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Sci Transl Med. 2015 Sep 30;7(307):307ra155. doi: 10.1126/scitranslmed.aac5380.

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

Author information

1
Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Preventive and Restorative Sciences, Division of Pediatric Dentistry, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany.
4
Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. geoh@upenn.edu.

Abstract

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.

PMID:
26424570
PMCID:
PMC4593066
DOI:
10.1126/scitranslmed.aac5380
[Indexed for MEDLINE]
Free PMC Article

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