title: Dysregulation of hedgehog signalling predisposes to synovial chondromatosis.
abstract: Synovial chondromatosis is a condition affecting joints in which metaplastic cartilage nodules arise from the synovium, causing pain, joint dysfunction, and ultimately joint destruction. Because dysregulation of hedgehog signalling is a feature of several benign cartilaginous tumours, expression of the hedgehog target genes PTC1 and GLI1 was examined in this study in samples from human synovial chondromatosis. Significantly higher expression levels were found in synovial chondromatosis than in the synovium, from which it arises. To determine if hedgehog-mediated transcription predisposes to synovial chondromatosis, the extra-toes mutant mouse, which harbours a heterozygous mutation in the hedgehog transcriptional repressor, Gli3, resulting in decreased expression of Gli3 protein, was studied. The extra-toes mutant mouse has a phenotype consistent with overactive hedgehog signalling, suggesting that Gli3 acts as a transcriptional repressor of limb development. Eighty-five per cent of Gli3 mutant mice developed synovial chondromatosis at 18 months of age, compared with 30% of wild-type littermates (p < 0.05). Three of the ten Gli3 mutant mice treated with triparanol, which blocks hedgehog signalling upstream of the Gli transcription factors, developed synovial chondromatosis, compared with eight of ten control mice. These data demonstrate that hedgehog signalling plays an important role in the development of synovial chondromatosis and suggest that blockade of hedgehog signalling may be a potential treatment for this disorder.
authors.affiliation: Program in Developmental Biology, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Sevan
authors.initials: S
authors.lastname: Hopyan
authors.forename: Puviindran
authors.initials: P
authors.lastname: Nadesan
authors.forename: Chunying
authors.initials: C
authors.lastname: Yu
authors.forename: Jay
authors.initials: J
authors.lastname: Wunder
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015838:Chondromatosis, Synovial / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014308:Triparanol / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C465571:Gli3 protein, mouse; C117596:HHIP protein, human; C498447:Hhip protein, mouse; D051741:Kruppel-Like Transcription Factors; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3; D014308:Triparanol; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human