The authors have no conflict of interest
Macrophage Inflammatory Protein-1α Induces Hypercalcemia in Adult T-Cell Leukemia†
Article first published online: 15 MAR 2004
Copyright © 2004 ASBMR
Journal of Bone and Mineral Research
Volume 19, Issue 7, pages 1105–1111, July 2004
How to Cite
Okada, Y., Tsukada, J., Nakano, K., Tonai, S., Mine, S. and Tanaka, Y. (2004), Macrophage Inflammatory Protein-1α Induces Hypercalcemia in Adult T-Cell Leukemia. J Bone Miner Res, 19: 1105–1111. doi: 10.1359/JBMR.040314
- Issue published online: 2 DEC 2009
- Article first published online: 15 MAR 2004
- Manuscript Accepted: 15 MAR 2004
- Manuscript Revised: 16 JAN 2004
- Manuscript Received: 27 AUG 2003
- humoral hypercalcemia of malignancy;
- macrophage inflammatory protein-1α;
- adult T-cell leukemia;
- bone resorption
Hypercalcemia is observed in >80% of ATL. Serum MIP-1α levels were elevated in all 24 ATL with hypercalcemia but undetectable in all 10 patients with humoral hypercalcemia of malignancy with solid tumors and in 34 of 37 ATL without hypercalcemia. We propose that serum MIP-1α is a clinical hallmark for hypercalcemia in ATL.
Introduction: High serum cytokines levels are not always associated with hypercalcemia in patients with adult T-cell leukemia (ATL), suggesting that other factors are involved in the pathogenesis of ATL patients with hypercalcemia. This study was designed to determine the role of macrophage inflammatory protein-1α (MIP-1α), a chemokine recently described as an osteoclast stimulatory factor, in ATL-associated hypercalcemia.
Materials and Methods: We measured serum interleukin (IL)-1β, IL-6, TNF-α, parathyroid hormone-related protein (PTHrP), and MIP-1α levels in ATL patients by enzyme-linked immunosorbent assays. FACScan was used to measure the expression of RANKL on ATL cells. Osteoclast formation in cocultures of ATL cells and peripheral blood mononuclear cells (PBMCs) was evaluated by TRACP staining.
Results: High serum MIP-1α levels were noted in all 24 ATL patients with hypercalcemia and in 3 of 37 ATL patients without hypercalcemia. The elevated levels of MIP-1α and calcium in ATL patients decreased after effective chemotherapy, emphasizing the role of MIP-1α in ATL hypercalcemia. ATL cells spontaneously produced MIP-1α. MIP-1α significantly enhanced human monocyte (precursor cells of osteoclasts) migration and induced RANKL expression on ATL cells. ATL cell-induced osteoclast formation from PBMCs was inhibited by anti-MIP-1α antibody and osteoprotegerin.
Conclusion: Our results suggest that MIP-1α can induce RANKL on ATL cells in autocrine fashion and that RANKL seems to mediate the hypercalcemic effect of MIP-1α in ATL. We propose that MIP-1α is the clinical hallmark of hypercalcemia in ATL and could be a potentially useful therapeutic target.