Lysyl oxidase propeptide stimulates osteoblast and osteoclast differentiation and enhances PC3 and DU145 prostate cancer
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RESEARCH ARTICLE
Lysyl oxidase propeptide stimulates osteoblast and osteoclast differentiation and enhances PC3 and DU145 prostate cancer cell effects on bone in vivo Mona Alsulaiman 1 & Manish V. Bais 1 & Philip C. Trackman 1
Received: 26 August 2015 / Accepted: 18 November 2015 # The International CCN Society 2015
Abstract Lysyl oxidase pro-enzyme is secreted by tumor cells and normal cells as a 50 kDa pro-enzyme into the extracellular environment where it is cleaved into the ~30 kDa mature enzyme (LOX) and 18 kDa pro-peptide (LOX-PP). Extracellular LOX enzyme activity is required for normal collagen and elastin extracellular cross-linking and maturation of the extracellular matrix. Extracellular LOX-PP acts as a tumor suppressor and can re-enter cells from the extracellular environment to induce its effects. The underlying hypothesis is that LOX-PP has the potential to promote bone cell differentiation, while inhibiting cancer cell effects in bone. Here we investigate the effect of LOX-PP on bone marrow cell proliferation and differentiation towards osteoblasts or osteoclasts, and LOX-PP modulation of prostate cancer cell conditioned media-induced alterations of proliferation and differentiation of bone marrow cells in vitro. Effects of overexpression of rLOX-PP in DU145 and PC3 prostate cancer cell lines on bone structure in vivo after intramedullary injections were determined. Data show that prostate cancer cell conditioned media inhibited osteoblast differentiation in bone marrowderived cells, which was reversed by rLOX-PP treatment. Prostate cancer conditioned media stimulated osteoclast differentiation which was further enhanced by rLOX-PP treatment. rLOX-PP stimulated osteoclast differentiation by inhibiting OPG expression, up-regulating CCN2 expression, and increasing osteoclast fusion. In vivo studies indicate that Mona Alsulaiman and Manish V. Bais contributed equally to this study. * Philip C. Trackman [email protected] 1
Henry M. Goldman School of Dental Medicine, Department of Molecular and Cell Biology, Boston University, 700 Albany Street, W-201, Boston, MA 02118, USA
rLOX-PP expression by PC3 cells implanted into the tibia of mice further enhanced PC3 cell ability to resorb bone, while rLOX-PP expression in DU145 cells resulted in nonsignificant increases in net bone formation. rLOX-PP enhances both osteoclast and osteoblast differentiation. rLOXPP may serve to enhance coupling interactions between osteoclasts and osteoblasts helping to maintain a normal bone turnover in health, while contributing to bone abnormalities in disease. Keywords Lysyl oxidase . Lysyl oxidase propeptide . Osteoblast . Osteoclast . Differentiation . Bone
Introduction Lysyl oxidase (LOX) is an extracellular copper-dependent enzyme that plays a critical role in extracellular matrix biosynthesis (Uauy et al. 1998). It is synthesized and secreted as 50 kDa pro-lysyl oxidase (Pro-LOX) enzyme followed by extracellular enzymatic processing by procollagen Cproteinases yielding a 32 kDa mature and active LOX enzyme and the 18
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