Osteoporosis is a frequent disease leading to an increased risk of fractures caused by a systemic impairment of bone mass, strength, and microarchitecture. Given the emerging role of the Wnt signaling pathway in bone biology, we focused on the function of the important Wnt inhibitor dickkopf-1 (Dkk-1) and examined how the deletion of Dkk-1 solely in osteoblasts or osteocytes influences bone homeostasis. Therefore, we used the Cre-LoxP recombination system and crossed Dkk-1-floxed mice with osterix-cre (Osx; osteoblast-specific) and dentin matrix protein1-cre (Dmp-1; osteocyte-specific) mice. Female and male mice were examined at 1012 weeks of age. However, the male mice did not show significant differences. Female mice without Dkk-1 in their osteoblasts showed a 3.75-fold increase in bone volume/total volume (BV/TV) compared to cre-negative controls. Furthermore, the trabecular number was increased by 59%, while the trabecular separation decreased by 38%. Cortical thickness and density were not changed. The deletion of Dkk-1 in osteoblasts seemed to have a significant impact on the amount of Dkk-1 in the serum as Dkk-1OsxCre mice had markedly lower Dkk-1 serum levels (−77%) compared to controls, whereas Dkk-1 serum levels were not changed in Dkk-1Dmp1Cre mice. However, Dkk-1Dmp1Cre mice also showed a significant increase in the BV/TV (twofold), the trabecular number (+33%), and the cortical thickness (+9%) while the separation was reduced (−26%). Histomorphometric parameters underlined these results as the mineral apposition rate and the bone formation rate were increased in both mouse lines. In summary, we show that most systemic Dkk-1 stems from osteoblasts and not from osteocytes. Nevertheless, the amount of Dkk-1 in osteoblasts and osteocytes is sufficient to modulate bone mass. Thus, the individual contribution of each cell type to the pathogenesis of specific bone diseases such as post-menopausal osteoporosis should be further investigated to potentially specifically target Dkk-1.
14 - 17 May 2016
European Calcified Tissue Society