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

• Published in: Leukemia Vol. 37; no. 5; pp. 1068 - 1079
• Main Authors: Bianchi, Elisa, Rontauroli, Sebastiano, Tavernari, Lara, Mirabile, Margherita, Pedrazzi, Francesca, Genovese, Elena, Sartini, Stefano, Dall’Ora, Massimiliano, Grisendi, Giulia, Fabbiani, Luca, Maccaferri, Monica, Carretta, Chiara, Parenti, Sandra, Fantini, Sebastian, Bartalucci, Niccolò, Calabresi, Laura, Balliu, Manjola, Guglielmelli, Paola, Potenza, Leonardo, Tagliafico, Enrico, Losi, Lorena, Dominici, Massimo, Luppi, Mario, Vannucchi, Alessandro Maria, Manfredini, Rossella
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2023; Nature Publishing Group
• Subjects: 14/63; 38/77; 38/79; 631/67/1990/2331; 631/80/86; 64/60; 692/420; 82/80; 96/1; 96/106; 96/95; Animals; Antibodies; Bone marrow; Cancer Research; Cell proliferation; Collagen; Critical Care Medicine; Disease Models, Animal; Extracellular signal-regulated kinase; Fibrosis; Fibrosis - drug therapy; Hematology; Humans; Intensive; Internal Medicine; Medicine; Medicine & Public Health; Mice; Myelofibrosis; Myeloproliferation; Neutralization; Oncology; Osteopontin; Osteopontin - antagonists & inhibitors; Osteopontin - blood; Osteopontin - metabolism; Plasma levels; Primary Myelofibrosis - drug therapy; Primary Myelofibrosis - metabolism; Primary Myelofibrosis - pathology; Signal Transduction - drug effects; Stromal cells
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-023-01867-3

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.