Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice
Related Experiment Video
Updated: Nov 24, 2025
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Xuekun Fu1,2, Bo Zhou3,4, Qinnan Yan1
1School 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.
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.
Insights
Kindlin-2 is essential for parathyroid hormone receptor 1 (PTH1R) signaling in bone cells. Its absence impairs bone formation and reduces bone mass, highlighting its role in skeletal homeostasis.
Area of Science:
- Bone Biology
- Cell Signaling
- Endocrinology
Background:
- The type 1 parathyroid hormone receptor (PTH1R) is crucial for skeletal development and homeostasis in vertebrates.
- The precise regulatory mechanisms of PTH1R signaling remain incompletely understood.
Purpose of the Study:
- To investigate the role of Kindlin-2 in osteoblastic cells and its contribution to PTH1R-mediated bone regulation.
- To elucidate the molecular mechanisms by which Kindlin-2 modulates PTH1R signaling and bone homeostasis.
Main Methods:
- Utilized Kindlin-2 deletion in osteoblastic cells (10-kb Dmp1-Cre mice) to assess effects on bone parameters.
- Employed single-cell profiling to analyze bone marrow cell populations.
- Investigated gene interactions through haploinsufficiency studies.
- Performed molecular analyses including cAMP production and CREB phosphorylation assays.
- Examined the impact of estrogen deficiency (ovariectomy) on Kindlin-2 expression and PTH response.
Main Results:
- Kindlin-2 deletion in osteoblastic cells significantly reduced PTH-stimulated bone volume and density by impairing osteoblast and osteoclast formation.
- Loss of Kindlin-2 altered bone marrow cell composition, increasing osteoblast proportion but decreasing mature osteoblasts on bone surfaces.
- Haploinsufficiency of Kindlin-2 and Pth1r genes synergistically decreased bone mass, indicating they function in the same pathway.
- Kindlin-2 interacts with PTH1R and is required for PTH-induced cAMP production and CREB phosphorylation.
- PTH positively regulates Kindlin-2 expression, forming a feedback loop.
- Estrogen deficiency reduced Kindlin-2 expression, and Kindlin-2 loss abolished PTH's anabolic effect in ovariectomized mice.
Conclusions:
- Kindlin-2 is an intrinsic component of the PTH1R signaling pathway in osteoblastic cells.
- Kindlin-2 plays a critical role in regulating bone mass accrual and maintaining skeletal homeostasis.
- Kindlin-2's function is crucial for the anabolic effects of PTH, particularly under conditions of estrogen deficiency.
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