多发性骨髓瘤骨病的分子机制研究

异常的破骨细胞（OCL）生成及骨溶解是多发性骨髓瘤骨病（MMBD）的重要标志，其潜在机制尚不清楚。我们发现，AKT信号通路在多发性骨髓瘤（MM）病人的原代骨髓单个核细胞中显著上调。AKT抑制剂有效阻断MM诱导的OCL生成及骨溶解。AKT激活RANK的表达依赖ATF4。AKT1激酶直接磷酸化ATF4蛋白。在大多数MM病人血清中，FGF2水平明显升高。FGF2上调RANKL在原代骨髓基质细胞（BMSC）中的表达需要有ATF4的存在。FGF2可以增加BMSC中ATF4蛋白水平。我们假设MM细胞通过调节以下两方面来促进OCL生成和激活，并促进骨溶解：（1）OCL前体细胞中AKT/PI3K-ATF4-RANK轴；（2）BMSC/成骨细胞中FGF2-ATF4-RANKL轴。我们将继续研究MM细胞激活OCL生成、激活及骨破坏的机制。完成本课题将为治疗MMBD及其他与溶骨性损伤相关的骨疾病提供分子基础。

Abnormal osteoclast formation and osteolysis are the hallmarks of multiple myeloma bone disease (MMBD), yet the underlying molecular mechanisms are poorly understood. We have recently demonstrated that the AKT pathway is greatly up-regulated in primary bone marrow monocytes (BMM) from multiple myeloma (MM) patients. Blocking AKT using a specific inhibitor suppresses the MM-induced osteoclast formation and bone osteolysis in vitro and in bone. AKT activates the expression of receptor activator of nuclear factor-κB (RANK) in osteoclast precursors in an ATF4-dependent manner. Purified AKT1 enzyme directly phosphorylates ATF4 protein, a key factor critical for osteoclast formation and bone resorption, in in vitro kinase assay. Fibroblast growth factor 2 (FGF-2), which is up-regulated in the sera of many MM patients, activates the expression of RANK ligand (RANKL), an osteoclastogenic factor, in primary bone marrow stromal cells (BMSC). Interestingly, this up-regulation is abolished in BMSCs lacking ATF4. Furthermore, FGF2 increases the level of ATF4 protein in BMSCs. Based on these important findings, we hypothesize that MM cells promote the osteoclast formation and activation and, thereby, osteolysis by modulating (1) the AKT/PI3K-ATF4-RANK axis in osteoclast precursors and (2) the FGF2-ATF4-RANKL axis in BMSC/osteoblasts. Using a combination of loss- and gain-of function approaches, we will continue our exciting studies to determine the underlying mechanisms whereby MM cells promote osteoclast formation and activation and bone destruction. Successful completion of this project will provide a molecular basis for development of new strategies for treating MMBD as well as other bone diseases associated with osteolytic lesions.