title: Interruption of glycosphingolipid synthesis enhances osteoarthritis development in mice.
abstract: OBJECTIVE
  Glycosphingolipids (GSLs) are ubiquitous membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions. GSL expression is decreased in the articular cartilage of humans with osteoarthritis (OA). This study was undertaken to determine the functional role of GSLs in cartilage metabolism related to OA pathogenesis in mice.
  
  
  METHODS
  We generated mice with knockout of the chondrocyte-specific Ugcg gene, which encodes an initial enzyme of major GSL synthesis, using the Cre/loxP system (Col2-Ugcg(-/-)  mice). In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of GSLs on the cartilage degradation process.
  
  
  RESULTS
  Although Col2-Ugcg(-/-)  mice developed and grew normally, OA changes in these mice were dramatically enhanced with aging, through the overexpression of matrix metalloproteinase 13 and chondrocyte apoptosis, compared to their wild-type (WT) littermates. Col2-Ugcg(-/-)  mice showed more severe instability-induced pathologic OA in vivo and interleukin-1α (IL-1α)-induced cartilage degradation in vitro. IL-1α stimulation of chondrocytes from WT mice significantly increased Ugcg messenger RNA expression and up-regulated GSL metabolism.
  
  
  CONCLUSIONS
  Our results indicate that GSL deficiency in mouse chondrocytes enhances the development of OA. However, this deficiency does not affect the development and organization of cartilage tissue in mice at a young age. These findings indicate that GSLs maintain cartilage molecular metabolism and prevent disease progression, although GSLs are not essential for chondrogenesis of progenitor and stem cells and cartilage development in young mice. GSL metabolism in the cartilage is a potential target for developing a novel treatment for OA.
authors.affiliation: Hokkaido University, Sapporo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Seito
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tsukuda
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Matsui
authors.forename: Atsushi
authors.initials: A
authors.lastname: Urita
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Onodera
authors.forename: Takeomi
authors.initials: T
authors.lastname: Mizutani
authors.forename: Hisashi
authors.initials: H
authors.lastname: Haga
authors.forename: Naoki
authors.initials: N
authors.lastname: Fujitani
authors.forename: Yasuro
authors.initials: Y
authors.lastname: Shinohara
authors.forename: Akio
authors.initials: A
authors.lastname: Minami
authors.forename: Norimasa
authors.initials: N
authors.lastname: Iwasaki
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024043:Collagen Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005964:Glucosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D066298:In Vitro Techniques; D053582:Interleukin-1alpha / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D017888:Medial Collateral Ligament, Knee / Q000293:injuries / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010003:Osteoarthritis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D024043:Collagen Type II; D006028:Glycosphingolipids; D053582:Interleukin-1alpha; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D053509:Matrix Metalloproteinase 13