C-reactive protein promotes myeloma cell-mediated bone destruction

描述（由申请人提供）：骨破坏是多发性骨髓瘤（MM）的标志，这是一种基本上无法治愈的b细胞恶性肿瘤，每年影响超过14,400名美国人。超过80%的骨髓瘤患者发生溶骨损伤，可导致病理性骨折和严重的骨痛。我们之前的研究表明，c反应蛋白（CRP）是第一个被描述的急性期蛋白，也是MM和其他癌症的预后指标，在体外和体内都能增强骨髓瘤细胞在应激条件下的增殖，并保护骨髓瘤细胞免受化疗药物诱导的凋亡。c反应蛋白结合活化的Fc？激活PI3K/Akt， ERK和NF-？B途径和抑制化疗药物诱导的caspase级联激活。CRP还能增强骨髓瘤细胞IL-6的分泌，并与IL-6协同保护骨髓瘤细胞免受化疗药物诱导的凋亡（Yang et al., Cancer cell 2007;12:252）。我们最近的研究进一步表明，CRP也可能参与骨髓瘤骨病。我们已经证明，在SCID和SCID-hu小鼠中，产生crp的骨髓瘤细胞系，而不是未经处理或对照载体转导的骨髓瘤细胞系，在小鼠和人骨中产生溶骨性病变。我们的体外研究进一步表明，与野生型或对照载体转导细胞相比，这两种细胞系产生的核因子受体激活剂的水平明显更高。B配体（RANKL）， TNF-a和dickkopf-1 （DKK1）。CRP的添加也刺激骨髓瘤细胞（来自患者的细胞系和原发性骨髓瘤细胞）分泌这些细胞因子。由于RANKL和TNF-a是破骨细胞（OC）分化和活性所必需的，而DKK1是成骨细胞（OB）分化抑制剂，本项目的中心假设是CRP可能通过影响OC和OB的分化和活性，在MM的溶骨破坏中发挥积极作用。在这个项目中，我们将在体外研究CRP对OC和OB分化和活性的作用（目的1），研究CRP介导的骨破坏机制，并制定策略来抵消CRP对体内骨骼的影响（目的2），并研究和验证CRP在MM患者骨破坏中的作用（目的3）。这些新颖的研究在科学上具有创新性和重要性，对MM及其相关骨病的治疗具有重要意义。

DESCRIPTION (provided by applicant): Bone destruction is a hallmark of multiple myeloma (MM), a largely incurable B-cell malignancy that affects more than 14,400 Americans annually. Over 80% myeloma patients develop osteolytic bone lesions that can cause pathological fractures and severe bone pain. Our previous study showed that C-reactive protein (CRP), the first acute-phase protein described and a prognostic indicator for MM and other cancers, enhances myeloma cell proliferation under stressed conditions and protects myeloma cells from chemotherapy drug-induced apoptosis in vitro and in vivo. CRP binds activating Fc? receptors, activates PI3K/Akt, ERK, and NF-?B pathways and inhibits caspase cascade activation induced by chemotherapy drugs. CRP also enhanced myeloma cell secretion of IL-6 and synergized with IL-6 to protect myeloma cells from chemotherapy drug-induced apoptosis (Yang et al., Cancer Cell 2007;12:252). Our recent studies have further suggested that CRP may also be involved in myeloma bone disease. We have shown that CRP-producing, but not the unmanipulated or control vector-transduced myeloma cell lines produce osteolytic lesions in both murine and human bones in SCID and SCID-hu mice. Our in vitro studies further showed that, compared with the wild-type or control vector-transduced cells, these two cell lines produced significantly higher levels of receptor activator of nuclear factor ?B ligand (RANKL), TNF-a, and dickkopf-1 (DKK1). Addition of CRP also stimulated myeloma cells (cell lines and primary myeloma cells from patients) to secrete these cytokines. As RANKL and TNF-a are required for osteoclast (OC) differentiation and activity, and DKK1 is an osteoblast (OB) differentiation inhibitor, the central hypothesis of this project is that CRP may play an active role in osteolytic bone destruction in MM via affecting OC and OB differentiation and activity. In this project, we will examine the role of CRP on OC and OB differentiation and activity in vitro (aim 1), examine the mechanism of CRP-mediated bone destruction and develop strategies to counteract the effects of CRP on bones in vivo (aim 2), and examine and validate the role of CRP in bone destruction in patients with MM (aim 3). These novel studies are scientifically innovative and important, and highly significant for the treatment of MM and its associated bone disease. PUBLIC HEALTH RELEVANCE: Multiple myeloma (MM) is a cancer of the bone marrow. We recently found that C-reactive protein (CRP), a serum protein that is highly elevated in myeloma and other cancers, can protect myeloma tumor cells from antimyeloma drug-induced apoptosis, and may also be involved in myeloma cell-mediated bone destruction in this disease. In this research project, we will focus on the ability of CRP to promote the generation of OCs and inhibit the generation of OBs in vitro; our studies will uncover a new mechanism by which bone destruction is caused by myeloma cells, and provide a new method to prevent the development of bone disease in patients with MM.