Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

Xuekun Fu, Bo Zhou, Qinnan Yan, Chu Tao, Lei Qin, Xiaohao Wu, Sixiong Lin, Sheng Chen, Yumei Lai, Xuenong Zou, Zengwu Shao, Meiqing Wang, Di Chen, Wenfei Jin, Youqiang Song, Huiling Cao*, Ge ZHANG, Guozhi Xiao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number297
JournalSignal Transduction and Targeted Therapy
Volume5
Issue number1
DOIs
Publication statusPublished - Dec 2020

Scopus Subject Areas

  • Genetics
  • Cancer Research

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