Volume 6 Issue 1, Jan 2021:
Article
Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice
Xuekun Fu,Bo Zhou
ORCID: orcid.org/0000-0003-4213-726X,Qinnan Yan,Chu Tao,Lei Qin,Xiaohao Wu,Sixiong Lin
ORCID: orcid.org/0000-0001-7155-5044,Sheng Chen,Yumei Lai,Xuenong Zou,Zengwu Shao,Meiqing Wang,Di Chen,Wenfei Jin
ORCID: orcid.org/0000-0002-0028-3739,Youqiang Song,Huiling Cao,Ge Zhang &…Guozhi Xiao
ORCID: orcid.org/0000-0002-4269-2450
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.
