C-reactive protein promotes myeloma cell-mediated bone destruction

描述(申请人提供)：骨质破坏是多发性骨髓瘤(MM)的标志，多发性骨髓瘤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性病变，可导致病理性骨折和严重的骨痛。我们先前的研究表明，C-反应蛋白(CRP)是第一个被描述的急性时相蛋白，是MM和其他癌症的预后指标，在体内外都能在应激条件下促进骨髓瘤细胞的增殖，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Fc？受体，激活PI3K/Akt、ERK和NF-β途径，抑制化疗药物诱导的caspase级联激活。CRP还促进骨髓瘤细胞分泌IL-6，并与IL-6协同作用以保护骨髓瘤细胞免受化疗药物诱导的凋亡(Yang等人，癌细胞2007；12：252)。我们最近的研究进一步表明，CRP可能也与骨髓瘤骨病有关。我们已经证明，在SCID和SCID-Hu小鼠中，产生CRP的骨髓瘤细胞系，而不是未经操纵或对照载体转导的骨髓瘤细胞系，在小鼠和人骨中都会产生溶骨性损伤。我们的体外研究进一步表明，与野生型或对照载体转导的细胞相比，这两种细胞株产生的核因子B受体激活物(RANKL)、肿瘤坏死因子-α(TNF-α)和Dickkopf-1(Dkk1)水平显著升高。CRP的加入也刺激骨髓瘤细胞(骨髓瘤细胞系和患者的原代骨髓瘤细胞)分泌这些细胞因子。由于破骨细胞(OC)的分化和活性需要RANKL和TNF-a，而Dkk1是成骨细胞(OB)分化抑制因子，本项目的中心假设是，CRP可能通过影响OC和OB的分化和活性而在MM的溶骨性骨破坏中发挥积极作用。在本项目中，我们将在体外检测CRP在成骨细胞和成骨细胞分化和活性中的作用(目标1)，研究CRP介导的骨破坏的机制，并开发在体内对抗CRP对骨的影响的策略(目标2)，并检验和验证CRP在多发性骨髓瘤患者骨破坏中的作用(目标3)。这些新颖的研究具有科学创新性和重要意义，对多发性骨髓瘤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.