01). At 5.6 mmol/l glucose, exposure in vitro to prostaglandin E2 caused an increase in hyaluronan production [maximal at 10−9 mol/l prostaglandin E2, 237±19 vs 42±4, ng hyaluronan per 250 glomerular cores, p〈0.001 (control) and 195±7 vs 103±5, ng hyaluronan per 250 glomerular cores, p〈0.001 (diabetic)]. In both control and diabetic glomerular cores hyaluronan production was reduced significantly by the cyclooxygenase inhibitor indomethacin (10−5 mol/l) [24.7±3.33 vs 40.25±4.11 ng hyaluronan per 250 glomerular cores, p〈0.05 (control) and 36.5±6.25 vs 118.0±22.6, p〈0.01 (diabetic)]. A direct spectrophotometric microassay was used to determine the concentration of sulphated glycosaminoglycans derived from papain-digested glomerular core proteoglycans. Release of sulphated glycosaminoglycans from diabetic glomerular cores maintained at 5.6 mmol/l glucose was decreased [41.9±1.1 vs 54.0±1.0 Μg of sulphated glycosaminoglycans (chondroitin sulphate) per 250 glomerular cores p〈0.01]. A decrease in sulphated glycosaminoglycans was also shown from control glomerular cores maintained at 25 mmol/l glucose. At this glucose concentration, addition of exogenous hyaluronan or prostaglandin E2 significantly reduced sulphated glycosaminoglycans from control and diabetic glomerular cores. It is concluded that increased prostaglandin production secondary to high glucose environment can lead to an increased glomerular hyaluronan synthesis. This can substantially affect the levels of sulphated glycosaminoglycans in the extracellular matrix. We propose that these effects provide a possible link between the initial biochemical consequences of hyperglycaemia and later structural changes seen in the glomerulus in diabetes.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Aggrecan is the major proteoglycan in cartilage, endowing this tissue with the unique capacity to bear load and resist compression. In arthritic cartilage, aggrecan is degraded by one or more ‘aggrecanases’ from the ADAMTS (a disintegrin and metalloproteinase with ...
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 413 (2001), S. 475-476 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Thrombotic thrombocytopenic purpura is a potentially fatal human disease. It results from the widespread, abnormal aggregation of platelets and a protein, called von Willebrand factor, in the small blood vessels of many organs, including the brain and kidneys. The accumulated clots of platelets and ...
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  • 6
    ISSN: 0008-6215
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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