MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts

Sonia Vallet, Noopur Raje, Kenji Ishitsuka, Teru Hideshima, Klaus Podar, Shweta Chhetri, Samantha Pozzi, Iris Breitkreutz, Tanyel Kiziltepe, Hiroshi Yasui, Enrique M. Ocio, Norihiko Shiraishi, Janice Jin, Yutaka Okawa, Hiroshi Ikeda, Siddhartha Mukherjee, Nileshwari Vaghela, Diana Cirstea, Marco Ladetto, Mario BoccadoroKenneth C. Anderson*

*Corresponding author for this work

Research output: Journal article (peer-reviewed)Journal article

126 Citations (Scopus)

Abstract

The interaction between osteoclasts (OCs) and multiple myeloma (MM) cells plays a key role in the pathogenesis of MM-related osteolytic bone disease (OBD). MM cells promote OC formation and, in turn, OCs enhance MM cell proliferation. Chemokines are mediators of MM effects on bone and vice versa; in particular, CCL3 enhances OC formation and promotes MM cell migration and survival. Here, we characterize the effects of MLN3897, a novel specific antagonist of the chemokine receptor CCR1, on both OC formation and OC-MM cell interactions. MLN3897 demonstrates significant impairment of OC formation (by 40%) and function (by 70%), associated with decreased precursor cell multinucleation and down-regulation of c-fos signaling. OCs secrete high levels of CCL3, which triggers MM cell migration; conversely, MLN3897 abrogates its effects by inhibiting Akt signaling. Moreover, MM cell-to-OC adhesion was abrogated by MLN3897, thereby inhibiting MM cell survival and proliferation. Our results therefore show novel biologic sequelae of CCL3 and its inhibition in both osteoclastogenesis and MM cell growth, providing the preclinical rationale for clinical trials of MLN3897 to treat OBD in MM.

Original languageEnglish
Pages (from-to)3744-3752
Number of pages9
JournalBlood
Volume110
Issue number10
DOIs
Publication statusPublished - 15 Nov 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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