Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
J Bone Miner Res. 2011 Nov;26(11):2610-21. doi: 10.1002/jbmr.472.
The physiological role of Dickkopf-1 (Dkk1) during postnatal bone growth in rodents and in adult rodents was examined utilizing an antibody to Dkk1 (Dkk1-Ab) that blocked Dkk1 binding to both low density lipoprotein receptor-related protein 6 (LRP6) and Kremen2, thereby preventing the Wnt inhibitory activity of Dkk1. Treatment of growing mice and rats with Dkk1-Ab resulted in a significant increase in bone mineral density because of increased bone formation. In contrast, treatment of adult ovariectomized rats did not appreciably impact bone, an effect that was associated with decreased Dkk1 expression in the serum and bone of older rats. Finally, we showed that Dkk1 plays a prominent role in adult bone by mediating fracture healing in adult rodents. These data suggest that, whereas Dkk1 significantly regulates bone formation in younger animals, its role in older animals is limited to pathologies that lead to the induction of Dkk1 expression in bone and/or serum, such as traumatic injury.
利用一种针对 Dickkopf-1（Dkk1）的抗体（Dkk1-Ab）研究了 Dkk1 在啮齿动物出生后骨骼生长和成年啮齿动物中的生理作用，该抗体可阻断 Dkk1 与低密度脂蛋白受体相关蛋白 6（LRP6）和 Kremen2 的结合，从而防止 Dkk1 的 Wnt 抑制活性。用 Dkk1-Ab 治疗生长中的小鼠和大鼠会因骨形成增加而导致骨矿物质密度显著增加。相比之下，用 Dkk1-Ab 治疗成年去卵巢大鼠不会明显影响骨骼，这一作用与老年大鼠血清和骨骼中 Dkk1 表达减少有关。最后，我们表明 Dkk1 通过介导成年啮齿动物的骨折愈合在成年骨骼中发挥重要作用。这些数据表明，虽然 Dkk1 在年幼动物中显著调节骨形成，但在老年动物中的作用仅限于导致骨和/或血清中 Dkk1 表达诱导的病理，例如创伤性损伤。
