Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice

Wang, Yishu1,2,3; Yan, Qinnan2,3; Zhao, Yiran2,3; Liu, Xin2,3; Lin, Simin2,3; Zhang, Peijun2,3; Ma, Liting2,3; Lai, Yumei4; Bai, Xiaochun5; Liu, Chuanju6,7; Wu, Chuanyue8; Feng, Jian Q.9; Chen, Di4; Cao, Huiling2,3; Xiao, Guozhi2,3,4

2019-11-14

10.1172/jci.insight.131692

JCI Insight   影响因子和分区

2324-7703

2379-3708

Mammalian focal adhesion proteins Pinch1 and Pinch2 regulate integrin activation and cell-extracellular matrix adhesion and migration. Here, we show that deleting Pinch1 in osteocytes and mature osteoblasts using the 10-kb mouse Omp1-Cre and Pinch2 globally (double KO; dKO) results in severe osteopenia throughout life, while ablating either gene does not cause bone loss, suggesting a functional redundancy of both factors in bone. Pinch deletion in osteocytes and mature osteoblasts generates signals that inhibit osteoblast and bone formation. Pinch-deficient osteocytes and conditioned media from dKO bone slice cultures contain abundant sclerostin protein and potently suppress osteoblast differentiation in primary BM stromal cells (BMSC) and calvarial cultures. Pinch deletion increases adiposity in the BM cavity. Primary dKO BMSC cultures display decreased osteoblastic but enhanced adipogenic, differentiation capacity. Pinch loss decreases expression of integrin beta 3, integrin-linked kinase (ILK), and alpha-parvin and increases that of active caspase-3 and -8 in osteocytes. Pinch loss increases osteocyte apoptosis in vitro and in bone. Pinch loss upregulates expression of both Ranki and Opg in the cortical bone and does not increase osteoclast formation and bone resorption. Finally, Pinch ablation exacerbates hindlimb unloading-induced bone loss and impairs active ulna loading-stimulated bone formation. Thus, we establish a critical role of Pinch in control of bone homeostasis.

SCI

英语

通讯

Science and Technology Innovation Commission of Shenzhen Municipal Government[JCYJ20180302174117738]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:000496959200021

AMER SOC CLINICAL INVESTIGATION INC

Web of Science

1.Harbin Inst Technol, Sch Life Sci & Technol, Harbin, Heilongjiang, Peoples R China
2.Southern Univ Sci & Technol SUSTech, Guangdong Prov Key Lab Cell Microenvironm & Dis R, Shenzhen Key Lab Cell Microenvironm, Shenzhen, Guangdong, Peoples R China
3.Southern Univ Sci & Technol SUSTech, Dept Biol, Shenzhen, Guangdong, Peoples R China
4.Rush Univ, Med Ctr, Dept Orthoped Surg, Chicago, IL 60612 USA
5.Southern Med Univ, Sch Basic Med Sci, Dept Cell Biol, Guangzhou, Guangdong, Peoples R China
6.NYU, Sch Med, Dept Orthoped Surg, New York, NY USA
7.NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA
8.Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA
9.Texas A&M Univ, Coll Dent, Dept Biomed Sci, Dallas, TX USA

Wang, Yishu,Yan, Qinnan,Zhao, Yiran,et al. Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice[J]. JCI Insight,2019,4(22).

Wang, Yishu.,Yan, Qinnan.,Zhao, Yiran.,Liu, Xin.,Lin, Simin.,...&Xiao, Guozhi.(2019).Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice.JCI Insight,4(22).

Wang, Yishu,et al."Focal adhesion proteins Pinch1 and Pinch2 regulate bone homeostasis in mice".JCI Insight 4.22(2019).