IGSF10调控骨质疏松骨缺损修复的作用及机制研究

Bone defects in craniofacial bone remain a severe clinical challenge, especially for osteoporosis patients like postmenopausal women. There is an acute need for new bone regeneration factors, given adverse effects associated with existing biologics..IGSF10 was first discovered as a highly differentially expressed gene in rat cranial osteoblasts after mechanical loading and it showed apparent expression in fracture callus. Its expression significantly increased in animal models such as estrogen injection and ovariectomized rats. IGSF10 mutation can cause delayed puberty development by affecting the migration of hormone-related neurons. Our previous findings also represented an original demonstration of IGSF10’s robust osteogenesis capacity, similar to that of BMP2, but the mechanism is different. Bioinformatics and lots of RNAseq data suggested it’s relevant to ossification and cell differentiation. And we also found that IGSF10 expression decreased significantly in OIM-treated bone marrow stem cells which harvested from osteoporotic model. These results together suggested that IGSF10 may act as a new osteogenic factor in osteoporosis or play an important role in the regulation of bone defect repair in osteoporosis..In this study, we will conduct an in-depth study on the role of IGSF10 in the regulation of osteoporotic bone marrow stem cells during bone regeneration and the underlying molecular mechanism, analysis gene expression data of normal and osteoporosis bone marrow stem cells before and after IGSF10 treatment, explore the putative osteogenesis roles of IGSF10 by calvarial bone defect in osteoporotic rat models. .This study will help further understand the significance of IGSF10 in bone regeneration, and is expected to provide new ideas for bone regeneration of primary osteoporosis, and lay foundation for the repair of bone defects of osteoporosis in advanced mammals and further clinical applications.

骨质疏松对雌激素水平下降的绝经后妇女影响巨大，其骨缺损的修复极具挑战。寻找新型促骨质疏松骨生长的生物活性蛋白尤为重要。IGSF10是在骨重建活跃区域显著表达的基因；其突变可影响激素释放神经元迁移导致青春期发育延迟。我们发现IGSF10能促进干细胞成骨分化，效果与BMP2类似但机制不同；IGSF10在雌激素注射和卵巢摘除等动物模型中表达明显提高，在成骨诱导后的骨质疏松骨髓细胞中显著降低。以上提示IGSF10可能对骨质疏松骨缺损修复有十分重要的作用，本研究将分析比较IGSF10处理前后正常和骨质疏松骨髓干细胞的基因表达变化，系统评估IGSF10调控骨质疏松骨髓干细胞成骨分化的作用及相关分子机制，并评价对骨质疏松大鼠的骨缺损修复效果。将有助于我们进一步理解IGSF10在骨再生中的意义，有望为原发性骨质疏松骨再生提供新的思路，并为高级哺乳大动物的骨质疏松骨缺损的修复乃至进一步的临床应用打下基础。

因创伤、肿瘤、感染、炎症等造成的颌面骨组织缺损在临床上十分常见，不同程度地影响了患者的容貌、咀嚼、吞咽、语音等功能，对患者的生活和工作带来极大不便。.尤其对原发性骨质疏松（Osteoporosis, OP）症病人来说，其所具有的高发病率，死亡率和伤残率，给人类健康带来极大危害，尤其是绝经后的女性。同时因其骨量低，骨组织微结构破坏显著的特点，导致骨缺损修复难度大、修复效果十分不理想。另一方面，目前可用于骨缺损修复的商品化生物材料修复效果有限，临床实际操作中常需与生长因子配伍使用。现有的商品化生长因子仍存在一些缺点和不足，使得寻找新的促进骨质疏松骨生长的生物活性蛋白已成为研究者们越来越感兴趣的领域。.IGSF10(Immunoglobulin Superfamily Member 10)是在机械力刺激后的鼠原代颅骨细胞中发现的与骨代谢有关的高表达差异基因。骨折模型原位杂交结果显示IGSF10在骨重建活跃区域显著表达，相关生物学分析也提示其与骨矿化相关。IGSF10在雌激素注射和卵巢摘除等动物模型中表达明显提高，但在单侧坐骨神经切除模型中表达降低。IGSF10突变导致促性腺激素释放激素(GnRH)神经元迁移异常，导致青春期延迟，揭示了性腺功能减退及其相关疾病之间的共同病理生理机制。转基因斑马鱼Tg(gnrh3:EGFP)Igsf10敲低导致GnRH3神经元迁移受阻和神经突延伸失败，提示IGSF10可能在调控原发性骨质疏松骨缺损修复中有十分重要的作用。.因此，本项目评估IGSF10调控骨质疏松骨髓干细胞对骨质疏松骨缺损修复的作用，分析IGSF10处理后正常和骨质疏松骨髓干细胞的基因表达变化，在此基础上进一步对IGSF10调控骨质疏松骨髓干细胞的分子机制展开深入研究、并评价其在体内修复骨质疏松骨缺损的效果。发现IGSF10在成骨诱导液环境下有显著促进干细胞成骨分化的能力，相比正常骨髓干细胞，IGSF10骨质疏松大鼠骨髓干细胞中的表达也显著降低，可促进细胞的迁移和铺展，与BMP2具有协同成骨向分化作用。可调节干扰素γ通路，并具有正向调节STAT和JNK途径作用，为探索IGSF10作为新型生物活性蛋白在原发性骨质疏松骨再生提供新的思路。