Calcified Tissue International

, Volume 102, Issue 2, pp 210–226 | Cite as

The Proteasome and Myeloma-Associated Bone Disease

  • Fabrizio Accardi
  • Denise Toscani
  • Federica Costa
  • Franco Aversa
  • Nicola Giuliani
Review

Abstract

Bone disease is the hallmark of multiple myeloma (MM), a hematological malignancy characterized by osteolytic lesions due to a severe uncoupled and unbalanced bone remodeling with pronounced osteoblast suppression. Bone metastasis is also a frequent complication of solid tumors including advanced breast or prostate cancer. In the past years, the ubiquitin–proteasome pathway has been proved critical in regulating the balance between bone formation and bone resorption. Proteasome inhibitors (PIs) are a new class of drugs, currently used in the treatment of MM, that affect both tumor cells and bone microenvironment. Particularly, PIs stimulate osteoblast differentiation by human mesenchymal stromal cells and increase bone regeneration in mice. Interestingly, in vitro data indicate that PIs block MM-induced osteoblast and osteocyte cell death by targeting both apoptosis and autophagy. The preclinical data are supported by the following effects observed in MM patients treated with PIs: increase of bone alkaline phosphatase levels, normalization of the markers of bone turnover, and reduction of the skeletal-related events. Moreover, the histomorphometric data indicate that the treatment with bortezomib stimulates osteoblast formation and maintains osteocyte viability in MM patients. This review updates the evidence on the effects of PIs on bone remodeling and on cancer-induced bone disease while focusing on MM bone disease.

Keywords

Proteasome Bone disease Osteolysis Multiple myeloma Cancer 

Notes

Funding

This work was supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG2014 n.15531 (NG). DT was supported by a fellowship Fondazione Italiana per la Ricerca sul Cancro n. 16462. We thank the “Associazione Italiana Contro le Leucemie” (AIL) Parma section for the support.

Conflict of interest

Fabrizio Accardi, Denise Toscani, Federica Costa, and Franco Aversa declare that they have no conflict of interest. Nicola Giuliani was supported by a research grant from Celgene Italy and Janssen.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Fabrizio Accardi
    • 1
    • 2
  • Denise Toscani
    • 1
  • Federica Costa
    • 1
  • Franco Aversa
    • 1
    • 2
  • Nicola Giuliani
    • 1
    • 2
  1. 1.Department of Medicine and SurgeryUniversity of ParmaParmaItaly
  2. 2.Hematology and BMT Center“Azienda Ospedaliero, Universitaria di Parma”ParmaItaly

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