title: Cathepsin K deficiency in mice induces structural and metabolic changes in the central nervous system that are associated with learning and memory deficits.
abstract: BACKGROUND
  Cathepsin K is a cysteine peptidase known for its importance in osteoclast-mediated bone resorption. Inhibitors of cathepsin K are in clinical trials for treatment of osteoporosis. However, side effects of first generation inhibitors included altered levels of related cathepsins in peripheral organs and in the central nervous system (CNS). Cathepsin K has been recently detected in brain parenchyma and it has been linked to neurobehavioral disorders such as schizophrenia. Thus, the study of the functions that cathepsin K fulfils in the brain becomes highly relevant.
  
  
  RESULTS
  Cathepsin K messenger RNA was detectable in all brain regions of wild type (WT) mice. At the protein level, cathepsin K was detected by immunofluorescence microscopy in vesicles of neuronal and non-neuronal cells throughout the mouse brain. The hippocampus of WT mice exhibited the highest levels of cathepsin K activity in fluorogenic assays, while the cortex, striatum, and cerebellum revealed significantly lower enzymatic activities. At the molecular level, the proteolytic network of cysteine cathepsins was disrupted in the brain of cathepsin K-deficient (Ctsk⁻/⁻) animals. Specifically, cathepsin B and L protein and activity levels were altered, whereas cathepsin D remained largely unaffected. Cystatin C, an endogenous inhibitor of cysteine cathepsins, was elevated in the striatum and hippocampus, pointing to regional differences in the tissue response to Ctsk ablation. Decreased levels of astrocytic glial fibrillary acidic protein, fewer and less ramified profiles of astrocyte processes, differentially altered levels of oligodendrocytic cyclic nucleotide phosphodiesterase, as well as alterations in the patterning of neuronal cell layers were observed in the hippocampus of Ctsk⁻/⁻ mice. A number of molecular and cellular changes were detected in other brain regions, including the cortex, striatum/mesencephalon, and cerebellum. Moreover, an overall induction of the dopaminergic system was found in Ctsk⁻/⁻ animals which exhibited reduced anxiety levels as well as short- and long-term memory impairments in behavioral assessments.
  
  
  CONCLUSIONS
  We conclude that deletion of the Ctsk gene can lead to deregulation of related proteases, resulting in a wide range of molecular and cellular changes in the CNS with severe consequences for tissue homeostasis. We propose that cathepsin K activity has an important impact on the development and maintenance of the CNS in mice.
authors.affiliation: School of Engineering and Science, Research Center MOLIFE-Molecular Life Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dauth
authors.forename: Ruxandra F
authors.initials: RF
authors.lastname: Sîrbulescu
authors.forename: Silvia
authors.initials: S
authors.lastname: Jordans
authors.forename: Maren
authors.initials: M
authors.lastname: Rehders
authors.forename: Linda
authors.initials: L
authors.lastname: Avena
authors.forename: Julia
authors.initials: J
authors.lastname: Oswald
authors.forename: Alexander
authors.initials: A
authors.lastname: Lerchl
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Klaudia
authors.initials: K
authors.lastname: Brix
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D056657:Cathepsin K / Q000378:metabolism*; D004789:Enzyme Activation; D007859:Learning Disabilities / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014018:Tissue Distribution
chemical_list: D056657:Cathepsin K; C534132:Ctsk protein, mouse