Alpl-ATP轴调控骨髓间充质干细胞外泌体形成及分泌在骨衰老中的作用研究

碱性磷酸酶（Alpl）在牙与骨的发育及矿化中不可或缺，然而其与骨衰老的关系尚不明确。我们首次揭示Alpl通过ATP调控骨髓间充质干细胞（BMMSC）分化，并由此引发由Alpl突变所致低碱性磷酸酶症患者的骨早衰及牙早脱。前期研究中，我们意外观察到Alpl抑制BMMSC外泌体分泌，而在Alpl缺乏BMMSC中减少胞内外ATP浓度后，外泌体分泌均下降。诸多学者及我们前期研究表明，外泌体是BMMSC旁分泌的重要媒介，也是其维持骨稳态的关键。由此，我们推测Alpl-ATP轴可能通过调控BMMSC外泌体影响骨衰老进程。本研究拟以关键ATP为突破口，系统阐明Alpl调控ATP影响BMMSC外泌体形成及分泌并解析其调控机制，最终建立Alpl缺乏小鼠的治疗策略。本项目首次系统阐明Alpl-ATP轴在调控BMMSC分化及旁分泌功能中的“双重”作用，揭示Alpl控制骨衰老进程的机制并为其治疗提供新的靶点和策略。

Alkaline phosphatase (Alpl) gene is necessary for the development of teeth and bone. However, how and where Alpl acts in bone ageing is largely unknown. We firstly unveil that Alpl regulates the lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs), and subsequently affects bone ageing and teeth exfoliation in hypophospatasia (HPP), which is caused by Alpl loss-of-function mutation. Besides, we found that the secretion of exosomes was inversely proportional to the level of Alpl. Furthermore, the decreased secretion of exosomes was observed after inhibiting the concentration of extracellular and intracellular ATP. Researchers and our group previously revealed that exosomes, which are the key mediators of paracrine of BMMSCs, could maintain the bone homeostasis and rescue bone deformities. Therefore, we infer that Alpl-ATP axis could also affect the progress of bone ageing via regulating the formation and secretion of exosomes in BMMSCs. In this study, we systematically investigate the effect of Alpl-ATP axis on the formation and secretion of exosomes and to reveal the mechanism, and finally to establish the treatment strategy of Alpl-knockout mice. This study firstly unveils the dual effect of Alpl-ATP axis in regulating differentiation and paracrine of BMMSCs, and reveals the mechanism of Alpl in controlling bone ageing process and provides a potential therapeutic option for its treatment.