Bone Marrow-Derived Cathepsin K Cleaves SPARC in Bone Metastasis

作者：Podgorski Izabela^*; Linebaugh Bruce E; Koblinski Jennifer E; Rudy Deborah L; Herroon Mackenzie K; Olive Mary B; Sloane Bonnie F

来源：American Journal Of Pathology, 2009, 175(3): 1255-1269.

DOI：10.2353/ajpath.2009.080906

Bone meta-stasis 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. (Am J Pathol 2009, 175:1255-1269; DOI: 10.2353/ajpath.2009.080906)

• 出版日期2009-9
• 单位西北大学