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.

The Effect of Anti-Oxidant and Iron Chelator on Metabolic E Bone Turnover in Ovariectomized Rats

“…This imbalance lead to increase Oxygen-derived free radicals such as and TNF α. on the other hand decreased in serum TNF α in all treated groups due to efficacy of vitamin E and desferal. This explanation is compatible with [14] . suggested that the level of blood cytokines increased and parallel with the condition of elevated bone resorption in ovariectomized women.…”

The imprinted gene Delta like non-canonical notch ligand 1 (Dlk1) associates with obesity and triggers insulin resistance through inhibition of skeletal muscle glucose uptake

“…Our short-term in vivo anti-DLK1 strategy did not result in any acute changes in glucose levels, which may suggest that the phenotype is due to more chronic changes or that the organ responsible for the DLK1 fraction mediating insulin resistance is not reached by the anti-DLK1 strategy. We have previously noted that antibody-based in vivo neutralization of DLK1 triggers an unknown compensatory feedback loop [58] and our unpublished data show that long-term anti-DLK1 targeting through the circulation indeed increases circulating DLK1 when treatment stops. Currently, we can only speculate on the underlying mechanism, yet in a treatment perspective that seeks minimal side effects, the major source of circulating DLK1 in this feedback loop needs to be pinpointed and may help further clarify the potential of targeting DLK1 in vivo in relation to preventing/treating T2D.…”

The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms

“…Since DLK1 is implicated in proliferation and differentiation of progenitors during development and re-expressed during times of disease and regeneration, the gene itself and the cells in which it is expressed are therefore exciting to pursue for regenerative medicine. Current literature suggests that DLK1 does impact regeneration of adrenal zona glomerulosa, endothelium [80,81], ear-wound [82], and bone [83,84]. But the majority of insight to DLK1's role in tissue regeneration derives…”