Background: Mast cell chymase may be both pro-inflammatory and anti-inflammatory during infection and tissue damage. Results: Human and mouse chymases modulate extracellular levels of the alarmins Hsp70, biglycan, HMGB1, and IL-33. Conclusion: Mast cell chymase degrades alarmins and may limit inflammation. Significance: Identifying the physiological chymase substrates is crucial for understanding the role of chymase in immune responses and could aid in drug development.
Background: In Hurler syndrome, heparan sulfate (HS) accumulates and is associated with early childhood mortality. Results: Accumulated HS is abnormally highly sulfated and positively regulates N-deacetylase/N-sulfotransferase activity during HS biosynthesis.
Conclusion:We have identified a positive feedback loop in HS biosynthesis in Hurler syndrome that exacerbates the disease. Significance: This will aid the design of therapeutic strategies for Hurler syndrome.
Background: HSPG interacts with growth factors to influence growth and differentiation.Results: ES cells lacking NDST1 and NDST2 show very limited differentiation potential. FGF and heparin rescued formation of neural progenitors.Conclusion: HS-mediated FGF signaling is rate-limiting for commitment of primitive ectoderm to the neural lineageSignificance: This study shows the importance of the ratio between HSPG and FGF for neural differentiation.
Analysis of heparan sulfate synthesized by HEK 293 cells overexpressing murine NDST1 and/or NDST2 demonstrated that the amount of heparan sulfate was increased in NDST2-but not in NDST1-overexpressing cells. Altered transcript expression of genes encoding other biosynthetic enzymes or proteoglycan core proteins could not account for the observed changes. However, the role of NDST2 in regulating the amount of heparan sulfate synthesized was confirmed by analyzing heparan sulfate content in tissues isolated from Ndst2 ؊/؊ mice, which contained reduced levels of the polysaccharide. Detailed disaccharide composition analysis showed no major structural difference between heparan sulfate from control and Ndst2 ؊/؊ tissues, with the exception of heparan sulfate from spleen where the relative amount of trisulfated disaccharides was lowered in the absence of NDST2. In vivo transcript expression levels of the heparan sulfate-polymerizing enzymes Ext1 and Ext2 were also largely unaffected by NDST2 levels, pointing to a mode of regulation other than increased gene transcription. Size estimation of heparan sulfate polysaccharide chains indicated that increased chain lengths in NDST2-overexpressing cells alone could explain the increased heparan sulfate content. A model is discussed where NDST2-specific substrate modification stimulates elongation resulting in increased heparan sulfate chain length.
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