Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
GLAZgo Discovery Centre, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Oncoimmunology. 2022 Aug 1;11(1):2104070. doi: 10.1080/2162402X.2022.2104070. eCollection 2022.
Bone disease represents a major cause of morbidity and mortality in Multiple Myeloma (MM); primarily driven by osteoclasts whose differentiation is dependent on expression of RANKL by MM cells. Notably, costimulation by ITAM containing receptors (i.e., FcγR) can also play a crucial role in osteoclast differentiation. Modeling the pathology of the bone marrow microenvironment with an culture system of primary human multiple myeloma cells, we herein demonstrate that FcγR-mediated signaling, via staphylococcal protein A (SpA) IgG immune-complexes, can act as a critical negative regulator of MM-driven osteoclast differentiation. Interrogation of the mode-of-action revealed that FcγR-mediated signaling causes epigenetic modulation of chromosomal 3D architecture at the RANK promoter; with altered spatial orientation of a proximal super enhancer. Combined this leads to substantial down-regulation of RANK at a transcript, protein, and functional level. These observations shed light on a novel mechanism regulating RANK expression and provide a rationale for targeting FcγR-signaling for the amelioration of osteolytic bone pathology in disease.
骨骼疾病是多发性骨髓瘤（MM）患者发病率和死亡率的主要原因，主要由破骨细胞引起，其分化依赖于 MM 细胞表达的 RANKL。值得注意的是，含免疫球蛋白受体酪氨酸激活基序（ITAM）的受体（如 FcγR）的共刺激也可以在破骨细胞分化中发挥关键作用。通过原代人多发性骨髓瘤细胞的培养系统来模拟骨髓微环境的病理学，我们在此证明 FcγR 介导的信号通过葡萄球菌蛋白 A（SpA）IgG 免疫复合物，可以作为 MM 驱动的破骨细胞分化的关键负调节剂。作用机制的研究表明，FcγR 介导的信号导致 RANK 启动子处染色体 3D 结构的表观遗传修饰；近端超级增强子的空间取向发生改变。这导致 RANK 在转录本、蛋白质和功能水平上的大量下调。这些观察结果揭示了调节 RANK 表达的新机制，并为针对 FcγR 信号来改善疾病中的溶骨性骨病理提供了依据。
