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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Bone Resorption / complications*
  • Bone Resorption / metabolism
  • Bone Resorption / pathology
  • Bone Resorption / prevention & control
  • Calcium-Binding Proteins
  • Carrier Proteins / metabolism*
  • Cell Adhesion Molecules
  • Cell Differentiation
  • Cell Movement
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Gingival Crevicular Fluid / metabolism
  • Humans
  • Inflammation / complications*
  • Inflammation / pathology
  • Intercellular Signaling Peptides and Proteins
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / pathology
  • Osteoclasts / metabolism*
  • Osteogenesis*
  • Periodontitis / pathology
  • Primates
  • Protein Structure, Tertiary

Substances

  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cell Adhesion Molecules
  • Cytokines
  • EDIL3 protein, human
  • Edil3 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Lymphocyte Function-Associated Antigen-1