Kobayashi Tatsuya
Endocrine Unit, Massachusetts General Hospital, USA.
Clin Calcium. 2009 Jul;19(7):911-8.
Treatment of osteoporosis aims to increase bone mass by suppressing bone resorption and/or stimulating bone formation. Among drugs clinically available for treatment of osteoporosis, only PTH stimulates bone formation. However, the mechanism by which PTH promotes bone formation is not clearly understood. PTH signaling in osteoblasts increases osteoblast progenitors. It appears that this effect of PTH is exerted mainly through multiple indirect pathways. Among them, the Wnt signaling pathway is of particular interest because of the strong human genetic evidence that Wnt signaling positively regulates bone mass. Activation of the PTH receptor increases Wnt signaling by down-regulating expression of Dkk1 and sclerostin, endogenous inhibitors for Wnt signaling, and by directly activating LRP6, a Wnt co-receptor. Understanding the mechanisms of the anabolic effect of PTH may lead to development of novel drugs to stimulate bone formation.
骨质疏松症的治疗旨在通过抑制骨吸收和/或刺激骨形成来增加骨量。在临床上可用于治疗骨质疏松症的药物中,只有甲状旁腺激素(PTH)能刺激骨形成。然而,PTH促进骨形成的机制尚不清楚。成骨细胞中的PTH信号增加了成骨细胞祖细胞。PTH的这种作用似乎主要通过多种间接途径发挥。其中,Wnt信号通路特别受关注,因为有强有力的人类遗传学证据表明Wnt信号正向调节骨量。PTH受体的激活通过下调Wnt信号的内源性抑制剂Dkk1和硬化蛋白的表达,以及直接激活Wnt共受体LRP6来增加Wnt信号。了解PTH合成代谢作用的机制可能会导致开发出刺激骨形成的新型药物。