骨桥蛋白对特发性脊柱侧凸软骨内成骨影响的机制研究

Adolescent idiopathic scoliosis (AIS) is a most common three-dimensional spinal deformity arising predominantly in otherwise healthy girls during the pubertal period. These recent studies showed that a significantly higher serum osteopontin (OPN) level was detected in AIS patients when compared with control adolescents and it was also found that the occurrence of AIS could be prevented by inhibiting the expression of OPN. All these above finding supported that OPN might play an important role in the development of AIS. Although the effect of OPN on osteoblasts and osteoclasts have been elucidated, its influence on chondrocyte is still unknown. Besides, it was widely known that abnormal endochondral ossification was the key factor during the development of AIS. On this background, our study will focus on the role of OPN in the difference, proliferation, apoptosis process of chondrocyte and explore its mechanism. Our team will further try to inhibit the expression of OPN in the bipedal mice with high central leptin level, in order to prevent the ocurrence of AIS and investigate the role of OPN in the development of AIS caused by high central leptin level. Finally, our team will estalish bipedal mice with high OPN level, control mice and OPN-/- mice for the purpose of further testifying the role of OPN during the development of AIS. The change of endochondral ossification in these three models would also be reseached on to determine the mechanism how high OPN level lead to AIS.

青少年特发性脊柱侧凸畸形（AIS）是一种常见于女性的脊柱三维畸形，其病因机制至今不明。近年来相关研究发现AIS患者血清中骨桥蛋白（OPN）浓度明显高于同龄青少年，并且通过抑制OPN表达成功遏制脊柱侧凸的发生，提出OPN是AIS的重要致病因素。虽然目前OPN对成骨细胞、破骨细胞影响的研究已较为透彻，但其对软骨细胞具体作用未知。而既往研究已证实软骨内成骨过程异常是特发性脊柱侧凸发病的核心中间环节。因此，本研究从探索OPN对软骨细胞分化、增殖、生长、凋亡过程的影响出发，探讨其产生作用的机制。此外，本研究团队还将在既往工作中独创的中枢高瘦素水平动物模型上研究抑制OPN是否也能够阻断中枢高瘦素所致脊柱侧凸的发生。最后，我们还将在上述研究的基础上建立高OPN、OPN-/-以及对照双足直立鼠模型，验证单独高OPN是否能够直接导致脊柱侧凸的发生，并研究高OPN对模型小鼠体内软骨内成骨过程的影响及其机制。

青少年特发性脊柱侧凸人群发病率较低，但该病造成巨大的生理、心理以及社会经济负担，且严重脊柱侧凸治疗代价沉重，因此预防脊柱侧凸的发生以及早期抑制的发展意义重大。但由于其发病原因与发病机制至今研究不清，相关领域研究进展缓慢。目前一般认为软骨内成骨活性异常在该病发病过程中发挥重要作用。而最新文献研究显示骨桥蛋白水平异常可能与特发性脊柱侧凸发生发展间存在显著相关性，并且有研究证实通过阻断骨桥蛋白的表达成功遏制低褪黑素双足直立小鼠脊柱侧凸的发生，提示骨桥蛋白水平异常可能是导致青少年特发性脊柱侧凸发生发展的重要因素。但目前尚缺乏直接证据验证骨桥蛋白异常与脊柱侧凸相关性。本研究则通过建立高骨桥蛋白双足直立小鼠模型，通过长达4月余的直立体态诱导，结果显示与对照组双足直立小鼠相比，该模型小鼠脊柱侧凸发生率与严重程度明显提升，从动物模型整体角度验证了高骨桥蛋白与脊柱侧凸发生发展间相关性；而另一方面，本研究团队通过对软骨细胞细胞系进行骨桥蛋白干预，结果显示骨桥蛋白组软骨细胞增殖活性明显增强，凋亡活性受到一定抑制，从而从细胞生物学角度证明骨桥蛋白可以有效影响软骨细胞活性，从而最终导致脊柱侧凸的发生。