TY - JOUR
T1 - Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice
AU - Fu, Xuekun
AU - Zhou, Bo
AU - Yan, Qinnan
AU - Tao, Chu
AU - Qin, Lei
AU - Wu, Xiaohao
AU - Lin, Sixiong
AU - Chen, Sheng
AU - Lai, Yumei
AU - Zou, Xuenong
AU - Shao, Zengwu
AU - Wang, Meiqing
AU - Chen, Di
AU - Jin, Wenfei
AU - Song, Youqiang
AU - Cao, Huiling
AU - Zhang, Ge
AU - Xiao, Guozhi
N1 - Funding Information:
We acknowledge the assistance of Core Research Facilities of Southern University of Science and Technology (SUSTech). This work was supported, in part, by the National Natural Science Foundation of China Grants (81991513, 82022047, 8163066, 81870532, and 81972100), the National Key Research and Development Program of China Grants (2019YFA0906004 and 2019YFA0906001), the Guangdong Provincial Science and Technology Innovation Council Grant (2017B030301018), and Science and Technology Innovation Commission of Shenzhen Municipal Government Grants (JCYJ20180302174117738, JCYJ20180302174246105, KQJSCX20180319114434843, and JSGG20180503182321166).
Publisher copyright:
© The Author(s) 2020
PY - 2020/12
Y1 - 2020/12
N2 - 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-kb Dmp1-Cre largely 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 of Kindlin-2 and Pth1r genes, 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.
AB - 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-kb Dmp1-Cre largely 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 of Kindlin-2 and Pth1r genes, 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.
UR - http://www.scopus.com/inward/record.url?scp=85098069429&partnerID=8YFLogxK
U2 - 10.1038/s41392-020-00328-y
DO - 10.1038/s41392-020-00328-y
M3 - Journal article
C2 - 33361757
AN - SCOPUS:85098069429
SN - 2095-9907
VL - 5
JO - Signal Transduction and Targeted Therapy
JF - Signal Transduction and Targeted Therapy
M1 - 297
ER -