骨质疏松和骨缺损在临床常见，治疗困难。甲状旁腺素（PTH）可增加骨形成和骨量，在治疗骨质疏松、骨缺损、加强骨折愈合等方面均发挥一定的作用，但其促进骨质合成的机制尚未彻底阐明。研究者（包括我们）发现，PTH在成骨系细胞中多水平激活Wnt/β-catenin信号，后者在骨的再生和修复过程发挥重要的调控作用。但现有模型无法确立其在PTH促成骨中的作用。申请者前期构建了基因敲除小鼠，实现了在出生后小鼠所有成骨系细胞中敲除β-catenin。本课题拟在前期工作基础上深入研究，通过骨组织形态计量、显微CT等技术检测小鼠骨量，流式细胞仪分选、原位杂交以及基因芯片等检测成骨细胞和破骨细胞的分化、增殖、凋亡、功能等，阐明敲除β-catenin对成骨系细胞、PTH的促骨质形成功能、骨缺损修复的影响。本课题成果有望为确定促骨质合成的新治疗靶点提供进一步的证据，促进更有效的促骨质合成药物的发现。

Osteoporosis and bone defect is commonly seen in clinic and difficult to treat. A unique strategy is intermittent administration of parathyroid hormone (PTH), which promotes bone formation; thereby increases bone mass and facilitate fracture healing. The underlying mechanisms are yet to be fully elucidated. Many lines of evidence, including ours, have indicated that PTH activates wnt/β-catenin signaling at multiple levels in osteoblastic cells and in mice. Nevertheless, current models have not been able to establish the role of β-catenin in PTH action on bone formation: inactivation of wnt/β-catenin signaling by constitutive disruption of β-catenin in osteoblast progenitors starting in fetal life leads to defective osteoblast differentiation and no bone formation, whereas deletion of β-catenin from differentiated osteoblasts and osteocytes causes increased bone resorption and low bone mass through decreased production of osteoprotegrin (OPG). Since wnt/β-catenin signaling is essential for prenatal bone formation and for normal bone remodeling directed by differentiated osteoblasts/cytes, we propose to determine whether postnatal disruption of β-catenin in early cells of the osteoblastic lineage may affect both bone formation and bone resorption, and further to determine whether PTH increases bone mass partly through activating wnt/β-catenin signaling.