title: Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence.
abstract: Pycnodysostosis is a genetic bone disease featuring the unique bone homeostasis disorders of osteolysis and osteopetrosis in the same organism. The pathomechanism for pycnodysostosis has been largely unknown due to the unavailability of a pycnodysostosis mouse model with all the traits of the disease. We generated cathepsin K(-/-) mouse strains in the 129/Sv and C57BL/6J backgrounds and found that, only in the 129/Sv background, cathepsin K(-/-) mice exhibit many characteristics of the human pycnodysostosis-like phenotype. Our data indicated that 129/Sv cathepsin K(-/-) osteoclasts (OCs) lacked normal apoptosis and senescence and exhibited over-growth both in vitro and in vivo. These abnormalities resulted in an unusually high OC number, which is consistent with a recent case study of human pycnodysostosis. Our results show that cathepsin K function has different effects around the skeleton due to site-specific variations in bone homeostasis, such as phenotypes of osteopetrosis in tibiae and osteolysis in calvariae as a result of cathepsin K mutation. Our data demonstrated that the expression levels of p19, p53 and p21 were significantly reduced in 129/Sv cathepsin K(-/-) OCs and forced expression of cathepsin K in pre-OCs induced premature senescence and increased expression of p19, p53 and p21. This is the first evidence that cathepsin K plays a key role in OC apoptosis and senescence, revealing the importance of OC senescence in bone homeostasis. The finding of this novel cathepsin K function provides insight into the pathomechanism of pycnodysostosis and may provide new drug targets for diseases involved in OC-related abnormal bone homeostasis.
authors.affiliation: Department of Cytokine Biology, The Forsyth Institute and Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
authors.forename: Yoke
authors.initials: Y
authors.lastname: Abe
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Shao
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000473:pathology; D001862:Bone Resorption / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics* / Q000502:physiology*; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000235:genetics*; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse