DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice.
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DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice. / Abdallah, Basem M; Ditzel, Nicholas; Mahmood, Amer; Isa, Adiba; Traustadottir, Gunnhildur A; Schilling, Arndt F; Ruiz-Hidalgo, María-José; Laborda, Jorge; Amling, Michael; Kassem, Moustapha.
In: J BONE MINER RES, Vol. 26, No. 7, 7, 2011, p. 1457-1471.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice.
AU - Abdallah, Basem M
AU - Ditzel, Nicholas
AU - Mahmood, Amer
AU - Isa, Adiba
AU - Traustadottir, Gunnhildur A
AU - Schilling, Arndt F
AU - Ruiz-Hidalgo, María-José
AU - Laborda, Jorge
AU - Amling, Michael
AU - Kassem, Moustapha
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Female
KW - Gene Expression Regulation
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Body Weight
KW - Phenotype
KW - Signal Transduction
KW - Cell Differentiation
KW - Organ Size
KW - Ovariectomy
KW - T-Lymphocytes/metabolism
KW - NF-kappa B/metabolism
KW - Body Patterning
KW - Bone Resorption/blood/metabolism/pathology
KW - Bone and Bones/abnormalities/metabolism/pathology
KW - Collagen Type I/metabolism
KW - Estrogens/deficiency/metabolism
KW - Immunologic Factors/genetics/metabolism
KW - Intercellular Signaling Peptides and Proteins/blood/metabolism
KW - Mesenchymal Stem Cells/cytology/metabolism
KW - Osteoblasts/metabolism/pathology
KW - Animals
KW - Female
KW - Gene Expression Regulation
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Body Weight
KW - Phenotype
KW - Signal Transduction
KW - Cell Differentiation
KW - Organ Size
KW - Ovariectomy
KW - T-Lymphocytes/metabolism
KW - NF-kappa B/metabolism
KW - Body Patterning
KW - Bone Resorption/blood/metabolism/pathology
KW - Bone and Bones/abnormalities/metabolism/pathology
KW - Collagen Type I/metabolism
KW - Estrogens/deficiency/metabolism
KW - Immunologic Factors/genetics/metabolism
KW - Intercellular Signaling Peptides and Proteins/blood/metabolism
KW - Mesenchymal Stem Cells/cytology/metabolism
KW - Osteoblasts/metabolism/pathology
M3 - SCORING: Journal article
VL - 26
SP - 1457
EP - 1471
JO - J BONE MINER RES
JF - J BONE MINER RES
SN - 0884-0431
IS - 7
M1 - 7
ER -
