title: Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization.
abstract: Cathepsin K is a cysteine protease expressed predominantly in osteoclasts. Activated cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Mutations in the human cathepsin K gene have been demonstrated to be associated with a rare skeletal dysplasia, pycnodysostosis. The degree of functional activity of the mutated forms of cathepsin K in these individuals has not been elucidated, but is predicted to be low or absent. To study the role of cathepsin K in bone resorption, we have generated mice deficient in the cathepsin K gene. Histologic and radiographic analysis of the mice revealed osteopetrosis of the long bones and vertebrae, and abnormal joint morphology. X-ray microcomputerized tomography images allowed quantitation of the increase in bone volume, trabecular thickness, and trabecular number in both the primary spongiosa and the metaphysis of the proximal tibiae. Not all bones were similarly affected. Chondrocyte differentiation was normal. The mice also had abnormalities in hematopoietic compartments, particularly decreased bone marrow cellularity and splenomegaly. The heterozygous animals appeared normal. Close histologic examination of bone histology revealed fully differentiated osteoclasts apposed to small regions of demineralized bone. This strongly suggests that cathepsin K-deficient osteoclasts are capable of demineralizing the extracellular matrix but are unable to adequately remove the demineralized bone. This is entirely consistent with the proposed function of cathepsin K as a matrix-degrading proteinase in bone resorption.
authors.affiliation: Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gowen
authors.forename: F
authors.initials: F
authors.lastname: Lazner
authors.forename: R
authors.initials: R
authors.lastname: Dodds
authors.forename: R
authors.initials: R
authors.lastname: Kapadia
authors.forename: J
authors.initials: J
authors.lastname: Feild
authors.forename: M
authors.initials: M
authors.lastname: Tavaria
authors.forename: I
authors.initials: I
authors.lastname: Bertoncello
authors.forename: F
authors.initials: F
authors.lastname: Drake
authors.forename: S
authors.initials: S
authors.lastname: Zavarselk
authors.forename: I
authors.initials: I
authors.lastname: Tellis
authors.forename: P
authors.initials: P
authors.lastname: Hertzog
authors.forename: C
authors.initials: C
authors.lastname: Debouck
authors.forename: I
authors.initials: I
authors.lastname: Kola
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001857:Bone Matrix / Q000378:metabolism*; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics*; D006132:Growth Plate / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010022:Osteopetrosis / Q000235:genetics*; D013163:Splenomegaly / Q000235:genetics
chemical_list: D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse