This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lindeman, J. H.N. Articles by Hogendoorn, P. C.W. Search for Related Content PubMed PubMed Citation Articles by Lindeman, J. H.N. Articles by Hogendoorn, P. C.W.

(American Journal of Pathology. 2004;165:593-600.)
© 2004 American Society for Investigative Pathology

Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone

Jan H.N. Lindeman^*, Roeland Hanemaaijer^*, Adri Mulder^*, P.D. Sander Dijkstra, Károly Szuhai^¶, Dieter Bromme^||, Jan H. Verheijen and Pancras C.W. Hogendoorn

From the Departments of Vascular Surgery,^* Pathology, Orthopedics, and Molecular Cell Biology,^¶ Leiden University Medical Center, Leiden, The Netherlands; the Division of Biomedical Research, TNO Prevention and Health, Leiden, The Netherlands; and the Department of Human Genetics,|| Mount Sinai School of Medicine, New York, New York

Giant cell tumor (GCT) of bone is a neoplasm of bone characterized by a localized osteolytic lesion. The nature of GCT is an enigma and the cell type(s) and protease(s) responsible for the extensive localized clinicoradiological osteolysis remain unresolved. We evaluated protease expression and cellular distribution of the proteolytic machinery responsible for the osteolysis. mRNA profiles showed that cathepsin K, cathepsin L, and matrix metalloproteinase (MMP)-9 were the preferentially expressed collagenases. Moderate expression was found for MMP-13, MMP-14, and cathepsin S. Specific protease activity assays revealed high cathepsin K activity but showed that MMP-9 was primarily present (98%) as inactive proenzyme. Activities of MMP-13 and MMP-14 were low. Immunohistochemistry revealed a clear spatial distribution: cathepsin K, its associated proton pump V-H⁺-ATPase, and MMP-9 were exclusively expressed in osteoclast-like giant cells, whereas cathepsin L expression was confined to mononuclear cells. To explore a possible role of cathepsin L in osteolysis, GCT-derived, cathepsin L-expressing, mononuclear cells were cultured on dentine disks. No evidence of osteolysis by these cells was found. These results implicate cathepsin K as the principal protease in GCT and suggest that osteoclast-like giant cells are responsible for the osteolysis. Inhibition of cathepsin K or its associated proton-pump may provide new therapeutic opportunities for GCT.

This article has been cited by other articles:

				R. E. Burden, P. Snoddy, R. J. Buick, J. A. Johnston, B. Walker, and C. J. Scott Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L-like proteases in tumor microenvironment Mol. Cancer Ther., March 1, 2008; 7(3): 538 - 547. [Abstract] [Full Text] [PDF]

				H. Abdul-Hussien, R. G.V. Soekhoe, E. Weber, J. H. von der Thusen, R. Kleemann, A. Mulder, J. H. van Bockel, R. Hanemaaijer, and J. H.N. Lindeman Collagen Degradation in the Abdominal Aneurysm: A Conspiracy of Matrix Metalloproteinase and Cysteine Collagenases Am. J. Pathol., March 1, 2007; 170(3): 809 - 817. [Abstract] [Full Text] [PDF]

				J. H. Verheijen, L. G.M. Huisman, N. van Lent, U. Neumann, P. Paganetti, C. E. Hack, F. Bouwman, J. Lindeman, E. L.E.M. Bollen, and R. Hanemaaijer Detection of a Soluble Form of BACE-1 in Human Cerebrospinal Fluid by a Sensitive Activity Assay Clin. Chem., June 1, 2006; 52(6): 1168 - 1174. [Abstract] [Full Text] [PDF]

				V. W.M. van Hinsbergh, M. A. Engelse, and P. H.A. Quax Pericellular Proteases in Angiogenesis and Vasculogenesis Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 716 - 728. [Abstract] [Full Text] [PDF]