BMP介导的骨免疫调控改善骨质疏松条件下口腔种植体骨结合力的可行性及机制研究

The incidence of osteoporosis in the elderly population will increase more frequently as the trend of population aging. The initial stability of the implant can be affected by osteoporosis with weakened osteointegration capacity. Bone homeostasis in mammals requires continuous remodeling that involved osteoblasts (OB)-related bone formation and osteoclast (OC)-related resorption. Mesenchymal stromal cells (MSC) are increasingly being utilized in clinical trials, largely due to their immunomodulatory and tissue regenerative properties. After injury, MSCs usually react quickly to proliferate, migrate and facilitate the healing process via their immunomodulation effects. Previous studies have indicated that MSCs mediate T cell induction. Therefore osteo-immunomodulation is implicated to play important role during the homeostasis. Although the effect of exogenous MSC-mediated modulation on immunity has been increasingly studied, the mechanism of endogenous MSC mediated immunity in the bone homeostasis remains obscure. Lineage tracing techniques enable the labeling of stem cells in a temporal and tissue-specific fashion, which has resulted in greater emphasis on in vivo identification and study of the interaction between MSCs and immunology. Gli1 is a marker for MSCs in both the incisor and sutures of mice, and Gli1 positive cells under the growth plate is osteogenic progenitors involved in bone formation and fracture healing. Our previous study found that after knocking out Bmpr1αin Gli1 positive cells, mice showed increased bone density and altered immune status. We therefore hypothesized that the expression of Bmpr1a in Gli1 labeled MSCs may affect the immune status of the body and play an important role in bone homeostasis and bone structure. In order to verify this hypothesis, Gli1creERT2;Bmpr1αfl/fl mice will be generated for examination of femoral trabecular structure. The changes of genes, proteins, cellular level related of femoral osteogenesis, osteoclastogenesis and immunology will be studied both in mutant and control mice. Then in vivo and in vitro methods will be used to explore the innermost mechanism of Bmpr1α-mediated immune regulation. Finally mouse model with osteoporosis will be used to verify whether Bmpr1α blocking improves osteointegration of implant. This study will help elucidate the role of endogenous MSCs mediated immune function via Bmpr1α expression, which in turn affects bone homeostasis. Our study could provide novel ideas and solutions for oral implant problems in elder population with osteoporosis.

随人口老龄化进程加快，骨质疏松在老年患者种植牙应用时的危害愈加明显。骨质疏松可影响种植体初期稳定性，并减弱骨结合能力。研究证实间充质干细胞可以介导骨免疫活动，进而改善骨质疏松。内源性间充质干细胞也可调节免疫功能，其应用可避免外源性干细胞输注的风险。申请人前期研究发现Gli1阳性骨祖细胞敲除Bmpr1α后，出现小鼠股骨和免疫状态改变。我们因此提出假设：Bmpr1α参与了Gli1阳性骨间质祖细胞介导的免疫调节，进而影响骨稳态和骨质结构。为验证此假说，拟首先检测Gli1细胞敲除Bmpr1α后股骨结构及相关（成骨/破骨/免疫）指标变化；采用多种试验手段，探索Bmpr1α介导的免疫调控机制；最后利用骨质疏松小鼠股骨种植体模型验证Bmpr1α的阻断能否改善种植体骨结合能力。本研究利于阐明内源性骨间质祖细胞对免疫功能的调控能力，探索可能的调控机制，为临床治疗骨质疏松带来的口腔种植难题提供新思路和新方法。

骨质疏松是困扰当前老龄化社会的难题之一，尤其是一些骨质疏松患者种植体初期稳定性差困扰着口腔医师的治疗策略。既往临床资料提示一些自身免疫状态受损的患者骨折愈合能力差，但具体原因仍不是很清楚。我本课题利用转基因小鼠动物模型和细胞实验，验证了 Bmpr1α敲除后可显著增加骨骨密度，同时体内成骨相关基因水平增强，破骨活动减弱；同时利用细胞生物学和分子生物学技术研究，阐明了 Bmpr1α通过影响Tgf-β1表达水平调控 Th/Treg 细胞分化进而影响骨骼结构的机制；利用动物模型证实鼠源性 Bmpr1α蛋白中和抗体可提高股骨骨小梁密度，增强种植体结合能力。本研究为深入理解内源性骨间质祖细胞调控免疫功能进而改善骨质疏松，以及在此基础上揭示的调控骨质结构方法具有重要的意义与价值，可为改善骨质疏松患者口腔种植体骨结合提供治疗新思路。

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