Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling

Yan，Qinnan1; Gao，Huanqing1; Yao，Qing1; Ling，Kun2; Xiao，Guozhi1

2022-03-01

10.1016/j.jbc.2022.101639

JOURNAL OF BIOLOGICAL CHEMISTRY   影响因子和分区

0021-9258

1083-351X

Phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) is a lipid kinase that plays a pivotal role in the regulation of receptor-mediated calcium signaling in multiple tissues; however, its role in the skeleton is not clear. Here, we show that while deleting Pip5k1c expression in the mesenchymal stem cells using Prx1-Cre transgenic mice does not impair the intramembranous and endochondral ossification during skeletal development, it does cause osteopenia in adult mice, but not rapidly growing young mice. We found Pip5k1c loss dramatically decreases osteoblast formation and osteoid and mineral deposition, leading to reduced bone formation. Furthermore, Pip5k1c loss inhibits osteoblastic, but promotes adipogenic, differentiation of bone marrow stromal cells. Pip5k1c deficiency also impairs cytoplasmic calcium influx and inactivates the calcium/calmodulin-dependent protein kinase, which regulates levels of transcription factor Runx2 by modulating its stability and subsequent osteoblast and bone formation. In addition, Pip5k1c loss reduces levels of the receptor activator of nuclear factor-κB ligand, but not that of osteoprotegerin, its decoy receptor, in osteoblasts in bone and in sera. Finally, we found Pip5k1c loss impairs the ability of bone marrow stromal cells to support osteoclast formation of bone marrow monocytes and reduces the osteoclast precursor population in bone marrow, resulting in reduced osteoclast formation and bone resorption. We conclude Pip5k1c deficiency causes a low-turnover osteopenia in mice, with impairment of bone formation being greater than that of bone resorption. Collectively, we uncover a novel function and mechanism of Pip5k1c in the control of bone mass and identify a potential therapeutic target for osteoporosis.

EI ; SCI

英语

NI论文

第一 ; 通讯

National Key Research and Development Program of China[2019YFA0906004] ; National Natural Science Foundation of China["81991513","81870532","81630066"] ; Guangdong Provincial Science and Technology Innovation Council["2017B030301018","20180302174246105"] ; Shenzhen Municipal Science and Technology Innovation Council[20200925150409001]

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

WOS:000789261900006

ELSEVIER

20221011753361

Bone ; Calcium ; Cell proliferation ; Enzymes ; Mammals ; Plants (botany) ; Stem cells

Biological Materials and Tissue Engineering:461.2 ; Biology:461.9 ; Alkaline Earth Metals:549.2

BIOLOGY & BIOCHEMISTRY

2-s2.0-85125718158

Scopus

1.Department of Biochemistry,School of Medicine,Southern University of Science and Technology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Shenzhen,China
2.Department of Biochemistry and Molecular Biology,Mayo Clinic,Rochester,United States

Yan，Qinnan,Gao，Huanqing,Yao，Qing,et al. Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2022,298(3).

Yan，Qinnan,Gao，Huanqing,Yao，Qing,Ling，Kun,&Xiao，Guozhi.(2022).Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling.JOURNAL OF BIOLOGICAL CHEMISTRY,298(3).

Yan，Qinnan,et al."Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling".JOURNAL OF BIOLOGICAL CHEMISTRY 298.3(2022).