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

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.

• Authors: Jieun Shin, Tomoki Maekawa, Toshiharu Abe, Evlambia Hajishengallis, Kavita Hosur, Kalyani Pyaram, Ioannis Mitroulis, Triantafyllos Chavakis, George Hajishengallis
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 307 Pg. 307ra155 (Sep 30 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 26424570 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• 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

Topics

• Amino Acid Motifs
• Animals
• Bone Resorption (complications, metabolism, pathology, 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, 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