Ionomycin ameliorates hypophosphatasia via rescuing alkaline phosphatase deficiency-mediated L-type Ca^(2+) channel internalization in mesenchymal stem cells  

作　　者：Bei Li Xiaoning He Zhiwei Dong Kun Xuan Wei Sun Li Gao Shiyu Liu Wenjia Liu Chenghu Hu Yimin Zhao Songtao Shi Yan Jin 

机构地区：[1]State Key Laboratory of Military Stomatology&National Clinical Research Center for Oral Diseases&Shaanxi International Joint Research Center for Oral Diseases,Center for Tissue Engineering,School of Stomatology,The Fourth Military Medical University,Xi’an 710032 Shaanxi,China [2]Xi’an Institute of Tissue Engineering and Regenerative Medicine,Xi’an,China [3]Department of Pediatric Dentistry,School of Stomatology,Fourth Military Medical University,Xi’an,China [4]Institute forBiomedical Sciences of Pain,Tangdu Hospital,Fourth Military Medical University,Xi’an,China [5]Department of Anatomy and Cell Biology,University of Pennsylvania School of Dental Medicine,Philadelphia,PA,USA [6]South China Center of Craniofacial Stem Cell Research,Guanghua School of Stomatology,Sun Yat-sen University,74 Zhongshan 2Rd,Guangzhou,Guangdong,China

出　　处：《Bone Research》2020年第2期182-196,共15页骨研究（英文版）

基　　金：funded by grants from the National Natural Science Foundation of China (Nos. 81620108007 and 81870768);the National Key Research and Development Program of China (Nos. 2016YFC1101400 and 2017YFA0104800);the Scientific Young Alma of Shaanxi province (2018KJXX-015)。

摘　　要：The loss-of-function mutations in the ALPL result in hypophosphatasia(HPP), an inborn metabolic disorder that causes skeletal mineralization defects. In adults, the main clinical features are early loss of primary or secondary teeth, osteoporosis, bone pain,chondrocalcinosis, and fractures. However, guidelines for the treatment of adults with HPP are not available. Here, we show that ALPL deficiency caused a reduction in intracellular Ca2+ influx, resulting in an osteoporotic phenotype due to downregulated osteogenic differentiation and upregulated adipogenic differentiation in both human and mouse bone marrow mesenchymal stem cells(BMSCs). Increasing the intracellular level of calcium in BMSCs by ionomycin treatment rescued the osteoporotic phenotype in alpl+/- mice and BMSC-specific(Prrx1-alpl-/-) conditional alpl knockout mice. Mechanistically, ALPL was found to be required for the maintenance of intracellular Ca2+ influx, which it achieves by regulating L-type Ca2+ channel trafficking via binding to the α2δsubunits to regulate the internalization of the L-type Ca2+ channel. Decreased Ca2+ flux inactivates the Akt/GSK3β/β-catenin signaling pathway, which regulates lineage differentiation of BMSCs. This study identifies a previously unknown role of the ectoenzyme ALPL in the maintenance of calcium channel trafficking to regulate stem cell lineage differentiation and bone homeostasis. Accelerating Ca2+ flux through L-type Ca2+ channels by ionomycin treatment may be a promising therapeutic approach for adult patients with HPP.

关 键 词：GSK3Β INTERNALIZATION HOMEOSTASIS 

分 类 号：R589[医药卫生—内分泌] R580[医药卫生—内科学]