DEL-1 Upregulation Promotes Bone Regeneration in Aged Mice – Fight Aging!

Bone is constantly remodeled throughout life. The extracellular matrix making up bone tissue is continually broken down by osteoclast cells and built up by osteoblast cells. In youth, these activities are balanced. With aging, however, the activity of osteoclast cells progressively outweighs the activity of osteoblast cells. The consequence is an ever greater loss of bone mineral density leading to osteoporosis. This process is also found in the bone loss characteristic of advanced periodontitis. There are many contributing factors leading to the imbalance in bone remodeling, and it isn’t all that clear as to which of them are more or less important than the others, even given the existence of treatments, such as bisphosphonates, that can slow the progression of osteoporosis. There is certainly a need for better therapies, those with the ability to dramatically increase bone mineral density.

In today’s open access paper, researchers discuss the role of DEL-1 in bone loss related to periodontitis. They demonstrate an approach to upregulation of DEL-1 expression, showing that it can regenerate bone in this context of gum disease. The researchers do a good job of laying out the various interactions along the way, and demonstrate that the treatment requires DEL-1 to function. Thus DEL-1 is the critical link, and expression of DEL-1 declines with age, perhaps an important contribution to loss of bone mineral density. This mechanism may additionally be worth exploring in the broader context of all bone loss experienced with age. Whether that is the case remains to be seen.

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

Development endothelial locus-1 (DEL-1) is a homeostatic protein secreted by tissue-resident cells in the gingiva and the periodontal ligament (PDL), endothelial and mesenchymal stromal/stem cells (MSCs) and some macrophage subsets, and contributes to inflammation resolution and tissue repair. Specifically, during the resolution phase of experimental periodontitis in mice, DEL-1 promotes efferocytosis and the emergence of the macrophage pro-resolving phenotype as well as stimulating alveolar bone regeneration. The pro-regenerative function of DEL-1 is largely independent of its efferocytic/pro-resolving function and involves activation of a β3 integrin–FAK–ERK1/2–RUNX2 pathway in osteoprogenitor cells. Alveolar bone regeneration fails in DEL-1-deficient mice or in mice that express a DEL-1 point mutant that cannot bind β3 integrins. The expression of DEL-1 is severely diminished in old age, both in mice and humans.

Given that DEL-1 levels decline severely in old age and mice ≥18 months of age are DEL-1 deficient, it is important to develop potential therapeutic approaches to stimulate DEL-1 expression, thereby restoring the levels of this important homeostatic protein in the elderly. We have recently shown that the macrolide antibiotic erythromycin (ERM) – but not other antibiotics, such as penicillin and josamycin – stimulates the production of DEL-1 in vascular endothelial cells. Specifically, erythromycin interacts with the growth hormone secretagogue receptor (GHSR) and activates JAK2 and p38 MAPK signaling, leading to C/EBPβ-dependent DEL-1 expression. Moreover, systemic erythromycin treatment in mice increased DEL-1 expression in the PDL, which connects the tooth to the surrounding alveolar bone. The PDL of humans and animals, including mice, contains a mostly perivascular MSC niche involved in periodontal tissue regeneration and includes progenitor cells that can differentiate into osteoblasts.

We show that erythromycin and other macrolides restore DEL-1 expression in old mice and promote regeneration of bone lost due to naturally occurring, aging-related periodontitis. The same treatment increased the bone mass in the femurs of old mice. Importantly, EM-523, a non-antibiotic derivative of erythromycin, that retains the ability to activate a homolog of the GHSR, motilin receptor, reproduced the DEL-1-dependent effect of erythromycin on bone regeneration. Mechanistically, macrolide and EM-523 treatments induced the formation of new bone by upregulating alkaline phosphatase (ALP) activity and the expression of osteogenic genes in periodontal tissue while reducing the number of osteoclasts, thereby favorably influencing the osteogenesis/osteoclastogenesis balance. Periodontal bone lost due to periodontitis has limited capacity for regeneration even after standard treatment (scaling and root planing) and surgical periodontal therapy, especially in elderly patients. Therefore, the non-antibiotic compound EM-523 may represent a safe, effective, and affordable new approach to regenerate bone lost due to periodontitis in humans and perhaps for increasing the mineral content of the skeletal bone in the elderly.