Gene profiling of cathepsin K deficiency in atherogenesis: Profibrotic but lipogenic

S. P.M. Lutgens, N. Kisters, E. Lutgens, R. I.M. van Haaften, C. T.A. Evelo, M. P.J. de Winther, P. Saftig, M. J.A.P. Daemen, S. Heeneman, K. B.J.M. Cleutjens

Research output: Contribution to journalArticlepeer-review


Recently, we showed that cathepsin K deficiency reduces atherosclerotic plaque progression, induces plaque fibrosis, but aggravates macrophage foam cell formation in the ApoE-/- mouse. To obtain more insight into the molecular mechanisms by which cathepsin K disruption evokes the observed phenotypic changes, we used microarray analysis for gene expression profiling of aortic arches of CatK-/-/ApoE-/- and ApoE-/- mice on a mouse oligo microarray. Out of 20 280 reporters, 444 were significantly differentially expressed (p-value of <0.05, fold change of ≥1.4 or ≤1.4, and intensity value of >2.5 times background in at least one channel). Ingenuity Pathway Analysis and GenMAPP revealed upregulation of genes involved in lipid uptake, trafficking, and intracellular storage, including caveolin - 1,-2, -3 and CD36, and profibrotic genes involved in transforming growth factor β (TGFβ) signalling, including TGFβ2, latent TGFβ binding protein-1 (LTBP1), and secreted protein, acidic and rich in cysteine (SPARC), in CatK-/-/ ApoE-/- mice. Differential gene expression was confirmed at the mRNA and protein levels. In vitro modified low density lipoprotein (LDL) uptake assays, using bone marrow derived macrophages preincubated with caveolae and scavenger receptor inhibitors, confirmed the importance of caveolins and CD36 in increasing modified LDL uptake in the absence of cathepsin K. In conclusion, we suggest that cathepsin K deficiency alters plaque phenotype not only by decreasing proteolytic activity, but also by stimulating TGFβ signalling. Besides this profibrotic effect, cathepsin K deficiency has a lipogenic effect owing to increased lipid uptake mediated by D36 and caveolins.

Original languageEnglish (US)
Pages (from-to)334-343
Number of pages10
JournalJournal of Pathology
Issue number3
StatePublished - Nov 2006


  • Atherosclerosis
  • Cathepsin K
  • Gene profiling
  • Lipid metabolism
  • Macrophages
  • Microarray

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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