Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma

Cancer Res. 2016 Mar 1;76(5):1089-100. doi: 10.1158/0008-5472.CAN-15-1703. Epub 2016 Feb 1.


In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3-dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis
  • Bone Marrow / physiology*
  • Bone Morphogenetic Proteins / genetics
  • Bone Resorption / etiology*
  • Cell Proliferation
  • Cellular Microenvironment / physiology*
  • Female
  • Genetic Markers / genetics
  • Humans
  • Mice
  • Multiple Myeloma / complications*
  • Multiple Myeloma / pathology
  • Osteoblasts / cytology
  • Osteocytes / physiology*
  • Osteogenesis
  • RANK Ligand / physiology
  • Receptors, Notch / physiology*
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / physiology


  • Adaptor Proteins, Signal Transducing
  • Bone Morphogenetic Proteins
  • Genetic Markers
  • RANK Ligand
  • Receptors, Notch
  • SOST protein, human
  • Tumor Necrosis Factor-alpha