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Originally published online as doi:10.2353/ajpath.2009.080906 on August 21, 2009

Published online before print August 21, 2009
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(American Journal of Pathology. 2009;175:1255-1269.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080906

Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis

Izabela Podgorski*{dagger}, Bruce E. Linebaugh*, Jennifer E. Koblinski{ddagger}, Deborah L. Rudy*, Mackenzie K. Herroon*, Mary B. Olive* and Bonnie F. Sloane*{dagger}

From the Department of Pharmacology,* and the Karmanos Cancer Institute,{dagger} Wayne State University School of Medicine, Detroit, Michigan; and the Department of Pathology,{ddagger} Northwestern University, Feinberg School of Medicine, R.H. Lurie Cancer Institute, Chicago, Illinois

Bone metastasis is a hallmark of advanced prostate and breast cancers, yet the critical factors behind attraction of tumors to the skeleton have not been validated. Here, we investigated the involvement of cathepsin K in the progression of prostate tumors in the bone, which occurs both by direct degradation of bone matrix collagen I and by cleavage of other factors in the bone microenvironment. Our results demonstrated that bone marrow-derived cathepsin K is capable of processing and thereby modulating SPARC, a protein implicated in bone metastasis and inflammation. The coincident up-regulation of SPARC and cathepsin K occurred both in vivo in experimental prostate bone tumors, and in vitro in co-cultures of bone marrow stromal cells with PC3 prostate carcinoma cells. PC3-bone marrow stromal cell interaction increased secretion and processing of SPARC, as did co-cultures of bone marrow stromal cells with two other cancer cell lines. In addition, bone marrow stromal cells that were either deficient in cathepsin K or treated with cathepsin K inhibitors had significantly reduced secretion and cleavage of SPARC. Increases in secretion of pro-inflammatory cytokines (ie, interleukin-6, -8) coincident with overexpression of cathepsin K suggest possible mechanisms by which this enzyme contributes to tumor progression in the bone. This is the first study implicating bone marrow cathepsin K in regulation of biological activity of SPARC in bone metastasis.






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Copyright © 2009 by the American Society for Investigative Pathology.