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

• Published in: Science translational medicine Vol. 7; no. 307; p. 307ra155
• Main Authors: Shin, Jieun, Maekawa, Tomoki, Abe, Toshiharu, Hajishengallis, Evlambia, Hosur, Kavita, Pyaram, Kalyani, Mitroulis, Ioannis, Chavakis, Triantafyllos, Hajishengallis, George
• Format: Journal Article
• Language: English
• Published: United States 30-09-2015
• Subjects: Amino Acid Motifs; Animals; Bone Resorption - complications; Bone Resorption - metabolism; Bone Resorption - pathology; Bone Resorption - prevention & control; Carrier Proteins - metabolism; Cell Differentiation; Cell Movement; Cytokines - metabolism; Disease Models, Animal; Female; Gingival Crevicular Fluid - metabolism; Humans; Inflammation - complications; Inflammation - pathology; Lymphocyte Function-Associated Antigen-1 - metabolism; Mice, Inbred C57BL; Mice, Knockout; Neutrophils - pathology; Osteoclasts - metabolism; Osteogenesis; Periodontitis - pathology; Primates; Protein Structure, Tertiary
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aac5380

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.