巨核细胞来源的TGF-β1调控LepR+SSCs中PTP1B水平对放射性骨质疏松的影响作用与机制研究

随着核技术的广泛应用，放射损伤也越发常见。放射性骨损伤后成骨障碍，导致骨质疏松甚至骨折。LepR+骨骼干细胞（SSCs）是成年后骨祖细胞的主要来源，在骨损伤时被激活，但激活机制不清。我们前期发现LepR+SSCs在辐照后成骨减弱，蛋白酪氨酸磷酸酶1B（PTP1B）水平上调。PTP1B能抑制LepR下游JAK2/STAT3信号通路，影响干细胞分化。我们前期证实巨核细胞（MKs）通过分泌TGF-β1能促进辐照损伤后骨生成；还发现MKs敲除小鼠骨生成减弱，且其LepR+SSCs中PTP1B水平明显高于对照。因此，推测巨核细胞来源的TGF-β1调控LepR+SSCs中PTP1B水平影响放射性骨质疏松。拟结合功能获得与缺失等体内外研究，探索TGF-β1调控PTP1B水平而激活LepR+SSCs的机制。本研究对阐明MKs调控放射性骨损伤的作用具有重要意义，提供了从造血系统治疗骨质疏松的新视角。

With the wide application of nuclear technology, radiative damage is becoming more and more common. Osteogenesis disorder after radiative bone injury leads to osteoporosis and even fracture. LepR+ skeletal stem cells (SSCs) are the main source of adult osteoprogenitor cells, which are activated during bone injury. However, it is unclear by which mechanism the SSCs are activated. We previously found that the osteogenesis of LepR+SSCs was weakened and the protein tyrosine phosphatase 1B (PTP1B) level was up-regulated after irradiation. PTP1B could inhibit the JAK2/STAT3 signaling pathway downstream of LepR and affect the differentiation of stem cells. We previously confirmed that megakaryocytes (MKs) could promote bone formation after radiative injury by secreting TGF-β1. Moreover, we found the bone formation of the mice which megakaryocytes were knockout was decreased, and the level of PTP1B in LepR+ SSCs was significantly higher than that of control mice. Therefore, it is speculated that TGF-β1 derived from megakaryocytes regulates the level of PTP1B in LepR+SSCs and affects radiation-induced osteoporosis. In combination with in vitro and in vivo experiments on functional gain and loss, we intended to explore the mechanism by which TGF-β1 regulates the level of PTP1B and activates LepR+ SSCs. This study is of great significance to elucidate the role of MKs in regulating radiative bone injury, and provides a new perspective for the treatment of osteoporosis from the hematopoietic system.