软骨下骨mTORC1通路活性在骨关节炎发病中的作用及机制研究

Osteoarthritis (OA) is the most common joint disease, which has been defined as one of the top ten health killers paralleling with cardiovascular disease and cancer. That the underlying pathogenesis of OA remains unclear leads to lack of effective prevention and therapy. OA is mainly characterized by subchondral bone alteration. Recent studies indicated mTORC1 signalling is involving in the OA development. but the relationship between mTORC1 signalling activity of subchondral bone and OA has not been investigated yet. Our preliminary study suggested that specific knock-out TSC1 in osteoblast during the skeletal development, which up-regulates the mTORC1 signalling, could result in the hypertrophy of cortex bone and high bone mineral density in subchondral bone. These result indicates that mTORC1 signalling pathway could play an important role in the development of subchondral bone and bone metabolism. Therefore, our proposal aims to study the mTORC1 signalling in OA patients and normal population by signaling array chip, dually modulate the mTORC1 signalling in the subchondral bone of tissue-specific knock-out animal model and mimic the crosstalk between mTORC1 signalling and subchondral bone pathological changes in co-culture system, which will be benefitical for the further OA treatment targeting for the mTORC1 signalling of subchondral bone.

骨关节炎（OA）是临床最常见的关节疾病，已成为危害人类健康的十大杀手之一。其发病机制至今不明，导致目前临床缺乏有效防治措施。软骨下骨改变在OA发病中至关重要。有研究提示mTORC1信号通路可能参与调节OA发病，但有关软骨下骨mTORC1活性与OA发病的关系尚未见报道。课题组预实验发现：发育过程中特异性敲除成骨细胞上TSC1基因（上调mTORC1活性），小鼠骨皮质厚度及软骨下骨骨密度显著增加。该结果提示：mTORC1在软骨下骨发育与骨代谢调节中起重要作用。本课题拟通过信号通路芯片比较临床OA患者与正常人软骨下骨标本mTORC1活性；并在可诱导的组织特异性基因敲除动物体内，分别上调和下调软骨下骨mTORC1活性，进一步验证mTORC1通路在OA发病中的作用；并通过体外细胞共培养模型初步探讨其分子机制。旨在为OA发病机制与mTORC1的功能提供新内容，为防治OA提供新的潜在靶点。

骨关节炎是最常见的关节疾病，关节软骨和软骨下骨破坏是其特征性的病理改变，然而其发病机理尚不清楚。研究显示mTORC1信号通路参与OA的发生发展，药物抑制mTORC1信号通路能有效延缓OA的病程，但是软骨和软骨下骨mTORC1活性改变在OA发生发展中的作用及机制尚不清楚。本研究将通过临床标本、基因敲除小鼠模型和细胞模型，深入探讨软骨细胞和成骨前体细胞mTORC1活性改变在OA病程中的作用及其分子机制，为防治OA提供新的潜在靶点。研究结果显示mTORC1 信号通路与 OA 密切相关。 OA 患者和小鼠 OA 模型中膝关节软骨和软骨下骨 mTORC1 信号通路高度活化，并且小鼠膝关节软骨细胞 mTORC1活性随着年龄增长而逐渐活化。mTORC1 活化通过下调 P73和 FGFR3 促进软骨细胞增殖、 通过下调 PPR 促进软骨细胞肥大分化，共同作用诱发并促进 OA 的发生发展。 OA 病程中， 软骨下骨成骨前体细胞 mTORC1 活化促进其异常增殖导致软骨下骨骨硬化，通过分泌CXCL12 促进软骨细胞肥大分化和终末分化，最终促进 OA的发生发展。因此在OA 病程中，膝关节软骨细胞和软骨下骨成骨前体细胞 mTORC1 信号通路高度活化，在OA 发生发展中起着重要作用，药物抑制软骨细胞和成骨前体细胞 mTORC1 通路活性是防治 OA 的潜在靶点。