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Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease

Author

Listed:
  • Sarah Gooding

    (University of Oxford
    Oxford University Hospitals NHS Trust
    University of Oxford
    University of Oxford)

  • Sam W. Z. Olechnowicz

    (University of Oxford
    University of Oxford)

  • Emma V. Morris

    (University of Oxford
    University of Oxford)

  • Andrew E. Armitage

    (University of Oxford)

  • Joao Arezes

    (University of Oxford)

  • Joe Frost

    (University of Oxford)

  • Emmanouela Repapi

    (University of Oxford)

  • James R. Edwards

    (University of Oxford
    University of Oxford)

  • Neil Ashley

    (University of Oxford)

  • Craig Waugh

    (University of Oxford)

  • Nicola Gray

    (University of Oxford)

  • Erik Martinez-Hackert

    (Michigan State University)

  • Pei Jin Lim

    (University of Oxford)

  • Sant-Rayn Pasricha

    (University of Oxford
    University of Oxford)

  • Helen Knowles

    (University of Oxford)

  • Adam J. Mead

    (Oxford University Hospitals NHS Trust
    University of Oxford
    University of Oxford)

  • Karthik Ramasamy

    (Oxford University Hospitals NHS Trust
    University of Oxford
    University of Oxford
    University of Oxford)

  • Hal Drakesmith

    (University of Oxford
    University of Oxford)

  • Claire M. Edwards

    (University of Oxford
    University of Oxford
    University of Oxford
    University of Oxford)

Abstract

Multiple myeloma is an incurable, bone marrow-dwelling malignancy that disrupts bone homeostasis causing skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, we find that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitor cells. BMP signalling has not previously been reported to be dysregulated in myeloma bone disease. Inhibition of BMP signalling in vivo using either a small molecule BMP receptor antagonist or a solubilized BMPR1a-FC receptor ligand trap prevents trabecular and cortical bone volume loss caused by myeloma, without increasing tumour burden. BMP inhibition directly reduces osteoclastogenesis, increases osteoblasts and bone formation, and suppresses bone marrow sclerostin levels. In summary we describe a novel role for the BMP pathway in myeloma-induced bone disease that can be therapeutically targeted.

Suggested Citation

  • Sarah Gooding & Sam W. Z. Olechnowicz & Emma V. Morris & Andrew E. Armitage & Joao Arezes & Joe Frost & Emmanouela Repapi & James R. Edwards & Neil Ashley & Craig Waugh & Nicola Gray & Erik Martinez-H, 2019. "Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12296-1
    DOI: 10.1038/s41467-019-12296-1
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