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

J Bone Miner Res. 2011 Jul;26(7):1457-71. doi: 10.1002/jbmr.346.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning
  • Body Weight
  • Bone Resorption / blood
  • Bone Resorption / metabolism*
  • Bone Resorption / pathology*
  • Bone and Bones / abnormalities
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Calcium-Binding Proteins
  • Cell Differentiation
  • Collagen Type I / metabolism
  • Estrogens / deficiency*
  • Estrogens / metabolism
  • Female
  • Gene Expression Regulation
  • Immunologic Factors / genetics
  • Immunologic Factors / metabolism
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Organ Size
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Ovariectomy
  • Phenotype
  • Signal Transduction
  • T-Lymphocytes / metabolism


  • Calcium-Binding Proteins
  • Collagen Type I
  • Dlk1 protein, mouse
  • Estrogens
  • Immunologic Factors
  • Intercellular Signaling Peptides and Proteins
  • NF-kappa B