title: DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice.
abstract: Delta-like 1/fetal antigen 1 (DLK1/FA-1) is a transmembrane protein belonging to the Notch/Delta family that acts as a membrane-associated or a soluble protein to regulate regeneration of a number of adult tissues. Here we examined the role of DLK1/FA-1 in bone biology using osteoblast-specific Dlk1-overexpressing mice (Col1-Dlk1). Col1-Dlk1 mice displayed growth retardation and significantly reduced total body weight and bone mineral density (BMD). Micro-computed tomographis (µCT) scanning revealed a reduced trabecular and cortical bone volume fraction. Tissue-level histomorphometric analysis demonstrated decreased bone-formation rate and enhanced bone resorption in Col1-Dlk1 mice compared with wild-type mice. At a cellular level, Dlk1 markedly reduced the total number of bone marrow (BM)-derived colony-forming units fibroblasts (CFU-Fs), as well as their osteogenic capacity. In a number of in vitro culture systems, Dlk1 stimulated osteoclastogenesis indirectly through osteoblast-dependent increased production of proinflammatory bone-resorbing cytokines (eg, Il7, Tnfa, and Ccl3). We found that ovariectomy (ovx)-induced bone loss was associated with increased production of Dlk1 in the bone marrow by activated T cells. Interestingly, Dlk1(-/-) mice were significantly protected from ovx-induced bone loss compared with wild-type mice. Thus we identified Dlk1 as a novel regulator of bone mass that functions to inhibit bone formation and to stimulate bone resorption. Increasing DLK1 production by T cells under estrogen deficiency suggests its possible use as a therapeutic target for preventing postmenopausal bone loss.
authors.affiliation: Endocrine Research Laboratory, KMEB, Department of Endocrinology, and Medical Biotechnlogy Center, Odense University Hospital and University of Southern Denmark, Odense, Denmark. babdallah@health.sdu.dk
authors.forename: Basem M
authors.initials: BM
authors.lastname: Abdallah
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ditzel
authors.forename: Amer
authors.initials: A
authors.lastname: Mahmood
authors.forename: Adiba
authors.initials: A
authors.lastname: Isa
authors.forename: Gunnhildur A
authors.initials: GA
authors.lastname: Traustadottir
authors.forename: Arndt F
authors.initials: AF
authors.lastname: Schilling
authors.forename: María-José
authors.initials: MJ
authors.lastname: Ruiz-Hidalgo
authors.forename: Jorge
authors.initials: J
authors.lastname: Laborda
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
mesh_terms: D000818:Animals; D019521:Body Patterning; D001835:Body Weight; D001862:Bone Resorption / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D001842:Bone and Bones / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D024042:Collagen Type I / Q000378:metabolism; D004967:Estrogens / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D010641:Phenotype; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D024042:Collagen Type I; C512925:Dlk1 protein, mouse; D004967:Estrogens; D007155:Immunologic Factors; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B