Multiple myeloma (MM) is a clonal plasma cell proliferative malignancy characterized by a debilitating bone disease. Osteolytic destruction, a hallmark of MM, is driven by increased osteoclast number and exacerbated bone resorption, primarily fueled by the excessive production of RANKL, the master regulator of osteoclast formation, within the tumor niche. We previously reported that osteocytes, the most abundant cells in the bone niche, promote tumor progression and support MM bone disease by overproducing RANKL. However, the molecular mechanisms underlying RANKL dysregulation in osteocytes in the context of MM bone disease are not entirely understood. Here, we present evidence that MM-derived CCL3 induces upregulation of RANKL expression in both human and murine osteocytes. Through a combination of in vitro, ex vivo, and in vivo models and clinical data, we demonstrate that genetic or pharmacologic inhibition of CCL3 prevents RANKL upregulation in osteocytes and attenuates the bone loss induced by MM cells. Mechanistic studies revealed that MM-derived CCL3 triggers the secretion of HMGB1 by osteocytes, a process required for osteocytic RANKL upregulation by MM cells. These findings identify a previously unknown CCL3-HMGB1 signaling axis in the MM tumor niche that drives bone resorption by promoting RANKL overproduction in osteocytes.

中文翻译：

---

新型 CCL3-HMGB1 信号轴调节多发性骨髓瘤中骨细胞 RANKL 表达。


多发性骨髓瘤 （MM） 是一种克隆性浆细胞增殖性恶性肿瘤，其特征是使人衰弱的骨病。溶骨性破坏是 MM 的一个标志，是由破骨细胞数量增加和骨吸收加剧驱动的，主要是由于肿瘤生态位内破骨细胞形成的主要调节因子 RANKL 的过量产生。我们之前报道过，骨细胞是骨生态位中最丰富的细胞，通过过量产生 RANKL 来促进肿瘤进展并支持 MM 骨病。然而，在 MM 骨病的情况下，骨细胞中 RANKL 失调的分子机制尚不完全清楚。在这里，我们提供了 MM 衍生的 CCL3 诱导人和小鼠骨细胞中 RANKL 表达上调的证据。通过体外、离体和体内模型与临床数据的结合，我们证明 CCL3 的遗传或药理学抑制可防止骨细胞中 RANKL 上调并减轻 MM 细胞诱导的骨质流失。机制研究表明，MM 来源的 CCL3 触发骨细胞分泌 HMGB1，这是 MM 细胞上调骨细胞 RANKL 所需的过程。这些发现在 MM 肿瘤生态位中确定了一个以前未知的 CCL3-HMGB1 信号轴，该轴通过促进骨细胞中 RANKL 的过度产生来驱动骨吸收。