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

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

Authors :
Claudia Fuoco
Marco Rosina
Giulio Giuliani
Alessio Reggio
Cesare Gargioli
Francesca Langone
Alberto Calderone
Luisa Castagnoli
A. Cerquone Perpetuini
Gianni Cesareni
Source :
Scientific Reports, Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019)
Publication Year :
2019
Publisher :
Springer Science and Business Media LLC, 2019.

Abstract

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.

Details

ISSN :
20452322
Volume :
9
Database :
OpenAIRE
Journal :
Scientific Reports
Accession number :
edsair.doi.dedup.....712d96b9763a63a226adf8fdecbfe732
Full Text :
https://doi.org/10.1038/s41598-019-41926-3