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Osteocyte Egln1/Phd2 links oxygen sensing and biomineralization via FGF23

Bone Research 2023年第1期11卷 178-192页

作者： Megan L.Noonan Pu Ni Emmanuel Solis Yamil G.Marambio Rafiou Agoro Xiaona Chu Yue Wang Hongyu Gao xiaoling xuei Erica L.Clinkenbeard Guanglong Jiang Sheng Liu Steve Stegen Geert Carmeliet William R.Thompson Yunlong Liu Jun Wan Kenneth E.White Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN46202USA Laboratory of Clinical and Experimental Endocrinology Department of Chronic Diseases and MetabolismKU Leuven3000LeuvenBelgium Department of Physical Therapy Indiana University School of MedicineIndianapolisIN46202USA Department of Anatomy Cell Biologyand PhysiologyIndiana University School of MedicineIndianapolisIN46202USA Center for Computational Biology and Bioinformatics Indiana University School of MedicineIndianapolisIN46202USA Departments of Medicine/Division of Nephrology Indiana University School of MedicineIndianapolisIN46202USA

Osteocytes act within a hypoxic environment to control key steps in bone ***23,a critical phosphate-regulating hormone,is stimulated by low oxygen/iron in acute and chronic diseases,however the molecular mechanisms directing this process remain *** goal was to identify the osteocyte factors responsible for FGF23 production driven by changes in oxygen/iron ***-inducible factor-prolyl hydroxylase inhibitors(HIF-PHI)which stabilize HIF transcription factors,increased Fgf23 in normal mice,as well as in osteocyte-like cells;in mice with conditional osteocyte Fgf23 deletion,circulating i FGF23 was *** inducible MSC cell line(‘MPC2’)underwent FG-4592 treatment and ATACseq/RNAseq,and demonstrated that differentiated osteocytes significantly increased HIF genomic accessibility versus progenitor *** genomics also revealed increased prolyl hydroxylase Egln1(Phd2)chromatin accessibility and expression,which was positively associated with osteocyte *** mice with chronic kidney disease(CKD),Phd1-3 enzymes were suppressed,consistent with FGF23 upregulation in this *** loss of Phd2 from osteocytes in vivo resulted in upregulated Fgf23,in line with our findings that the MPC2 cell line lacking Phd2(CRISPR Phd2-KO cells)constitutively activated Fgf23 that was abolished by HIF1α*** vitro,Phd2-KO cells lost iron-mediated suppression of Fgf23 and this activity was not compensated for by Phd1 *** sum,osteocytes become adapted to oxygen/iron sensing during differentiation and are directly sensitive to bioavailable ***,Phd2 is a critical mediator of osteocyte FGF23 production,thus our collective studies may provide new therapeutic targets for skeletal diseases involving disturbed oxygen/iron sensing.

关键词： FGF23 collective adapted

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