青少年特发性脊柱侧凸异常骨骼发育相关的褪黑素信号通路研究

Adolescent idiopathic scoliosis(AIS) is the most common spinal deformity of adolescent population, the exact etiology of which is still unknown. "Melatonin signaling dysfunction" is one of the most important hypotheses of AIS. Our previous studies found that melatonin could enhance osteogenesis and chondrogenesis of human bone marrow-derived mesenchymal stem cells (BMSCs), and abnormal effects of melatonin on regulating osteogenesis and chondrogenesis of BMSCs from AIS patients were found in our pre-experiments. Thus we suspect that there may exist melatonin signaling dysfunction in osteogenesis and chondrogenesis of BMSCs from AIS patients, which leads to the abnormal responses to melatonin in the process of BMSCs differentiation, and eventually causes the skeletal dysplasia of AIS. In this work, a case-control study will be perfromed to investigate the molecular mechanism of melatonin signaling dysfunction in osteogenesis and chondrogenesis of BMSCs from AIS patients. First of all, we will further identify that there is a difference between AIS and control in functional response toward melatonin in osteogenesis and chondrogenesis of BMSCs. And then the expression and function of melatonin receptor and melatonin signal transduction pathways related to osteogenesis and chondrogenesis of BMSCs from AIS patients will be studied.

青少年特发性脊柱侧凸(AIS)是青少年期最常见的脊柱畸形，目前病因尚不明确。"褪黑素信号通路异常"是其发病的重要假说之一，我们前期研究表明褪黑素在调控干细胞(BMSCs)向骨、软骨方向分化中发挥重要作用，进一步预实验提示褪黑素干预下AIS患者BMSCs向骨、软骨分化的能力弱于正常对照。因此我们推测AIS患者骨骼系统的畸形发育可能是其BMSCs在向骨、软骨分化中存在褪黑素信号通路异常而对褪黑素的调控作用不敏感所致。故本项目拟从骨骼系统生长发育的起始点- - 干细胞分化水平，对AIS的发病机制进行研究。首先进一步明确褪黑素干预下AIS患者BMSCs向骨、软骨分化存在异常；然后，研究患者BMSCs分化中褪黑素受体的表达、功能及下游相关通路的信号转导过程是否存在异常改变，以期进一步明确AIS的发病机制、定位病变靶点，从而推动临床AIS诊疗技术的发展。

青少年特发性脊柱侧凸(Adolescent Idiopathic Scoliosis, AIS)是青少年期最常见的脊柱畸形，目前病因尚不明确。我们研究的核心要点是褪黑素信号通路异常在AIS发病的作用机制AIS患者存在着广泛的、全身性的骨骼系统生长发育异常。本项目我们首先进行AIS患者脊柱形态学研究，明确AIS患者脊椎骨骼存在发育异常并总结其畸形改变的规律，即患者偏曲脊柱凹侧脊椎椎弓根宽度明显小于凸侧，并且明显比正常人的窄。椎弓根凹凸侧间的这种差异在结构弯区、顶椎区较非结构弯区、非顶椎区更为明显。因为“褪黑素信号通路异常”作为AIS发病的重要假说之一，所以我们从骨骼系统发育的起始点——干细胞分化阶段，研究褪黑素BMSCs分化过程中的调控作用。研究发现褪黑素能显著促进其向骨、软骨方向的分化。我们进一步通过病例对照研究AIS患者和正常对照组BMSCs成骨、成软骨分化中褪黑素信号通路的差异。结果提示AIS患者BMSCs的褪黑素受体MT2表达较正常人下降。褪黑素干预下AIS患者BMSCs向骨、软骨分化的能力弱于正常对照。AIS患者骨骼系统的畸形发育可能是其BMSCs在向骨、软骨分化中存在褪黑素信号通路异常而对褪黑素的调控作用不敏感所致。最后我们研究患者BMSCs分化中褪黑素受体的表达、功能及下游相关通路的信号转导过程是否存在异常改变，以期进一步明确AIS的发病机制、定位病变靶点，从而推动临床AIS诊疗技术的发展。