title: 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.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jieun
authors.initials: J
authors.lastname: Shin
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Preventive and Restorative Sciences, Division of Pediatric Dentistry, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Evlambia
authors.initials: E
authors.lastname: Hajishengallis
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Hosur
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Pyaram
authors.affiliation: Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Mitroulis
authors.affiliation: Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. geoh@upenn.edu.
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001862:Bone Resorption / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D015815:Cell Adhesion Molecules; D002454:Cell Differentiation; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005883:Gingival Crevicular Fluid / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism*; D010012:Osteogenesis; D010518:Periodontitis / Q000473:pathology; D011323:Primates; D017434:Protein Structure, Tertiary
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D016207:Cytokines; C110183:EDIL3 protein, human; C491706:Edil3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1