title: Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice.
abstract: Cathepsin K is a recently identified lysosomal cysteine proteinase. It is abundant in osteoclasts, where it is believed to play a vital role in the resorption and remodeling of bone. Pycnodysostosis is a rare inherited osteochondrodysplasia that is caused by mutations of the cathepsin-K gene, characterized by osteosclerosis, short stature, and acroosteolysis of the distal phalanges. With a view to delineating the role of cathepsin K in bone resorption, we generated mice with a targeted disruption of this proteinase. Cathepsin-K-deficient mice survive and are fertile, but display an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space. Cathepsin-K-deficient osteoclasts manifested a modified ultrastructural appearance: their resorptive surface was poorly defined with a broad demineralized matrix fringe containing undigested fine collagen fibrils; their ruffled borders lacked crystal-like inclusions, and they were devoid of collagen-fibril-containing cytoplasmic vacuoles. Assaying the resorptive activity of cathepsin-K-deficient osteoclasts in vitro revealed this function to be severely impaired, which supports the contention that cathepsin K is of major importance in bone remodeling.
authors.affiliation: Zentrum Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II, Universität Göttingen, Gosslerstrasse 12 d, 37073 Göttingen, Germany. saftig@uni-bc2.gwdg.de
authors.forename: P
authors.initials: P
authors.lastname: Saftig
authors.forename: E
authors.initials: E
authors.lastname: Hunziker
authors.forename: O
authors.initials: O
authors.lastname: Wehmeyer
authors.forename: S
authors.initials: S
authors.lastname: Jones
authors.forename: A
authors.initials: A
authors.lastname: Boyde
authors.forename: W
authors.initials: W
authors.lastname: Rommerskirch
authors.forename: J D
authors.initials: JD
authors.lastname: Moritz
authors.forename: P
authors.initials: P
authors.lastname: Schu
authors.forename: K
authors.initials: K
authors.lastname: von Figura
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D056657:Cathepsin K; D002403:Cathepsins / Q000172:deficiency* / Q000235:genetics*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism*
chemical_list: D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse