The Role of Osteocyte Kindlin-2 in the Anabolic Actions of PTH in Bone

伏学坤

11752008

博士

中医药

肖国芝/张戈

2020-03-05

2020-05-26

香港浸会大学

香港

In vertebrates, PTH receptor 1 (PTH1R) plays a pivotal role in control of bone development and homeostasis; however, how it is regulated is poorly defined. Here we report that Kindlin-2 binds to and modulates PTH1R to regulate bone mass and PTH actions. Deleting Kindlin-2 expression using the 10-kb mouse Dmp1-Cre severely impairs the anabolic effects of intermittent PTH on bone in adult mice with or without ovariectomy. Of particular interest, Kindlin-2 and Pth1r double heterozygous mice (Dmp1-Cre; Kindlin-2 f/+ ; Pth1r f/+ ), but not either singly heterozygous mice (Dmp1-Cre; Kindlin-2 f/+ or Dmp1-Cre; Pth1r f/+ ), display severe osteopenia and fail to increase bone mass in response to administration of intermittent PTH. Mechanistically, Kindlin-2 interacts with the C-terminal cytoplasmic region of PTH1R. When overexpressed, this region efficiently inhibits the endogenous PTH/PTH1R signaling in osteoblasts, which is reversed by introduction of a point mutation thatabolishes the Kindlin-2 interaction. Furthermore, Kindlin-2 loss inhibits PTH-induced CREB phosphorylation and cAMP production in vitro and in bone. PTH upregulates, while estrogen deficiency downregulates, expression of Kindlin-2 in vitro and in bone. Collectively, we demonstrate that interplay between Kindlin-2 and PTH1R regulates bone mass by modulating PTH1R and provide a potential therapeutic target formetabolic bone diseases.

Kindlin-2 Bone Osteocyte PTH PTH1R G protein

英语

联合培养

南方科技大学/香港浸会大学

Fu XK. The Role of Osteocyte Kindlin-2 in the Anabolic Actions of PTH in Bone[D]. 香港. 香港浸会大学,2020.