Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency-induced bone loss in mice

Florence Figeac, Ditte C. Andersen, Casper A. Nipper Nielsen, Nicholas Ditzel, Søren P. Sheikh, Karsten Skjødt, Moustapha Kassem, Charlotte H. Jensen*, Basem M. Abdallah

*Kontaktforfatter for dette arbejde

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Resumé

Soluble delta-like 1 homolog (DLK1) is a circulating protein that belongs to the Notch/Serrate/delta family, which regulates many differentiation processes including osteogenesis and adipogenesis. We have previously demonstrated an inhibitory effect of DLK1 on bone mass via stimulation of bone resorption and inhibition of bone formation. Further, serum DLK1 levels are elevated and positively correlated to bone turnover markers in estrogen (E)-deficient rodents and women. In this report, we examined whether inhibition of serum DLK1 activity using a neutralizing monoclonal antibody protects from E deficiency-associated bone loss in mice. Thus, we generated mouse monoclonal anti-mouse DLK1 antibodies (MAb DLK1) that enabled us to reduce and also quantitate the levels of bioavailable serum DLK1 in vivo. Ovariectomized (ovx) mice were injected intraperitoneally twice weekly with MAb DLK1 over a period of one month. DEXA-, microCT scanning, and bone histomorphometric analyses were performed. Compared to controls, MAb DLK1 treated ovx mice were protected against ovx-induced bone loss, as revealed by significantly increased total bone mass (BMD) due to increased trabecular bone volume fraction (BV/TV) and inhibition of bone resorption. No significant changes were observed in total fat mass or in the number of bone marrow adipocytes. These results support the potential use of anti-DLK1 antibody therapy as a novel intervention to protect from E deficiency associated bone loss.

OriginalsprogEngelsk
TidsskriftBone
Vol/bind110
Sider (fra-til)312-320
ISSN8756-3282
DOI
StatusUdgivet - maj 2018

Fingeraftryk

Estrogens
Osteogenesis
Serum
X-Ray Microtomography
Adipogenesis
Adipocytes
Rodentia
Fats
Proteins

Citer dette

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title = "Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency-induced bone loss in mice",
abstract = "Soluble delta-like 1 homolog (DLK1) is a circulating protein that belongs to the Notch/Serrate/delta family, which regulates many differentiation processes including osteogenesis and adipogenesis. We have previously demonstrated an inhibitory effect of DLK1 on bone mass via stimulation of bone resorption and inhibition of bone formation. Further, serum DLK1 levels are elevated and positively correlated to bone turnover markers in estrogen (E)-deficient rodents and women. In this report, we examined whether inhibition of serum DLK1 activity using a neutralizing monoclonal antibody protects from E deficiency-associated bone loss in mice. Thus, we generated mouse monoclonal anti-mouse DLK1 antibodies (MAb DLK1) that enabled us to reduce and also quantitate the levels of bioavailable serum DLK1 in vivo. Ovariectomized (ovx) mice were injected intraperitoneally twice weekly with MAb DLK1 over a period of one month. DEXA-, microCT scanning, and bone histomorphometric analyses were performed. Compared to controls, MAb DLK1 treated ovx mice were protected against ovx-induced bone loss, as revealed by significantly increased total bone mass (BMD) due to increased trabecular bone volume fraction (BV/TV) and inhibition of bone resorption. No significant changes were observed in total fat mass or in the number of bone marrow adipocytes. These results support the potential use of anti-DLK1 antibody therapy as a novel intervention to protect from E deficiency associated bone loss.",
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author = "Florence Figeac and Andersen, {Ditte C.} and {Nipper Nielsen}, {Casper A.} and Nicholas Ditzel and Sheikh, {S{\o}ren P.} and Karsten Skj{\o}dt and Moustapha Kassem and Jensen, {Charlotte H.} and Abdallah, {Basem M.}",
year = "2018",
month = "5",
doi = "10.1016/j.bone.2018.02.030",
language = "English",
volume = "110",
pages = "312--320",
journal = "Bone",
issn = "8756-3282",
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Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency-induced bone loss in mice. / Figeac, Florence; Andersen, Ditte C.; Nipper Nielsen, Casper A.; Ditzel, Nicholas; Sheikh, Søren P.; Skjødt, Karsten; Kassem, Moustapha; Jensen, Charlotte H.; Abdallah, Basem M.

I: Bone, Bind 110, 05.2018, s. 312-320.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Antibody-based inhibition of circulating DLK1 protects from estrogen deficiency-induced bone loss in mice

AU - Figeac, Florence

AU - Andersen, Ditte C.

AU - Nipper Nielsen, Casper A.

AU - Ditzel, Nicholas

AU - Sheikh, Søren P.

AU - Skjødt, Karsten

AU - Kassem, Moustapha

AU - Jensen, Charlotte H.

AU - Abdallah, Basem M.

PY - 2018/5

Y1 - 2018/5

N2 - Soluble delta-like 1 homolog (DLK1) is a circulating protein that belongs to the Notch/Serrate/delta family, which regulates many differentiation processes including osteogenesis and adipogenesis. We have previously demonstrated an inhibitory effect of DLK1 on bone mass via stimulation of bone resorption and inhibition of bone formation. Further, serum DLK1 levels are elevated and positively correlated to bone turnover markers in estrogen (E)-deficient rodents and women. In this report, we examined whether inhibition of serum DLK1 activity using a neutralizing monoclonal antibody protects from E deficiency-associated bone loss in mice. Thus, we generated mouse monoclonal anti-mouse DLK1 antibodies (MAb DLK1) that enabled us to reduce and also quantitate the levels of bioavailable serum DLK1 in vivo. Ovariectomized (ovx) mice were injected intraperitoneally twice weekly with MAb DLK1 over a period of one month. DEXA-, microCT scanning, and bone histomorphometric analyses were performed. Compared to controls, MAb DLK1 treated ovx mice were protected against ovx-induced bone loss, as revealed by significantly increased total bone mass (BMD) due to increased trabecular bone volume fraction (BV/TV) and inhibition of bone resorption. No significant changes were observed in total fat mass or in the number of bone marrow adipocytes. These results support the potential use of anti-DLK1 antibody therapy as a novel intervention to protect from E deficiency associated bone loss.

AB - Soluble delta-like 1 homolog (DLK1) is a circulating protein that belongs to the Notch/Serrate/delta family, which regulates many differentiation processes including osteogenesis and adipogenesis. We have previously demonstrated an inhibitory effect of DLK1 on bone mass via stimulation of bone resorption and inhibition of bone formation. Further, serum DLK1 levels are elevated and positively correlated to bone turnover markers in estrogen (E)-deficient rodents and women. In this report, we examined whether inhibition of serum DLK1 activity using a neutralizing monoclonal antibody protects from E deficiency-associated bone loss in mice. Thus, we generated mouse monoclonal anti-mouse DLK1 antibodies (MAb DLK1) that enabled us to reduce and also quantitate the levels of bioavailable serum DLK1 in vivo. Ovariectomized (ovx) mice were injected intraperitoneally twice weekly with MAb DLK1 over a period of one month. DEXA-, microCT scanning, and bone histomorphometric analyses were performed. Compared to controls, MAb DLK1 treated ovx mice were protected against ovx-induced bone loss, as revealed by significantly increased total bone mass (BMD) due to increased trabecular bone volume fraction (BV/TV) and inhibition of bone resorption. No significant changes were observed in total fat mass or in the number of bone marrow adipocytes. These results support the potential use of anti-DLK1 antibody therapy as a novel intervention to protect from E deficiency associated bone loss.

KW - Dlk1

KW - Monoclonal antibody

KW - Osteoblast

KW - Osteoclast

KW - Osteoporosis

KW - Pref-1

KW - NIH 3T3 Cells

KW - Humans

KW - Osteoclasts/drug effects

KW - Intercellular Signaling Peptides and Proteins/immunology

KW - X-Ray Microtomography

KW - Flow Cytometry

KW - Female

KW - Osteoporosis/prevention & control

KW - Cell Line

KW - Ovariectomy

KW - Antibodies, Neutralizing/therapeutic use

KW - Bone Resorption/prevention & control

KW - Osteoblasts/drug effects

KW - Antibodies/therapeutic use

KW - Osteogenesis/drug effects

KW - Estrogens/deficiency

KW - Animals

KW - Bone Density/drug effects

KW - Mice

U2 - 10.1016/j.bone.2018.02.030

DO - 10.1016/j.bone.2018.02.030

M3 - Journal article

VL - 110

SP - 312

EP - 320

JO - Bone

JF - Bone

SN - 8756-3282

ER -