title: Depletion of gangliosides enhances cartilage degradation in mice.
abstract: OBJECTIVE
  Glycosphingolipids (GSLs) are ubiquitous membrane components that play a functional role in maintaining chondrocyte homeostasis. We investigated the potential role of gangliosides, one of the major components of GSLs, in osteoarthritis (OA) pathogenesis.
  
  
  METHODS
  Both age-associated and instability-induced OA models were generated using GM3 synthase knockout (GM3S(-/-)) mice. A cartilage degradation model and transiently GM3S-transfected chondrocytes were analyzed to evaluate the function of gangliosides in OA development. The amount of each series of GSLs in chondrocytes after IL-1α stimulation was profiled using mass spectrometry (MS).
  
  
  RESULTS
  OA changes in GM3S(-/-) mice were dramatically enhanced with aging compared to those in wild-type (WT) mice. GM3S(-/-) mice showed more severe instability-induced pathologic OA in vivo. Ganglioside deficiency also led to the induction of matrix metalloproteinase (MMP)-13 and ADAMTS-5 secretion and chondrocyte apoptosis in vitro. In contrast, transient GM3S transfection of chondrocytes suppressed MMP-13 and ADAMTS-5 expression after interleukin (IL)-1α stimulation. GSL profiling revealed the presence of abundant gangliosides in chondrocytes after IL-1α stimulation.
  
  
  CONCLUSIONS
  Gangliosides play a critical role in OA pathogenesis by regulating the expression of MMP-13 and ADAMTS-5 and chondrocyte apoptosis. Based on the obtained results, we propose that gangliosides are potential target molecules for the development of novel OA treatments.
authors: Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: sasazawa230@gmail.com.
authors: F
authors: F
authors: Sasazawa
authors: Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: tomozou@med.hokudai.ac.jp.
authors: T
authors: T
authors: Onodera
authors: Laboratory of Biochemistry, Azabu University, Graduate School of Veterinary Medicine, Sagamihara, Japan. Electronic address: yamashita@azabu-u.ac.jp.
authors: T
authors: T
authors: Yamashita
authors: Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: naoki_seito@yahoo.co.jp.
authors: N
authors: N
authors: Seito
authors: Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: tsukudani2004@yahoo.co.jp.
authors: Y
authors: Y
authors: Tsukuda
authors: Laboratory of Medical and Functional Glycomics, Graduate School of Advanced Life Science, Hokkaido University, Sapporo, Japan. Electronic address: integrar98nf@yahoo.co.jp.
authors: N
authors: N
authors: Fujitani
authors: Laboratory of Medical and Functional Glycomics, Graduate School of Advanced Life Science, Hokkaido University, Sapporo, Japan. Electronic address: yshinohara@sci.hokudai.ac.jp.
authors: Y
authors: Y
authors: Shinohara
authors: Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: niwasaki@med.hokudai.ac.jp.
authors: N
authors: N
authors: Iwasaki
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005732:Gangliosides / Q000172:deficiency* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D053582:Interleukin-1alpha / Q000494:pharmacology; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques
chemical_list: D005732:Gangliosides; D053582:Interleukin-1alpha; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D019278:Matrix Metalloproteinase 3
keywords: Gangliosides; Glycosphingolipids; Interleukin-1α; Mice; Osteoarthritis