Dickkopf-1 (Dkk1) is a potent inhibitor of the Wnt/β-catenin signaling pathway in both tooth and bone development. Deletion of the Dkk1 gene in mice leads to embryonic lethality, whereas transgenic mice over-expressing Dkk1 in mature osteoblasts result in osteopenia. Targeted expression of Dkk1 in dental epithelial cells leads to the formation of dysfunctional enamel knots and subsequent tooth defects during embryonic development. However, the direct role of Dkk1 in post-natal dentinogenesis and calvarial osteogenesis is largely unknown. To address this issue, we analyzed 2.3-kb Col1a1 Dkk1-transgenic (Tg) mice, which over-express Dkk1 in immature and mature odontoblasts and osteoblasts.

The Dkk1 transgene was highly expressed in pulp and odontoblast cells during post-natal developmental stages. A disruption in tooth development was obvious with the 1st mandibular molar displaying short roots, an enlarged pulp/root canal region, and a decreased dentin formation rate. Also within the mandible, the 2nd molar is small and malformed and the 3rd molar is absent. The molars possess an increased number of immature odontoblasts, very few mature odontoblasts, and a sharp reduction in dentinal tubule number accompanying a dramatic change in expression of certain odontoblast markers, such as Osterix and Nestin.

The calvarial bone presents with a significantly pronounced bone defect within Dkk1-Tg mice. The defect exhibits a markedly reduced calvarial bone density and multiple regions lacking any bone mineralization, which is indicative of an osteogenic deficiency. A greater than 60% reduction of parietal bone volume as well as an incomplete articulation of the parietal bones abutting the sagittal suture is evident. Irregularly shaped and abnormally small osteocytes are housed within the underdeveloped bone presenting more as osteoblastic-like cells in structure/function. Most obviously, the calvaria rather unusually presents with a considerable increase in osteoclast cell number, maturation, and activity present on the endo-cranial surface. An increase in immature osteoblast markers, as well as a decrease in mature osteoblast markers combined with an increase in active osteoclast markers was evidence of a disrupted bone homeostasis.

From our studies we propose that within molar development and calvarial bone development, Dkk1 over-expression disrupts post-natal dentin formation and instigates an uncoupling of the osteoblastic/osteoclastic bone remodeling activities in favor of bone resorption with an increase in osteoclast-mediated destruction. Dkk1 is able to exert its effects directly via the inhibition of Wnt signaling or indirectly via its regulation of Osterix expression.