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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-12-3905. This Article Full Text (PDF) All Versions of this Article: 2002-12-3905v1 102/1/311    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Oyajobi, B. O Articles by Mundy, G. R Search for Related Content PubMed PubMed Citation Articles by Oyajobi, B. O Articles by Mundy, G. R Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted December 30, 2002 Accepted March 5, 2003 Dual effects of macrophage inflammatory protein-1 on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease Babatunde O Oyajobi*, Giovanni Franchin, Paul J Williams, Donna Pulkrabek, Anjana Gupta, Steve Munoz, Barry Grubbs, Ming Zhao, Di Chen, Barbara Sherry, and Gregory R Mundy Departments of Molecular Medicine & Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Molecular Therapeutics Division, CTRC Institute of Drug Development, San Antonio, TX, USA Laboratory of Cytokine Biology, The Picower Institute for Medical Research, Manhasset, NY, USA * Corresponding author; email: oyajobi{at}uthscsa.edu. Recent data has implicated MIP-1, in osteolysis associated with multiple myeloma (MM). However it is not clear whether the effects of the chemokine are direct, to enhance osteolysis or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1 requires other factors such as RANKL for its effects on bone. To clarify the role of MIP-1 in MM bone disease, we used the well characterized murine 5T (Radl) model. Administration of neutralizing anti-MIP-1 antibodies to 5TGM1 myeloma-bearing mice significantly reduced tumor load assessed by titers of the paraprotein, prevented splenomegaly and limited development of osteolytic lesions with a concomitant reduction in tumor in bone. To determine the effects of MIP-1 on bone in vivo, we used two approaches. First, Chinese hamster ovary (CHO) cells engineered to secrete active human MIP-1 (CHO/MIP-1 cells), were inoculated into athymic mice. Mice bearing CHO/MIP-1 tumors in thigh muscles developed lytic bone lesions at distant skeletal sites which occurred earlier and were significantly larger than those in mice with empty vector-transfected (CHO/EV) tumors. Similarly, when experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1 tumors developed hypercalcemia and significantly more osteolytic lesions than CHO/EV-bearing mice with intra-medullary CHO/MIP-1 tumors associated with significantly more TRAP+ osteoclasts at bone and marrow interfaces. Second, recombinant MIP-1 was injected over calvariae of normal mice where it evoked a striking increase in osteoclast formation and bone resorption, an effect dependent on intact RANK/RANKL signaling since MIP-1 had no effect in RANK null mutant mice. Taken together with the data on neutralization of MIP-1 bioactivity in the 5TGM1 model, our results establish that MIP-1 is sufficient to induce MM-like destructive lesions in bone in vivo. Since in the 5TGM1 model, blockade of osteoclastic bone resorption in other situations does not decrease tumor burden (Dallas et al. 1999 Blood), we conclude that MIP-1 exerts a dual effect in myeloma, on osteoclasts as well as tumor cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: New insight into myeloma lytic bone disease Joshua Epstein Blood 2003 102: 5. [Full Text] [PDF] This article has been cited by other articles: J. A. Fowler, G. R. Mundy, S. T. Lwin, C. C. Lynch, and C. M. Edwards A murine model of myeloma that allows genetic manipulation of the host microenvironment Dis. Model. Mech., November 1, 2009; 2(11-12): 604 - 611. [Abstract] [Full Text] [PDF] O. Sezer Myeloma Bone Disease: Recent Advances in Biology, Diagnosis, and Treatment Oncologist, March 1, 2009; 14(3): 276 - 283. [Abstract] [Full Text] [PDF] N. Giuliani, G. Lisignoli, S. Colla, M. Lazzaretti, P. Storti, C. Mancini, S. Bonomini, C. 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