PGRN促进炎性环境下牙周膜干细胞成骨分化和牙周再生的研究

Periodontal ligament stem cells (PDLSCs) is the most important functional cell of periodontal regeneration. Using bioactive factors to induce the proliferation and osteogenic differentiation of PDLSCs is an important direction for periodontal regeneration research. However, osteogenic differentiation of PDLSCs and periodontal regeneration effect of bioactive factors is under the influence of inflammatory factors such as TNF-α. Exploring factors with ability to enhance osteogenic differentiation of PDLSCs and block inflammatory factors has important theoretical significance and clinical application values. It has been found that Progranulin(PGRN) can antagonize the inhibitory effect of TNF-α on osteoblast differentiation, and also induce bone regeneration directly. Our preliminary study showed that PGRN plays a role in protection of chronic periodontitis; Local injections of PGRN on rats with experimental periodontitis inhibit the inflammatory cells infiltration, expression of TNF-α and IL-1β and alveolar bone resorption; in vitro studies, PGRN can directly induce osteogenic differentiation of PDLSCs and antagonize the inhibitory effect of TNF-α on osteogenic differentiation. Thus , PGRN may play an important role in the control of periodontitis and periodontal regeneration under inflammatory condition. We propose to investigate the following functions of PGRN and their mechanisms in directly inducing the osteogenic differentiation/ cementoblast differentiation of PDLSCs, antagonizing the inhibition of osteogenic differentiation/ cementoblast differentiation of PDLSCs mediated by TNF-α and promoting periodontal regeneration under the inflammatory conditions. This project can provide new ideas for periodontal regeneration under the inflammatory conditions.

牙周膜干细胞（PDLSCs）是牙周再生最主要的细胞，采用生物因子诱导PDLSCs成骨分化是牙周再生研究的重要方向。然而，PDLSCs的成骨分化和生物因子促牙周再生效果受TNF-α等炎性因子影响。寻找既能促进PDLSCs成骨分化，又能抗炎的因子具有重要意义。颗粒蛋白前体（PGRN）能拮抗TNF-α对成骨分化的抑制作用，亦能直接诱导骨再生。项目组的临床研究显示PGRN在慢性牙周炎中起保护作用；体内局部注射PGRN可抑制TNF-α及IL-1β表达和骨吸收;体外PGRN可直接刺激PDLSCs成骨分化，且可拮抗TNF-α介导的对成骨分化的抑制。提示，PGRN在牙周炎的控制和炎性环境下的牙周再生中有重要作用。本研究拟进一步观察PGRN对PDLSCs成骨分化的直接诱导作用、对TNF-α介导的成骨分化抑制的拮抗作用和炎性环境下牙周再生的促进作用，并探讨相关作用机制，为炎性环境下牙周再生治疗提供新的思路。

牙周炎是口腔中以菌斑生物膜为始动因素的慢性感染性炎症性疾病，会造成牙周软硬支持组织的破坏。因此，恢复或部分恢复牙周软硬组织是牙周组织工程的重要目标。牙周膜干细胞（PDLSCs）是牙周再生最主要的细胞，采用生物因子诱导PDLSCs成骨分化是牙周再生研究的重要方向。然而，PDLSCs的成骨分化和生物因子促牙周再生效果受TNF-α等炎性因子影响。寻找既能促进PDLSCs成骨分化，又能抗炎的因子具有重要意义。颗粒蛋白前体（PGRN）是一种自分泌多效生长因子，研究表明PGRN与肿瘤坏死因子受体（TNFR）的亲和力高于TNF-α。还有研究表明，PGRN可以逆转TNF-α诱导的促进破骨细胞分化和抑制成骨分化的作用。此外，PGRN可与肿瘤坏死因子受体2（TNFR2）相结合，拮抗TNF-α对成骨分化的抑制作用，直接诱导骨再生。项目组主要研究内容主要有：PGRN 对炎性环境下 PDLSCs 成骨/成牙骨质分化的作用及机制； PGRN对巨噬细胞极化的影响； PGRN 对炎性环境下牙周组织再生的作用。项目组的研究结果表明PGRN能直接促进牙周膜干细胞成骨分化，其机制与激活TNFR2及JNK信号通路有关；PGRN能逆转TNF对牙周膜干细胞成骨分化的抑制，其机制与对TNFR1及NF-κB的抑制有关；PGRN抑制LPS诱导的M1巨噬细胞极化，其机制与NF-кB/MAPK信号通路的抑制有关；PGRN在炎性牙周骨缺损中能够发挥抗炎和促成骨的作用。研究结果提示，PGRN在牙周炎的控制和炎性环境下的牙周再生中有重要作用，这为炎性环境下牙周再生治疗提供了新的思路。