This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Wilson, T. J. Articles by Singh, R. K. Search for Related Content PubMed PubMed Citation Articles by Wilson, T. J. Articles by Singh, R. K.

Cathepsin G Enhances Mammary Tumor–Induced Osteolysis by Generating Soluble Receptor Activator of Nuclear Factor-B Ligand

¹ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska and ² Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan

Requests for reprints: Rakesh K. Singh, Department of Pathology and Microbiology, University Nebraska Medical Center, 985845 Nebraska Medical Center, Omaha, NE 68198-5845. Phone: 402 559 9949; Fax: 402 559 4077; E-mail: rsingh{at}unmc.edu.

Key Words: Bone metastasis • Proteases • RANKL

Breast cancer commonly causes osteolytic metastases in bone, a process that is dependent on tumor-stromal interaction. Proteases play an important role in modulating tumor-stromal interactions in a manner that favors tumor establishment and progression. Whereas several studies have examined the role of proteases in modulating the bone microenvironment, little is currently known about their role in tumor-bone interaction during osteolytic metastasis. In cancer-induced osteolytic lesions, cleavage of receptor activator of nuclear factor-B ligand (RANKL) to a soluble version (sRANKL) is critical for widespread osteoclast activation. Using a mouse model that mimics osteolytic changes associated with breast cancer–induced bone metastases, we identified cathepsin G, cathepsin K, matrix metalloproteinase (MMP)-9, and MMP13 to be proteases that are up-regulated at the tumor-bone interface using comparative cDNA microarray analysis and quantitative reverse transcription-PCR. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of RANKL, generating active sRANKL that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G at the tumor-bone interface seems to be osteoclasts that up-regulate production of cathepsin G via interaction with tumor cells. Furthermore, we showed that in vitro osteoclastogenesis is reduced by inhibition of cathepsin G in a coculture model and that in vivo inhibition of cathepsin G reduces mammary tumor–induced osteolysis. Together, our data indicate that cathepsin G activity at the tumor-bone interface plays an important role in mammary tumor–induced osteolysis and suggest that cathepsin G is a potentially novel therapeutic target in the treatment of breast cancer bone metastasis. [Cancer Res 2008;68(14):5803–11]

This article has been cited by other articles:

				T. J. Wilson, K. C. Nannuru, and R. K. Singh Cathepsin G Recruits Osteoclast Precursors via Proteolytic Activation of Protease-Activated Receptor-1 Cancer Res., April 1, 2009; 69(7): 3188 - 3195. [Abstract] [Full Text] [PDF]