title: Digestion products of the PH20 hyaluronidase inhibit remyelination.
abstract: OBJECTIVE
  Oligodendrocyte progenitor cells (OPCs) recruited to demyelinating lesions often fail to mature into oligodendrocytes (OLs) that remyelinate spared axons. The glycosaminoglycan hyaluronan (HA) accumulates in demyelinating lesions and has been implicated in the failure of OPC maturation and remyelination. We tested the hypothesis that OPCs in demyelinating lesions express a specific hyaluronidase, and that digestion products of this enzyme inhibit OPC maturation.
  
  
  METHODS
  Mouse OPCs grown in vitro were analyzed for hyaluronidase expression and activity. Gain of function studies were used to define the hyaluronidases that blocked OPC maturation. Mouse and human demyelinating lesions were assessed for hyaluronidase expression. Digestion products from different hyaluronidases and a hyaluronidase inhibitor were tested for their effects on OPC maturation and functional remyelination in vivo.
  
  
  RESULTS
  OPCs demonstrated hyaluronidase activity in vitro and expressed multiple hyaluronidases, including HYAL1, HYAL2, and PH20. HA digestion by PH20 but not other hyaluronidases inhibited OPC maturation into OLs. In contrast, inhibiting HA synthesis did not influence OPC maturation. PH20 expression was elevated in OPCs and reactive astrocytes in both rodent and human demyelinating lesions. HA digestion products generated by the PH20 hyaluronidase but not another hyaluronidase inhibited remyelination following lysolecithin-induced demyelination. Inhibition of hyaluronidase activity lead to increased OPC maturation and promoted increased conduction velocities through lesions.
  
  
  CONCLUSIONS
  We determined that PH20 is elevated in demyelinating lesions and that increased PH20 expression is sufficient to inhibit OPC maturation and remyelination. Pharmacological inhibition of PH20 may therefore be an effective way to promote remyelination in multiple sclerosis and related conditions.
authors: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA.
authors: Marnie
authors: M
authors: Preston
authors: Xi
authors: X
authors: Gong
authors: Weiping
authors: W
authors: Su
authors: Steven G
authors: SG
authors: Matsumoto
authors: Fatima
authors: F
authors: Banine
authors: Clayton
authors: C
authors: Winkler
authors: Scott
authors: S
authors: Foster
authors: Rubing
authors: R
authors: Xing
authors: Jaime
authors: J
authors: Struve
authors: Justin
authors: J
authors: Dean
authors: Bruce
authors: B
authors: Baggenstoss
authors: Paul H
authors: PH
authors: Weigel
authors: Thomas J
authors: TJ
authors: Montine
authors: Stephen A
authors: SA
authors: Back
authors: Larry S
authors: LS
authors: Sherman
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006820:Hyaluronic Acid / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology*; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009836:Oligodendroglia / Q000166:cytology* / Q000502:physiology
chemical_list: D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; C066852:hyaluronidase PH-20