蛋白酶体抑制介导的内质网压力信号通路调控成骨分化的分子机制

Multiple myeloma (MM) is a plasma cell malignancy. Myeloma bone disease (MBD) is a devastating complication of MM, also is a main cause of disability and morbidity in MM patients. Bone destruction and lack of bone formation are main factors in the development of MBD. In recent years, the introduction of novel drug bortezomib has significantly improved the treatment of MM. As a reversible inhibitor of 20S proteasome, bortezomib is effectively cytotoxic to MM cells. Bortezomib has also been found to improve osteolytic lesions in MM patients, however, the mechanisms behind the benefits are still unclear. Based on evidence-based literature search and our preliminary results, we propose here that the activation of ER stress signaling branch Atf6 and Xbp1 is involved in the regulating of bone formation by bortezomib (or other proteasome inhibitors). The activation of Atf6 and Xbp1 will drive differentiation of BMSCs and MSCs into osteoblasts (OBs). We will use primary BMSCs, MSCs, pre-osteoblastic cell lines and 5TMM murine models to investigate how Atf6 and Xbp1 regulate the expressions of OB-differentiation related genes. The anticipated results will enhance our understanding of the mechanisms underlying bone formation, provide novel therapeutic targets for treating MBD, and even provide novel strategies for treatment of osteoporosis.

多发性骨髓瘤(MM)是一种浆细胞恶性血液系肿瘤。以溶骨性病变、成骨缺失为主要特点的骨髓瘤骨病(MBD)是MM重要的并发症与死亡原因。近年来，以硼替佐米为代表的蛋白酶体抑制剂类药物的出现，极大改善了MM的治疗。硼替佐米不仅能有效的杀死MM细胞，而且在临床上表现出骨保护的有益作用，但背后的机制并不清楚。基于广泛的文献调研和预实验，我们认为蛋白酶体抑制所引起的内质网压力信号通路的活化很可能是驱动骨髓基质细胞细胞(BMSCs)和间充质干细胞(MSCs)发生成骨分化的重要原因。在本研究中，我们将以原代培养的BMSCs、MSCs、成骨前体细胞系和5TMM小鼠动物模型等为研究对象，深入解析蛋白酶体抑制如何通过内质网压力信号通路Atf6或Xbp1来调控成骨分化的分子机制。预期结果不仅将加深我们对于成骨分化机制的认识，也能为MBD的治疗提供重要的理论与实验依据，并能为骨质疏松的治疗与预防提供重要的借鉴。