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- Title
Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma.
- Authors
Breitkreutz, I.; Raab, M. S.; Vallet, S.; Hideshima, T.; Raje, N.; Mitsiades, C.; Chauhan, D.; Okawa, Y.; Munshi, N. C.; Richardson, P. G.; Anderson, K. C.
- 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 αVβ3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-κB 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-α, 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.Leukemia (2008) 22, 1925–1932; doi:10.1038/leu.2008.174; published online 3 July 2008
- Subjects
MULTIPLE myeloma; OSTEOCLAST inhibition; EXTRACELLULAR matrix proteins; B cell lymphoma; DENTAL pulp
- Publication
Leukemia (08876924), 2008, Vol 22, Issue 10, p1925
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/leu.2008.174