Dickkopf-1 is a critical mediator of obesity-induced bone loss

Introduction:

Besides postmenopausal osteoporosis, the significance of osteoporosis in overweight individuals and patients with type 2 diabetes mellitus is increasing. More than 40% of adults worldwide are overweight and 13% are obese. The reduced bone mass in overweight individuals and diabetes is primarily due to increased differentiation of progenitor cells into adipocytes at the expense of osteoblasts. One important pathway for the differentiation of osteoblasts is the Wnt signaling pathway. We recently showed that Dickkopf-1 (Dkk1), a potent Wnt inhibitor, is upregulated in obese mice. In this study, we investigated the role of Dkk1 in the pathogenesis of obesity-induced bone loss using transgenic global and tissue-specific knockout mice.

Methods:

Obesity was induced in 8 week-old male mice with an inducible global (Rosa26-ERT2cre) or osteoprogenitor (Osx-cre)-specific deletion of Dkk1 with a high-fat diet (HFD) containing 60% fat. After 12 weeks, weight, bone volume, bone fat mass and bone turnover were assessed.

Results:

In Dkk1fl/fl;Rosa26-CreERT2 and controls, HFD significantly increased body weight by 42 – 45%. HFD reduced bone mass in Cre- mice significantly (-16%), while Dkk1fl/fl;Rosa26-CreERT2 mice showed a smaller, non-significant decrease (-10%). Furthermore, HFD was associated with increased bone marrow fat in the femur, which was less pronounced in Dkk1fl/fl;Rosa26-CreERT2 mice. Dkk1 serum levels were only increased in Cre- HFD mice, while almost absent in Cre+ mice, independent of the diet. Histomorphometric analysis revealed that the mineralizing surface and bone formation rate were lower in Cre- mice, but unchanged in Cre+ mice on a HFD. In contrast to global Dkk1 deletion, osteoprogenitor-specific Dkk1 deletion only partially protected against obesity-induced bone loss. HFD significantly increased the body weight in Cre- and Dkk1fl/fl;Osx:Cre mice to a similar extent (43 – 44%). Here, HFD significantly reduced bone volume in Cre- (-34%) and Cre+ (-21%) mice compared to ND controls, while fat volume in the femora was increased by 58% and 46%. Similar to the global knockout mice, Dkk-1 serum levels were only increased in Cre- HFD mice, while Dkk1fl/fl;Osx:Cre mice showed a markedly reduced Dkk1 serum level. Histomorphometric analyses underlined these results, as the mineralizing surface and bone formation rate were reduced by HFD in Cre- mice, while Dkk1fl/fl;Osx:Cre showed a less pronounced effect.

Discussion:

In summary, Dkk1 is a critical mediator of obesity-induced bone loss. However, besides osteoblasts, other cells must contribute to elevated levels of Dkk1 in obesity and its subsequent effects on bone.