An anti-RANKL treatment reduces muscle inflammation and dysfunction and strengthens bone in dystrophic mice.
Hum Mol Genet
; 28(18): 3101-3112, 2019 09 15.
Article
em En
| MEDLINE
| ID: mdl-31179501
ABSTRACT
Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy which leads to progressive muscle degeneration and inflammation. The receptor activator of nuclear factor NF-κB ligand (RANKL) and its receptor (RANK), which are expressed in bone and skeletal and cardiac muscles, form a signaling network upstream from nuclear factor-kappa B (NF-κB). We thus hypothesized that prolonged silencing RANKL/RANK signaling would significantly improve DMD. We showed that RANK and RANKL protein levels were increased in the microenvironment of myofibers of 5-month-old utrophin haploinsufficient mdx (mdx/utrn+/-) mice and that a 4 mg/kg dose of anti-RANKL antibody every 3 d for 28 days is optimal and more effective than 1 mg/kg every 3 d for improving the ex vivo maximum specific force (sP0) of dystrophic EDL muscles from mdx/utrn+/- mice. This functional improvement was associated with a reduction in muscle edema, damage, and fibrosis and a marked reduction in serum CK levels. The anti-RANKL treatment inhibited the NF-κB pathway, increased the proportion of anti-inflammatory and non-cytotoxic M2 macrophages, and reduced the number of centrally-nucleated myofibers and the frequency of small myofibers, suggesting that anti-RANKL inhibits the cycle of degeneration/regeneration in dystrophic mice. A three-point bending test showed that a 28-d anti-RANKL treatment increases the mechanical properties of bone in mdx/utrn+/- dystrophic mice. In conclusion, the anti-RANKL treatment protected against skeletal muscle dysfunctions while enhancing bone mechanical properties, filling two needs with one deed in the context of muscular dystrophy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osso e Ossos
/
Músculo Esquelético
/
Ligante RANK
/
Miosite
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Hum Mol Genet
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Canadá