Premium
Potential role of insulin‐like growth factor binding protein‐4 in the uncoupling of bone turnover in multiple myeloma
Author(s) -
Feliers Denis,
Woodruff Kathleen,
Abboud Sherry
Publication year - 1999
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1999.01243.x
Subject(s) - multiple myeloma , insulin like growth factor , bone remodeling , endocrinology , medicine , growth factor , insulin like growth factor binding protein , insulin , cancer research , chemistry , receptor
Decreased bone formation plays an important role in the development of lytic lesions during the late stage of multiple myeloma (MM). Release of insulin‐like growth factor binding protein‐4 (IGFBP4) by tumour cells adjacent to bone may inhibit IGF‐I‐stimulated osteoblast growth and contribute to decreased bone formation. The present study demonstrates that the human MM cell line, ARH‐77, expresses IGFBP4 and, to a lesser extent, IGFBP6 mRNA and protein. IGFBP4 expression in myeloma cells may be modulated by cytokines released by stromal cells and T cells in the microenvironment. We tested the effect of recombinant interferon‐gamma (INF) on IGFBP4 expression in ARH‐77. INF increased IGFBP4 mRNA and protein levels at 12 h, with a decline to baseline by 24 h. In contrast, IGFBP4 was not regulated in response to IL‐6, TNF‐alpha, PDGF BB, bFGF, TGF‐beta or the cAMP agonist, forskolin. In other systems, IGFBP4 may also be regulated post‐transcriptionally by a protease that is activated by IGF‐I or ‐II. Conditioned medium from ARH‐77 cultures incubated with IGF‐I or ‐II for up to 24 h failed to demonstrate proteolytic activity. Proteolysis was also not observed when conditioned medium containing exogenous rhIGFBP4 was incubated with IGF‐I or ‐II under cell‐free conditions. To determine if human myeloma tumours also express IGFBP4, total RNA was isolated from four tumour biopsies. All samples expressed detectable levels of IGFBP4 mRNA. These findings indicate that interferon‐gamma may indirectly modulate bone formation via the the release of tumour‐derived IGFBP4, suggesting that the immune system may influence bone turnover in MM. Failure of myeloma cells to release protease activity may promote IGFBP4 accumulation in the microenvironment during tumour growth.