2. Academic Validation
  3. Inhibition of ERK1/2 signaling prevents bone marrow fibrosis by reducing osteopontin plasma levels in a myelofibrosis mouse model

Inhibition of ERK1/2 signaling prevents bone marrow fibrosis by reducing osteopontin plasma levels in a myelofibrosis mouse model

  • Leukemia. 2023 Mar 16. doi: 10.1038/s41375-023-01867-3.
Elisa Bianchi # 1 2,  Sebastiano Rontauroli # 3 4,  Lara Tavernari # 3 5,  Margherita Mirabile 3 5,  Francesca Pedrazzi 3 5,  Elena Genovese 3 4,  Stefano Sartini 3 5,  Massimiliano Dall'Ora 6,  Giulia Grisendi 7,  Luca Fabbiani 8,  Monica Maccaferri 9,  Chiara Carretta 3 5,  Sandra Parenti 3 4,  Sebastian Fantini 4,  Niccolò Bartalucci 10,  Laura Calabresi 10,  Manjola Balliu 10,  Paola Guglielmelli 10,  Leonardo Potenza 11,  Enrico Tagliafico 11,  Lorena Losi 12,  Massimo Dominici 7,  Mario Luppi 11,  Alessandro Maria Vannucchi 10,  Rossella Manfredini 13 14
Affiliations

Affiliations

  • 1 Centre for Regenerative Medicine "Stefano Ferrari", University of Modena and Reggio Emilia, Modena, Italy. elisa.bianchi@unimore.it.
  • 2 Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. elisa.bianchi@unimore.it.
  • 3 Centre for Regenerative Medicine "Stefano Ferrari", University of Modena and Reggio Emilia, Modena, Italy.
  • 4 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 5 Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 6 Evotec (Modena) Srl, Medolla, MO, Italy.
  • 7 Division of Oncology, Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences of Children & Adults, University of Modena and Reggio Emilia, Modena, Italy.
  • 8 Department of Medical and Surgical Sciences of Children & Adults, Pathology Unit, University of Modena and Reggio Emilia, Modena, Italy.
  • 9 Department of Laboratory Medicine and Pathology, Diagnostic Hematology and Clinical Genomics, AUSL/AOU Policlinico, 41124, Modena, Italy.
  • 10 Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Department of Experimental and Clinical Medicine, AOU Careggi, University of Florence, Florence, Italy.
  • 11 Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AUSL/AOU Policlinico, 41124, Modena, Italy.
  • 12 Department of Life Sciences, Pathology Unit, University of Modena and Reggio Emilia, Modena, Italy.
  • 13 Centre for Regenerative Medicine "Stefano Ferrari", University of Modena and Reggio Emilia, Modena, Italy. rossella.manfredini@unimore.it.
  • 14 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. rossella.manfredini@unimore.it.
  • # Contributed equally.
PMID: 36928007 DOI: 10.1038/s41375-023-01867-3
Abstract

Clonal myeloproliferation and development of bone marrow (BM) fibrosis are the major pathogenetic events in myelofibrosis (MF). The identification of novel antifibrotic strategies is of utmost importance since the effectiveness of current therapies in reverting BM fibrosis is debated. We previously demonstrated that osteopontin (OPN) has a profibrotic role in MF by promoting mesenchymal stromal cells proliferation and collagen production. Moreover, increased plasma OPN correlated with higher BM fibrosis grade and inferior overall survival in MF patients. To understand whether OPN is a druggable target in MF, we assessed putative inhibitors of OPN expression in vitro and identified ERK1/2 as a major regulator of OPN production. Increased OPN plasma levels were associated with BM fibrosis development in the Romiplostim-induced MF mouse model. Moreover, ERK1/2 inhibition led to a remarkable reduction of OPN production and BM fibrosis in Romiplostim-treated mice. Strikingly, the antifibrotic effect of ERK1/2 inhibition can be mainly ascribed to the reduced OPN production since it could be recapitulated through the administration of anti-OPN neutralizing antibody. Our results demonstrate that OPN is a novel druggable target in MF and pave the way to antifibrotic therapies based on the inhibition of ERK1/2-driven OPN production or the neutralization of OPN activity.

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