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

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, stromalderived factor-1A (SDF-1A) in the recruitment of osteoclast precursors to the bone marrow. Our studies show that MM PC produce significant levels of SDF-1A protein and exhibit elevated plasma levels of SDF-1A when compared with normal, age-matched subjects. The level of SDF-1A positively correlated with the presence of multiple radiological bone lesions in individuals with MM, suggesting a potential role for SDF-1A 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-1A. Although failing to stimulate an increase in TRAP + , multinucleated osteoclast formation, our studies show that SDF-1A mediated a dramatic increase in both the number and the size of the resorption lacunae formed.

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…36 Other studies explored the activity of these agents in acute 76,77 and chronic leukemias, 54 multiple myeloma, 78 small cell lung cancer (SCLC), 50 malignant melanoma 74 and pancreatic cancer. 79 Besides these disease-oriented studies, T140 and its analogs have been used in basic studies exploring the function of CXCR4 in dendritic cell development 80 and migration, 81 B-cell homing and germinal center positioning within lymphatic tissues, 82 and HSC homing.…”

The pleiotropic effects of the SDF-1–CXCR4 axis in organogenesis, regeneration and tumorigenesis

“…62 Finally, elevated serum levels of SDF-1 are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma (MM) patients. 63 Regulation of CXCR4 expression CXCR4 expression/function is regulated at several levels ( Figure 2). First, CXCR4 is regulated at the transcriptional level by hypoxia.…”

The pathogenesis of the bone disease of multiple myeloma

“…Recent data showed SDF-1 can not only mediate the migration and homing of myeloma cells (44), but increase osteoclast motility and bone resorbing activity (45). This was associated with an overexpression of osteoclast activationrelated genes, including RANKL, RANKL, TRAP, MMP-9, CA-II and Cathepsin K. Osteoclast activation mediated by myeloma cells could be reduced by CXCR-4 specific inhibitor (45). These findings suggest that SDF-1α is an important factor in the pathogenesis of myeloma bone disease.…”