title: Regulation of Cholesterol Homeostasis by Hedgehog Signaling in Osteoarthritic Cartilage.
abstract: OBJECTIVE
  With no effective therapies to attenuate cartilage degeneration in osteoarthritis (OA), the result is pain and disability. Activation of hedgehog (HH) signaling causes changes related to the progression of OA, with higher levels of Gli-mediated transcriptional activation associated with increased disease severity. To elucidate the mechanism through which this occurs, this study sought to identify genes regulated by HH signaling in human OA chondrocytes.
  
  
  METHODS
  Using human OA cartilage samples, microarray analyses were performed to detect changes in gene expression when the HH pathway was modulated. Results were analyzed for differentially expressed genes, grouped into functional networks, and validated in independent samples. To investigate the effects of chondrocyte-specific sterol accumulation, we generated mice lacking Insig1 and Insig2, which are major negative regulators of cholesterol homeostasis, under Col2a1 regulatory elements.
  
  
  RESULTS
  HH signaling was found to regulate genes that govern cholesterol homeostasis, and this led to alterations in cholesterol accumulation in chondrocytes. A higher level of Gli-mediated transcription resulted in accumulation of intracellular cholesterol. In genetically modified mice, chondrocyte-specific cholesterol accumulation was associated with an OA phenotype. Reducing cholesterol accumulation attenuated the severity of OA in mice in vivo and decreased the expression of proteases in human OA cartilage in vitro.
  
  
  CONCLUSIONS
  HH signaling regulates cholesterol homeostasis in chondrocytes, and intracellular cholesterol accumulation contributes to the severity of OA. Our findings have therapeutic implications, since reduction of HH signaling reversed cholesterol accumulation and statin treatment attenuated cartilage degeneration.
authors: University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Shabana Amanda
authors: SA
authors: Ali
authors: University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Mushriq
authors: M
authors: Al-Jazrawe
authors: University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Henry
authors: H
authors: Ma
authors: Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Heather
authors: H
authors: Whetstone
authors: Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Raymond
authors: R
authors: Poon
authors: University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Sarah
authors: S
authors: Farr
authors: Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Mark
authors: M
authors: Naples
authors: University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Khosrow
authors: K
authors: Adeli
authors: Duke University, Durham, North Carolina.
authors: Benjamin A
authors: BA
authors: Alman
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071116:ADAMTS5 Protein; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D024043:Collagen Type II / Q000235:genetics; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008148:Lovastatin / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D012720:Severity of Illness Index; D015398:Signal Transduction; D013261:Sterols / Q000378:metabolism*; D013264:Stifle / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D000075746:Zinc Finger Protein Gli2
chemical_list: D000924:Anticholesteremic Agents; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; C506119:Insig1 protein, mouse; C506120:Insig2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D013261:Sterols; D000075746:Zinc Finger Protein Gli2; D002784:Cholesterol; D008148:Lovastatin; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse