JDP2-MMP14-RANKL轴调控多发性骨髓瘤细胞诱导破骨细胞分化参与骨髓瘤溶骨性病变的机制研究

多发性骨髓瘤（MM）是一类浆细胞恶性克隆增殖性疾病，发病率居血液系统肿瘤的第二位。骨髓瘤溶骨性病变（MBD）是MM最常见的并发症之一，严重影响患者生活质量与疾病预后。MM细胞是触发MBD的始动因素和维持因素，即使在肿瘤负荷极低的情况下，MBD的发生仍不可避免。骨髓肿瘤微环境中的炎性细胞因子是促进破骨细胞（OC）分化的主要因素。其中，MM细胞来源的RANKL是触发/维持OC分化和MBD发生的关键。我们发现MM细胞中的JDP2可以调控MMP14转录，且可能通过notch通路的激活促进MM来源的RANKL合成与释放，诱导OC的分化成熟和MBD的发生，但具体的分子调控机制有待阐明。本研究拟通过多种分子生物学手段及体内外实验探索MM细胞内JDP2-MMP14-RANKL轴促进OC分化及MBD发生的具体分子机制，为MM溶骨性病变的靶向治疗及临床转化提供理论依据。

Multiple myeloma is a clonal B-cell malignancy characterized by proliferation of plasma cell in bone marrow (BM) and secreted monoclonal immunoglobulins into blood. Myeloma bone disease (MBD), which results from the imbalance of bone resorption and bone formation, is the commonest complications of MM and decrease the quality of life and survival time of patients with MM. MM cells are the mainstay of MBD pathogenesis, BM cellular components such as BM stromal cells (BMSC), macrophages and T cells interact with myeloma cells, promoting inflammatory cytokines secreted into BM and induing osteoclasts maturation. Of note, myeloma derived RANKL is the key factor for OC differentiation and MBD happening. When RANKL biding to RANK on the surface of OC progenitors, cell signaling pathways such as NF-κB and JNK were activated and OC maturation was triggering off. Our previous research showed that BM microenvironment induced JDP2 in MM cells, which regulating MMP14 expression at the transcriptive level. MMP14 could promote RANKL expression in MM cells which mingt induced by activating of notch signaling and stimulate maturation of OC ex vivo and bone loss in myeloma murine models. Our current project is going to investigate the detail mechanism of MBD though JDP2 and its targets by variety of molecular methods.