Osteogenic differentiation of skeletal muscle progenitor cells is activated by the DNA damage response.
Sci Rep
; 9(1): 5447, 2019 04 01.
Article
em En
| MEDLINE
| ID: mdl-30931986
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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Osteogênese
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Dano ao DNA
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Diferenciação Celular
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Músculo Esquelético
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Células-Tronco Multipotentes
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article