Sirisereephap, K.; Tamura, H.; Lim, J.-H.; Surboyo, M. D. C.; Isono, T.; Hiyoshi, T.; Rosenkranz, A. L.; Sato-Yamada, Y.; Domon, H.; Ikeda, A.; Hirose, T.; Sunazuka, T.; Yoshiba, N.; Okada, H.; Terao, Y.; Maeda, T.; Tabeta, K.; Chavakis, T.; Hajishengallis, G.; Maekawa, T.
Aging is associated with increased susceptibility to chronic inflammatory bone loss disorders, such as periodontitis, in large part due to the impaired regenerative potential of aging tissues. DEL-1 exerts osteogenic activity and promotes bone regeneration. However, DEL-1 expression declines with age. Here we show that systemically administered macrolide antibiotics and a non-antibiotic erythromycin derivative, EM-523, restore DEL-1 expression in 18-month-old ("aged") mice while promoting regeneration of bone lost due to naturally occurring age-related periodontitis. These compounds failed to induce bone regeneration in age-matched DEL-1-deficient mice. Consequently, these drugs promoted DEL-1-dependent functions, including alkaline phosphatase activity and osteogenic gene expression in the periodontal tissue while inhibiting osteoclastogenesis, leading to net bone growth. Macrolide-treated aged mice exhibited increased skeletal bone mass, suggesting that this treatment may be pertinent to systemic bone loss disorders. In conclusion, we identified a macrolide-DEL-1 axis that can regenerate bone lost due to aging-related disease.