The subchondral bone destruction is an mayjor pathological change in osteoarthritis (OA). The inhibition of from bone marrow mesenchymal stem cells (BMC) is a key factor in the OA subchondral bone destruction. After data analysis, we found that the bone formation protein (BMP) 5/2 plays a central role in regulating BMC osteoblast differentiation of subchondral bone through Smad protein. Rehabilitation medicine has confirmed that ultrasound and magnetic field therapy could promote BMC osteogenesis differentiation by bmp5/2. The down-regulation of bmp5/2 will lead to the reduction of its therapeutic effect. Therefore, it is particularly important to clarify the mechanism of the down-regulation of bmp5/2. Study found that a mutation in an upstream microsatellite sequence of BMP5 (microsatellite instability) was the direct cause of its down regulation. The excavated software, we developed, found that there were microsatellite sequences in the upstream of bmp5/2, and the mutation could still affect its expression.In addition, we found that the mutation rate of bmp5/2 microsatellite gene was higher than that in normal group. Therefore, we hypothesized that the microsatellite instability of BMP2 and BMP5 led to the inhibition of gene expression, then to inhibit osteogenic differentiation of the BMC in subchondral bone of OA through Smad. This study intends to explain the bmp5/2 down-regulation mechanism through clinical and cellular studies to provide a theoretical evidencefor rehabilitation therapy.
软骨下骨破坏是骨关节炎(OA)特征性变化,而骨髓间充质干细胞(BMC)成骨细胞分化抑制是其关键因素。我们挖掘数据后发现骨形成蛋白(BMP)5/2调控Smad在OA软骨下骨BMC成骨分化中的核心作用。康复医学发现BMP5/2可介导超声与磁场促进BMC成骨分化,BMP5/2表达下调将导致其疗效减弱,因此明确BMP5/2表达下调的机制则尤为重要。研究提示BMP5启动子下游的一个微卫星序列发生突变(微卫星不稳定)是其表达下调的直接原因。我们研发的挖掘软件发现BMP5/2上游还存在微卫星序列,其突变仍可能影响其表达。并且,我们预实验发现OA患者软骨下骨组织中BMP5/2微卫星基因突变率高于正常组。据此,我们假设BMP5/2的微卫星不稳定导致其基因表达抑制,并通过Smad产生抑制OA软骨下骨BMC成骨分化的作用。本研究拟通过临床与细胞研究验证科学假设,解释BMP5/2下调机制,为康复治疗提供理论基础。
课题组分析来自 GSE51588 数据库的 50 组数据发现,TGF-β信号通路是OA 软骨下骨代谢的核心通路。核心基因骨形成蛋白(BMP)基因的激活将导致其蛋白表达增加,加速细胞内信号转导分子 Smad 向核内传递信息,促进 BMC 向成骨细胞分化。在BMP基因组内BMP2和BMP5参与成骨分化,而OA 患者软骨下骨 BMP5/2 表达较低,并呈现家族遗传性。BMP5/2 表达下调导致 OA 软骨下骨BMC 成骨分化抑制是软骨下骨破坏的核心因素。通过自主研发高信度与效度的微卫星筛查工具——Krait,发现 BMP2 启动子上游常规影响启动子活性区域存在微卫星序列,BMP2 与 BMP5 的微卫星不稳定导致其基因表达抑制,并通过 Smad 产生抑制 OA 软骨下骨 BMC 成骨分化的作用。对软骨退变相关的重要mRNA进行了测序及验证,S100A8,S100A9,IL7R,Lipocalin-2,BTK,CD28,HLA-DQA1和HLA-DQB1与BMP2均存在明确的相关性。发现了中度至重度骨关节炎软骨退变相关的几种基因和关键代谢途径,BMP2在其中的作用更加明确。并且MSC的成软骨分化过程中BMP2是最直接最重要的诱导分化因子,基于此基础,进行临床实验发现,超声波具有修复软骨损伤的治疗潜力,加强髋关节外展肌对缓解疼痛和改善KOA患者的功能比单独增强股四头肌更有效,且全身振动可能加速膝关节骨OA软骨破坏等。并且在OA患者中观察到BMP2表达的下调,其原因可能与神经调控有关。我们临床中同时观察到股四头肌肌肉功能抑制,也与神经调控存在关系,因此,BMP2与肌肉抑制间可能存在潜在的联系。对骨代谢与肌肉抑制的具体模式进行进一步探索,可能发现BMP2同股四头肌功能抑制的内在联系,通过打破其内在循环,进一步改善OA患者功能,提高康复结局。目前项目资助发表核心论文7篇,硕士毕业研究生2名,还有一名项目参与人员在该课题培养方案下,已成功从初级职称晋升为中级职称。项目投入经费21万元,支出19.597万元,各项支出基本于预算相符。剩余经费1.403万元,剩余经费计划用于本项目后续支出。
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数据更新时间:2023-05-31
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