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Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients.
Cancer Res. 2005 Mar 01; 65(5):1700-9.CR

Abstract

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-1alpha (SDF-1alpha) in the recruitment of osteoclast precursors to the bone marrow. Our studies show that MM PC produce significant levels of SDF-1alpha protein and exhibit elevated plasma levels of SDF-1alpha when compared with normal, age-matched subjects. The level of SDF-1alpha positively correlated with the presence of multiple radiological bone lesions in individuals with MM, suggesting a potential role for SDF-1alpha 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-1alpha. Although failing to stimulate an increase in TRAP+, multinucleated osteoclast formation, our studies show that SDF-1alpha 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-1alpha 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-1alpha 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-1alpha axis may provide an effective means of treatment for MM-induced osteolysis.

Authors+Show Affiliations

Myeloma and Mesenchymal Research Group, Matthew Roberts Foundation Laboratory and Mesenchymal Stem Cell Group, Division of Haematology, Institute of Medical and Veterinary Science, Hanson Institute, Adelaide, Australia. andrew.zannettino@imvs.sa.gov.auNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15753365

Citation

Zannettino, Andrew C W., et al. "Elevated Serum Levels of Stromal-derived Factor-1alpha Are Associated With Increased Osteoclast Activity and Osteolytic Bone Disease in Multiple Myeloma Patients." Cancer Research, vol. 65, no. 5, 2005, pp. 1700-9.
Zannettino AC, Farrugia AN, Kortesidis A, et al. Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Res. 2005;65(5):1700-9.
Zannettino, A. C., Farrugia, A. N., Kortesidis, A., Manavis, J., To, L. B., Martin, S. K., Diamond, P., Tamamura, H., Lapidot, T., Fujii, N., & Gronthos, S. (2005). Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Research, 65(5), 1700-9.
Zannettino AC, et al. Elevated Serum Levels of Stromal-derived Factor-1alpha Are Associated With Increased Osteoclast Activity and Osteolytic Bone Disease in Multiple Myeloma Patients. Cancer Res. 2005 Mar 1;65(5):1700-9. PubMed PMID: 15753365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. AU - Zannettino,Andrew C W, AU - Farrugia,Amanda N, AU - Kortesidis,Angela, AU - Manavis,Jim, AU - To,L Bik, AU - Martin,Sally K, AU - Diamond,Peter, AU - Tamamura,Hirokazu, AU - Lapidot,Tsvee, AU - Fujii,Nobutaka, AU - Gronthos,Stan, PY - 2005/3/9/pubmed PY - 2005/4/20/medline PY - 2005/3/9/entrez SP - 1700 EP - 9 JF - Cancer research JO - Cancer Res VL - 65 IS - 5 N2 - 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-1alpha (SDF-1alpha) in the recruitment of osteoclast precursors to the bone marrow. Our studies show that MM PC produce significant levels of SDF-1alpha protein and exhibit elevated plasma levels of SDF-1alpha when compared with normal, age-matched subjects. The level of SDF-1alpha positively correlated with the presence of multiple radiological bone lesions in individuals with MM, suggesting a potential role for SDF-1alpha 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-1alpha. Although failing to stimulate an increase in TRAP+, multinucleated osteoclast formation, our studies show that SDF-1alpha 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-1alpha 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-1alpha 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-1alpha axis may provide an effective means of treatment for MM-induced osteolysis. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/15753365/Elevated_serum_levels_of_stromal_derived_factor_1alpha_are_associated_with_increased_osteoclast_activity_and_osteolytic_bone_disease_in_multiple_myeloma_patients_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15753365 DB - PRIME DP - Unbound Medicine ER -