DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice

Basem M Abdallah, Nicholas Ditzel, Amer Mahmood, Adiba Isa, Gunnhildur A Traustadottir, Arndt F Schilling, María-José Ruiz-Hidalgo, Jorge Laborda, Michael Amling, Moustapha Kassem

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
TidsskriftJournal of Bone and Mineral Research
Vol/bind26
Udgave nummer7
Sider (fra-til)1457-71
Antal sider15
ISSN0884-0431
DOI
StatusUdgivet - 2011

Fingeraftryk

Estrogens
Osteogenesis
Osteoblasts
Postmenopausal Osteoporosis
Ovariectomy
Bone Density
Proteins
Fibroblasts
Membranes
Growth

Citer dette

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. / DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice. I: Journal of Bone and Mineral Research. 2011 ; Bind 26, Nr. 7. s. 1457-71.
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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.",
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author = "Abdallah, {Basem M} and Nicholas Ditzel and Amer Mahmood and Adiba Isa and Traustadottir, {Gunnhildur A} and Schilling, {Arndt F} and Mar{\'i}a-Jos{\'e} Ruiz-Hidalgo and Jorge Laborda and Michael Amling and Moustapha Kassem",
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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.

I: Journal of Bone and Mineral Research, Bind 26, Nr. 7, 2011, s. 1457-71.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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

N1 - Copyright © 2011 American Society for Bone and Mineral Research.

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 - Body Patterning

KW - Body Weight

KW - Bone Resorption

KW - Bone and Bones

KW - Cell Differentiation

KW - Collagen Type I

KW - Estrogens

KW - Female

KW - Gene Expression Regulation

KW - Immunologic Factors

KW - Intercellular Signaling Peptides and Proteins

KW - Mesenchymal Stem Cells

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - NF-kappa B

KW - Organ Size

KW - Osteoblasts

KW - Ovariectomy

KW - Phenotype

KW - Signal Transduction

KW - T-Lymphocytes

U2 - 10.1002/jbmr.346

DO - 10.1002/jbmr.346

M3 - Journal article

C2 - 21308776

VL - 26

SP - 1457

EP - 1471

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 7

ER -