Mastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation

• Published in: Nature communications Vol. 12; no. 1; pp. 2527 - 18
• Main Authors: Kim, Do-Kyun, Bandara, Geethani, Cho, Young-Eun, Komarow, Hirsh D., Donahue, Danielle R., Karim, Baktiar, Baek, Moon-Chang, Kim, Ho Min, Metcalfe, Dean D., Olivera, Ana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-05-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 13/95; 14/63; 38/77; 38/88; 38/90; 631/337/384/331; 631/67/1990/2331; 631/80/304; 64/60; Adolescent; Adult; Aged; Aged, 80 and over; Animals; Biomedical materials; Bone diseases; Bone growth; Bone marrow; Bone mass; Calcification, Physiologic - physiology; Cancellous bone; Cbfa-1 protein; Cell culture; Cell Differentiation; Cell Line; Child; Child, Preschool; Computer architecture; Core Binding Factor Alpha 1 Subunit - metabolism; Differentiation; Extracellular vesicles; Extracellular Vesicles - metabolism; Female; Humanities and Social Sciences; Humans; Male; Mast cells; Mast Cells - metabolism; Mastocytosis; Mastocytosis - metabolism; Mice; Mice, Inbred C57BL; MicroRNAs - metabolism; Middle Aged; Mineralization; miRNA; multidisciplinary; Myeloproliferative Disorders - metabolism; Osteoblastogenesis; Osteoblasts; Osteoblasts - metabolism; Osteogenesis; Osteogenesis - physiology; Osteoporosis; Science; Science (multidisciplinary); Smad1 Protein - metabolism; Smad5 Protein - metabolism; Vesicles; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22754-4

Osteoporosis and other manifestations of bone disease are frequent in patients with systemic mastocytosis (SM) in association with the presence of mast cell infiltrates in bone marrow, although the mechanisms behind bone disease remain poorly understood. We find that extracellular vesicles (EVs) released by neoplastic mast cells and present in the serum of patients with SM (SM-EVs) block osteoblast differentiation and mineralization in culture, and when injected into mice diminish the expression of osteoblast markers, and trabecular bone volume and microarchitecture. We demonstrate that miRNA-30a and miRNA-23a, increased in SM-EVs and neoplastic mast cell-derived EVs, attenuate osteoblast maturation by suppressing expression of RUNX2 and SMAD1/5, essential drivers of osteogenesis. Thus, SM-EVs carry and deliver miRNAs that epigenetically interfere with bone formation and can contribute to bone mass reduction in SM. These findings also suggest possibilities for novel approaches to the management of bone disease in mast cell proliferative disorders.
Osteoporosis and bone disease are common in patients with systemic mastocytosis. Here, the authors show that extracellular vesicles released by neoplastic mast cells of the patients block osteoblast differentiation and bone mineralization when injected into mice, via a mechanism involving suppression of osteogenic factors via miRNA-30a and miRNA-23a.