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Published on: May 15, 2019

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

I Breitkreutz1, M S Raab, S Vallet

  • 1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Iris_Breitkreutz@dfci.harvard.edu

Leukemia
|July 4, 2008
PubMed

Insights

Lenalidomide and bortezomib inhibit osteoclast formation and function, crucial for multiple myeloma bone disease. These drugs target key pathways, reducing bone resorption and potentially disrupting the myeloma-osteoclast-stromal cell loop.

Area of Science:

  • Hematology
  • Oncology
  • Bone Biology

Background:

  • Multiple myeloma (MM) causes osteolytic bone disease via increased osteoclast (OCL) activity and reduced osteoblast function.
  • Lenalidomide and bortezomib are effective MM treatments; bortezomib is known to inhibit OCLs.

Purpose of the Study:

  • To investigate the effects of lenalidomide on OCL formation and osteoclastogenesis, comparing its mechanisms to bortezomib.
  • To elucidate the molecular targets and pathways affected by these drugs in the context of MM bone disease.

Main Methods:

  • Comparison of lenalidomide and bortezomib effects on OCL formation markers (e.g., alpha V beta 3-integrin, TRAP-positive cells) and bone resorption.
  • Analysis of receptor activator of nuclear factor-kappaB ligand (RANKL) secretion by bone marrow stromal cells (BMSCs) from MM patients.
  • Identification of molecular targets (PU.1, pERK, NFAT) and downstream effects on gene expression and protein levels.

Main Results:

  • Both lenalidomide and bortezomib reduced OCL markers, bone resorption, and RANKL secretion from MM patient BMSCs.
  • Lenalidomide targeted PU.1 and pERK, while bortezomib targeted NFAT, inhibiting osteoclastogenesis.
  • Downregulation of cathepsin K and reduced levels of growth/survival factors (e.g., MIP-1α, BAFF, APRIL) were observed.
  • In MM patients treated with lenalidomide, serum RANKL and RANKL/OPG ratio decreased, while OPG increased.

Conclusions:

  • Lenalidomide and bortezomib effectively target critical factors in osteoclastogenesis.
  • These agents may directly impact the activation loop between myeloma cells, osteoclasts, and BMSCs contributing to osteolytic bone disease.

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