This Article Full Text Full Text (PDF) 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zannettino, A. C.W. Articles by Gronthos, S. Search for Related Content PubMed PubMed Citation Articles by Zannettino, A. C.W. Articles by Gronthos, S.

Elevated Serum Levels of Stromal-Derived Factor-1 Are Associated with Increased Osteoclast Activity and Osteolytic Bone Disease in Multiple Myeloma Patients

¹ Myeloma and Mesenchymal Research Group, Matthew Roberts Foundation Laboratory and ² Mesenchymal Stem Cell Group, Division of Haematology, Institute of Medical and Veterinary Science, Hanson Institute, and Department of Medicine, University of Adelaide; ³ Centre for Neurological Disease, Hanson Institute; ⁴ Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia; ⁵ Department of Bioorganic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; and ⁶ Department of Immunology, Wiezmann Institute of Science, Rehovot, Israel

Requests for reprints: Andrew C.W. Zannettino, Myeloma and Mesenchymal Research Group, Matthew Roberts Foundation Laboratory, Division of Haematology, Institute of Medical and Veterinary Science, P.O. Box 14, Rundle Mall, Adelaide 5000, Australia. Phone: 61-8-8222-3455; Fax: 61-8-8222-3139; E-mail: andrew.zannettino{at}imvs.sa.gov.au.

Multiple myeloma (MM) is an incurable plasma cell (PC) malignancy able to mediate massive destruction of the axial and craniofacial skeleton. The aim of this study was to investigate the role of the potent chemokine, stromal-derived factor-1 (SDF-1) in the recruitment of osteoclast precursors to the bone marrow. Our studies show that MM PC produce significant levels of SDF-1 protein and exhibit elevated plasma levels of SDF-1 when compared with normal, age-matched subjects. The level of SDF-1 positively correlated with the presence of multiple radiological bone lesions in individuals with MM, suggesting a potential role for SDF-1 in osteoclast precursor recruitment and activation. To examine this further, peripheral blood–derived CD14⁺ osteoclast precursors were cultured in an in vitro osteoclast-potentiating culture system in the presence of recombinant human SDF-1. Although failing to stimulate an increase in TRAP⁺, multinucleated osteoclast formation, our studies show that SDF-1 mediated a dramatic increase in both the number and the size of the resorption lacunae formed. The increased osteoclast motility and activation in response to SDF-1 was associated with an increase in the expression of a number of osteoclast activation–related genes, including RANKL, RANK, TRAP, MMP-9, CA-II, and Cathepsin K. Importantly, the small-molecule CXCR4-specific inhibitor, 4F-Benzoyl-TE14011 (T140), effectively blocked osteoclast formation stimulated by the myeloma cell line, RPMI-8226. Based on these findings, we believe that the synthesis of high levels of SDF-1 by MM PC may serve to recruit osteoclast precursors to local sites within the bone marrow and enhance their motility and bone-resorbing activity. Therefore, we propose that inhibition of the CXCR4-SDF-1 axis may provide an effective means of treatment for MM-induced osteolysis.

Key Words: Multiple Myeloma • Osteolysis • SDF-1 • CXCL12 • CXCR4 • Osteoclast • Resorption

This article has been cited by other articles:

				A. Labrinidis, P. Diamond, S. Martin, S. Hay, V. Liapis, I. Zinonos, N. A. Sims, G. J. Atkins, C. Vincent, V. Ponomarev, et al. Apo2L/TRAIL Inhibits Tumor Growth and Bone Destruction in a Murine Model of Multiple Myeloma Clin. Cancer Res., March 15, 2009; 15(6): 1998 - 2009. [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]

				J. Lorenzo, M. Horowitz, and Y. Choi Osteoimmunology: Interactions of the Bone and Immune System Endocr. Rev., June 1, 2008; 29(4): 403 - 440. [Abstract] [Full Text] [PDF]

				S. Hassan, A. Baccarelli, O. Salvucci, and M. Basik Plasma Stromal Cell-Derived Factor-1: Host Derived Marker Predictive of Distant Metastasis in Breast Cancer Clin. Cancer Res., January 15, 2008; 14(2): 446 - 454. [Abstract] [Full Text] [PDF]

				K. Kabashima, N. Shiraishi, K. Sugita, T. Mori, A. Onoue, M. Kobayashi, J.-i. Sakabe, R. Yoshiki, H. Tamamura, N. Fujii, et al. CXCL12-CXCR4 Engagement Is Required for Migration of Cutaneous Dendritic Cells Am. J. Pathol., October 1, 2007; 171(4): 1249 - 1257. [Abstract] [Full Text] [PDF]

				E. Terpos, O. Sezer, P. Croucher, and M.-A. Dimopoulos Myeloma bone disease and proteasome inhibition therapies Blood, August 15, 2007; 110(4): 1098 - 1104. [Abstract] [Full Text] [PDF]

				P. G. Richardson, T. Hideshima, and K. C. Anderson Plasma cell dyscrasias ASH Self-Assessment Program, January 1, 2007; 2007(1): 298 - 327. [Full Text] [PDF]

				S. K. Martin, A. L. Dewar, A. N. Farrugia, N. Horvath, S. Gronthos, L. B. To, and A. C.W. Zannettino Tumor Angiogenesis Is Associated with Plasma Levels of Stromal-Derived Factor-1{alpha} in Patients with Multiple Myeloma Clin. Cancer Res., December 1, 2006; 12(23): 6973 - 6977. [Abstract] [Full Text] [PDF]

				A. L. Dewar, A. N. Farrugia, M. R. Condina, L. Bik To, T. P. Hughes, B. Vernon-Roberts, and A. C. W. Zannettino Imatinib as a potential antiresorptive therapy for bone disease Blood, June 1, 2006; 107(11): 4334 - 4337. [Abstract] [Full Text] [PDF]

				E. Seeman and G. J. Strewler Clinical and Basic Research Papers - February 2005 Selections IBMS BoneKEy, March 1, 2005; 2(3): 1 - 5. [Full Text] [PDF]