Dissecting the role of Dkk-1 in the pathogenesis of postmenopausal osteoporosis

点击翻译按钮获取中文摘要

Approximately 40% of the postmenopausal women suffer from osteoporosis, one of the most frequent diseases in women. This disease is characterized by a decrease in bone density and a compromised bone quality leading to an increased fracture risk. Loss of estrogens induced by the menopause leads to an increased production of osteoclasts which further promotes the induction of postmenopausal osteoporosis. Furthermore, it seems that the inhibition of Wnt signaling, which is a critical regulator of bone mass, could be one possible reason for the development of this disease. So far, little is known about its regulation by estrogens and its role in the pathogenesis of osteoporosis. Recent studies reported increased levels of Dickkopf-1 (Dkk-1), an inhibitor of Wnt signaling, in patients suffering from postmenopausal osteoporosis suggesting a role for Dkk-1 in the pathogenesis of postmenopausal osteoporosis. Thus, we hypothesize that Dkk-1 which is produced by osteoblasts, osteocytes, and T cells contributes to bone loss induced by estrogen deficiency. To test this hypothesis we will investigate the influence of Dkk-1, produced by osteoblasts or osteocytes, on the inhibited bone formation in postmenopausal osteoporosis by utilizing corresponding animal models. Therefore, Dkk-1-floxed mice will be crossed with Osx- and Dmp1-Cre mice, respectively, to generate mice lacking Dkk-1 specifically in osteoblasts and osteocytes. By performing an ovariectomy, estrogen deficiency and the resulting loss of bone mass should be imitated and investigated. Furthermore, we will analyze the regulation of Dkk-1 by 17b-estradiol in osteoblasts and osteocytes in vitro. Here, we planned different cell culture experiments using primary osteoblasts as well as immortalized cell lines (MC3T3-E1, IDG-SW3) which should be treated with different concentrations of 17b-estradiol. In addition, the influence of the estrogen receptor should be analyzed too, by using siRNA to reduce its expression or DNA to induce its expression. The effect of current osteoporosis therapeutics should also be addressed by treating osteoblasts and osteocytes with PTH or bisphosphonates. Because also T cells could contribute to the pathogenesis of postmenopausal osteoporosis, we will analyze the influence of Dkk-1 produced by T cells. Therefore, Dkk-1-floxed mice will be crossed with Lck-Cre mice to generate mice lacking Dkk-1 especially in T cells. Subsequently, estrogen deficiency will be readjusted by performing ovariectomy. To test this in vitro, co-culture experiments of osteoblasts and T cells should be established. A detailed knowledge of the molecular mechanisms underlying inhibited bone formation in postmenopausal women may help to better prevent or treat bone loss in these patients.