2. Academic Validation
  3. Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

  • Signal Transduct Target Ther. 2020 Dec 26;5(1):297. doi: 10.1038/s41392-020-00328-y.
Xuekun Fu 1 2,  Bo Zhou 3 4,  Qinnan Yan 1,  Chu Tao 1,  Lei Qin 1,  Xiaohao Wu 1,  Sixiong Lin 1 5,  Sheng Chen 1 6,  Yumei Lai 7,  Xuenong Zou 5,  Zengwu Shao 6,  Meiqing Wang 8,  Di Chen 9,  Wenfei Jin 3,  Youqiang Song 4,  Huiling Cao 10,  Ge Zhang 11,  Guozhi Xiao 12
Affiliations

Affiliations

  • 1 School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, 1088 Xue Yuan Road, 518055, Shenzhen, Guangdong, China.
  • 2 Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.
  • 3 Department of Biology, Southern University of Science and Technology, 518055, Shenzhen, China.
  • 4 School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
  • 5 Department of Spine Surgery, Orthopedic Research Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, 510080, Guangzhou, China.
  • 6 Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
  • 7 Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA.
  • 8 State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology and TMD, School of Stomatology, the Fourth Military Medical University, 145 Changle West Road, Xi'an, China.
  • 9 Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 518055, Shenzhen, China.
  • 10 School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, 1088 Xue Yuan Road, 518055, Shenzhen, Guangdong, China. [email protected].
  • 11 Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China. [email protected].
  • 12 School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, 1088 Xue Yuan Road, 518055, Shenzhen, Guangdong, China. [email protected].
PMID: 33361757 DOI: 10.1038/s41392-020-00328-y
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.

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