In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and high-throughput analyses, we demonstrate that prolonged HIF-1α signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1α in B cells prevents estrogen deficiency-induced bone loss in mice. Mechanistically, estrogen controls HIF-1α protein stabilization through HSP70-mediated degradation in bone marrow B cells. The stabilization of HIF-1α protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis. Induction of HSP70 expression by geranylgeranylacetone (GGA) administration alleviates ovariectomy-induced osteoporosis. Moreover, RANKL gene expression has a positive correlation with HIF1A expression in human B cells. In conclusion, HIF-1α signaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1α axis may serve as a new therapeutic target for osteoporosis.

在骨髓中，B 细胞和骨吸收破骨细胞共定位并形成特定的微环境。B 细胞如何在功能上影响破骨细胞和骨结构尚不清楚。使用转基因小鼠和高通量分析，我们证明 B 细胞中延长的 HIF-1α 信号传导导致 RANKL 产生和破骨细胞形成增强。此外，B 细胞中 HIF-1α 的缺失可防止雌激素缺乏引起的小鼠骨质流失。从机制上讲，雌激素通过 HSP70 介导的骨髓 B 细胞降解来控制 HIF-1α 蛋白的稳定性。HIF-1α 蛋白在 HSP70 缺陷型骨髓 B 细胞中的稳定性促进了 RANKL 的产生和破骨细胞生成。通过香叶基香叶基丙酮 (GGA) 给药诱导 HSP70 表达可减轻卵巢切除术引起的骨质疏松症。而且，RANKL基因表达与人B细胞中HIF1A的表达呈正相关。总之，B细胞中的HIF-1α信号传导对于破骨细胞生成的控制至关重要，HSP70/HIF-1α轴可作为骨质疏松症的新治疗靶点。