Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice.
Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice.
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Kindlin-2 通过调节小鼠 PTH1R 调节骨骼稳态
DOI：
10.1038/s41392-020-00328-y
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发表时间：
2020-12-26
影响因子：
39.3
通讯作者：
Xiao G
中科院分区：
文献类型：
--
作者：
Fu X;Zhou B;Yan Q;Tao C;Qin L;Wu X;Lin S;Chen S;Lai Y;Zou X;Shao Z;Wang M;Chen D;Jin W;Song Y;Cao H;Zhang G;Xiao G
在脊椎动物中，1型甲状旁腺激素受体（PTH1R）是骨骼发育和体内平衡的关键调节器；然而，它是如何调制的还不完全清楚。在这里，我们报告使用小鼠10- kbdmp1 - cre1删除成骨细胞中的Kindlin-2，通过损害小鼠成骨中的成骨细胞和破骨细胞的形成，在很大程度上中和了pth刺激的骨体积百分比和骨矿物质密度的间歇性增加。单细胞分析显示，kindin -2缺失会增加非造血骨髓细胞中成骨细胞的比例，但不会增加间充质干细胞、软骨细胞和成纤维细胞的比例，并伴随骨表面成骨细胞的消耗，尤其是那些受甲状旁腺激素刺激的成骨细胞。此外，kindlin -2和pth1基因的单倍不足，而不是任何一个基因的单倍不足，在小鼠中显著降低了pth刺激的基础骨量，并在更大程度上降低了pth刺激的骨量，支持了这两个因素在同一遗传途径中起作用的观点。机制上，Kindlin-2通过aa 474-475和Gsα与PTH1R的c端胞质结构域相互作用。在培养的成骨细胞和骨中，Kindlin-2缺失抑制PTH诱导cAMP产生和CREB磷酸化。有趣的是，PTH促进Kindlin-2在体内和体外的表达，从而形成一个正反馈调节回路。最后，卵巢切除引起的雌激素缺乏显著降低了嵌入骨基质的骨细胞中Kindlin-2蛋白的表达，Kindlin-2的缺失基本上消除了去卵巢小鼠骨中PTH合成代谢活性。因此，我们证明了kindin -2作为成骨细胞中PTH1R信号通路的内在组成部分，调节骨量的积累和体内平衡。
In vertebrates, the type 1 parathyroid hormone receptor (PTH1R) is a critical regulator of skeletal development and homeostasis; however, how it is modulated is incompletely understood. Here we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kbDmp1-Crelargely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult bone. Single-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts, but not mesenchymal stem cells, chondrocytes and fibroblasts, in non-hematopoietic bone marrow cells, with concomitant depletion of osteoblasts on the bone surfaces, especially those stimulated by PTH. Furthermore, haploinsufficiency ofKindlin-2andPth1rgenes, but not that of either gene, in mice significantly decreases basal and, to a larger extent, PTH-stimulated bone mass, supporting the notion that both factors function in the same genetic pathway. Mechanistically, Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα. Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in bone. Interestingly, PTH promotes Kindlin-2 expression in vitro and in vivo, thus creating a positive feedback regulatory loop. Finally, estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized mice. Thus, we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis.
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