1. Academic Validation
  2. Inhibition of C5AR1 impairs osteoclast mobilization and prevents bone loss

Inhibition of C5AR1 impairs osteoclast mobilization and prevents bone loss

  • Mol Ther. 2023 May 3;S1525-0016(23)00256-3. doi: 10.1016/j.ymthe.2023.04.022.
Carolina Pimenta-Lopes 1 Cristina Sánchez-de-Diego 1 Alexandre Deber 1 Andrea Egea-Cortés 1 José Antonio Valer 1 Albert Alcalá 1 Andrés Méndez-Lucas 1 Anna Esteve-Codina 2 Jose Luis Rosa 1 Francesc Ventura 3
Affiliations

Affiliations

  • 1 Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain.
  • 2 CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science & Technology, 08028 Barcelona, Spain; Universitat Pompeu Fabra, 08003 Barcelona, Spain.
  • 3 Departament de Ciències Fisiològiques, Universitat de Barcelona, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain. Electronic address: fventura@ub.edu.
Abstract

Age-related and chemotherapy-induced bone loss depends on cellular senescence and the cell secretory phenotype. However, the factors secreted in the senescent microenvironment that contribute to bone loss remain elusive. Here, we report a central role for the inflammatory alternative Complement System in skeletal bone loss. Through transcriptomic analysis of bone samples, we identified complement Factor D, a rate-limiting factor of the alternative pathway of complement, which is among the most responsive factors to chemotherapy or oestrogen deficiency. We show that osteoblasts and osteocytes are major inducers of complement activation, while monocytes and osteoclasts are their primary targets. Genetic deletion of C5ar1, the receptor of the anaphylatoxin C5a, or treatment with a C5AR1 inhibitor reduced monocyte chemotaxis and osteoclast differentiation. Moreover, genetic deficiency or inhibition of C5AR1 partially prevented bone loss and osteoclastogenesis upon chemotherapy or ovariectomy. Altogether, these lines of evidence support the idea that inhibition of alternative complement pathways may have some therapeutic benefit in osteopenic disorders.

Figures
Products