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Human Molecular Genetics Advance Access published online on January 8, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddl474
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© The Author 2007. Published by Oxford University Press. All rights reserved

Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence

Wei Chen1,2, Shuying Yang1,2, Yoke Abe1, Ming Li1, Yucheng Wang1, Jianzhong Shao1, En Li3 and Yi-Ping Li1,2,*

1 Department of Cytokine Biology, The Forsyth Institute, Boston, MA 02115, USA 2 Harvard-Forsyth Department of Oral Biology, The Forsyth Institute & Harvard School of Dental Medicine, Boston, MA 02115, USA 3 Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA

* Corresponding Author: Dr. Yi-Ping Li Department of Cytokine Biology, The Forsyth Institute, 140 The Fenway, Boston, MA 02115 Tel: 617-892-8260 Fax: 617-262 4021 E-mail: ypli{at}forsyth.org

Received October 18, 2006; Revised December 20, 2006; Accepted December 20, 2006

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 lacked normal apoptosis and senescence and exhibited over-growth both in vitro and in vivo. These abnormalities resulted in an unusually high osteoclast 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-/- osteoclasts and forced expression of cathepsin K in pre-osteoclasts induced premature senescence and increased expression of p19, p53, and p21. This is the first evidence that cathepsin K plays a key role in osteoclast apoptosis and senescence, revealing the importance of osteoclast 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 osteoclast-related abnormal bone homeostasis.


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