Osteogenic differentiation of skeletal muscle progenitor cells is activated by the DNA damage response

Heterotopic ossification (HO) is a pathological condition characterized by the deposition of mineralized tissue in ectopic locations such as the skeletal muscle. The precise cellular origin and molecular mechanisms underlying HO are still debated. In our study we focus on the differentiation of meso...

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Bibliographic Details
Published in:Scientific reports 2019-04, Vol.9 (1), p.5447, Article 5447
Main Authors: Rosina, M., Langone, F., Giuliani, G., Cerquone Perpetuini, A., Reggio, A., Calderone, A., Fuoco, C., Castagnoli, L., Gargioli, C., Cesareni, G.
Format: Article
Language:English
Subjects:
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Animals
Bone Morphogenetic Protein 2 - metabolism
Cbfa-1 protein
Cell Differentiation - drug effects
Core Binding Factor Alpha 1 Subunit - metabolism
Deoxyribonucleic acid
DNA
DNA Damage
Humanities and Social Sciences
Idoxuridine - pharmacology
Molecular modelling
multidisciplinary
Multipotent Stem Cells - drug effects
Multipotent Stem Cells - pathology
Muscle, Skeletal - drug effects
Muscle, Skeletal - pathology
Musculoskeletal system
Myogenesis
Ossification (ectopic)
Ossification, Heterotopic
Osteogenesis
Phosphorylation
Progenitor cells
Radiation therapy
Science
Science (multidisciplinary)
Skeletal muscle
Smad Proteins - metabolism
Stem cells
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Summary:Heterotopic ossification (HO) is a pathological condition characterized by the deposition of mineralized tissue in ectopic locations such as the skeletal muscle. The precise cellular origin and molecular mechanisms underlying HO are still debated. In our study we focus on the differentiation of mesoangioblasts (MABs), a population of multipotent skeletal muscle precursors. High-content screening for small molecules that perturb MAB differentiation decisions identified Idoxuridine (IdU), an antiviral and radiotherapy adjuvant, as a molecule that promotes MAB osteogenic differentiation while inhibiting myogenesis. IdU-dependent osteogenesis does not rely on the canonical BMP-2/SMADs osteogenic pathway. At pro-osteogenic conditions IdU induces a mild DNA Damage Response (DDR) that activates ATM and p38 eventually promoting the phosphorylation of the osteogenesis master regulator RUNX2. By interfering with this pathway IdU-induced osteogenesis is severely impaired. Overall, our study suggests that induction of the DDR promotes osteogenesis in muscle resident MABs thereby offering a new mechanism that may be involved in the ectopic deposition of mineralized tissue in the muscle.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-41926-3