DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates

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Science Translational Medicine  30 Sep 2015:
Vol. 7, Issue 307, pp. 307ra155
DOI: 10.1126/scitranslmed.aac5380

DELivering new therapies for chronic inflammation

Chronic inflammation is prevalent in nearly half of adult teeth and gums in the U.S. population, and this so-called periodontitis can increase a patient’s risk of developing other inflammatory diseases in the heart (atherosclerosis) and joints (rheumatoid arthritis). Shin et al. capitalized on the natural anti-inflammatory activity of the protein DEL-1, finding that it not only blocked excessive immune cell infiltration into the periodontium but also had innate anti-osteoclastogenic activity; that is, it stopped bone loss by interrupting the signaling pathways to osteoclasts, the bone-resorbing cells. In vitro, in human and mice osteoclast precursor cells, DEL-1 prevented osteoclast differentiation by inhibiting NFATc1 activity. In vivo, in mouse and nonhuman primate models of periodontitis, giving DEL-1 locally reduced inflammation and tissue destruction, thus halting any tissue loss. The mechanism appears to be two-pronged: working “upstream” in disease signaling pathways to prevent inflammatory cell recruitment to the teeth and gums, as well as acting “downstream” to stop osteoclastogenesis. With data in a monkey model that represents the human disease, anatomy, and immune system closely, it is likely that DEL-1–based therapeutics could translate soon once safety of this endogenous molecule is confirmed.


DEL-1 (developmental endothelial locus–1) is an endothelial cell–secreted protein that regulates LFA-1 (lymphocyte function–associated antigen–1) integrin–dependent leukocyte recruitment and inflammation in various tissues. We identified a novel regulatory mechanism of DEL-1 in osteoclast biology. Specifically, we showed that DEL-1 is expressed by human and mouse osteoclasts and regulates their differentiation and resorptive function. Mechanistically, DEL-1 inhibited the expression of NFATc1, a master regulator of osteoclastogenesis, in a Mac-1 integrin–dependent manner. In vivo mechanistic analysis has dissociated the anti-inflammatory from the anti–bone-resorptive action of DEL-1 and identified structural components thereof mediating these distinct functions. Locally administered human DEL-1 blocked inflammatory periodontal bone loss in nonhuman primates—a relevant model of human periodontitis. The ability of DEL-1 to regulate both upstream (inflammatory cell recruitment) and downstream (osteoclastogenesis) events that lead to inflammatory bone loss paves the way to a new class of endogenous therapeutics for treating periodontitis and perhaps other inflammatory disorders.

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