A novel macrolide-Del-1 axis to regenerate bone in old age

Aging is associated with increased susceptibility to chronic inflammatory bone loss disorders, such as peri- odontitis, in large part due to the impaired regenerative potential of aging tissues. DEL -1 exerts osteo- genic 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 deriva- tive, 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 -depen- dent 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 ex- hibited 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.