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Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma.

Abstract：

:Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.

journal_name

Leukemia

journal_title

Leukemia

authors

Breitkreutz I,Raab MS,Vallet S,Hideshima T,Raje N,Mitsiades C,Chauhan D,Okawa Y,Munshi NC,Richardson PG,Anderson KC

doi

10.1038/leu.2008.174

subject

Has Abstract

pub_date

2008-10-01 00:00:00

pages

1925-32

issue

10

eissn

0887-6924

issn

1476-5551

pii

leu2008174

journal_volume

22

pub_type

杂志文章,随机对照试验

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