Exercise can prevent osteoporosis and improve immune function, but the mechanism remains unclear. Here, we show that exercise promotes reticulocalbin-2 secretion from the bone marrow macrophages to initiate bone marrow fat lipolysis. Given the crucial role of lipolysis in exercise-stimulated osteogenesis and lymphopoiesis, these findings suggest that reticulocalbin-2 is a pivotal regulator of a local adipose-osteogenic/immune axis. Mechanistically, reticulocalbin-2 binds to a functional receptor complex, which is composed of neuronilin-2 and integrin beta-1, to activate a cAMP-PKA signaling pathway that mobilizes bone marrow fat via lipolysis to fuel the differentiation and function of mesenchymal and hematopoietic stem cells. Notably, the administration of recombinant reticulocalbin-2 in tail-suspended and old mice remarkably decreases bone marrow fat accumulation and promotes osteogenesis and lymphopoiesis. These findings identify reticulocalbin-2 as a novel mechanosensitive lipolytic factor in maintaining energy homeostasis in bone resident cells, and it provides a promising target for skeletal and immune health.

运动可以预防骨质疏松，提高免疫功能，但机制尚不清楚。在这里，我们展示了运动促进骨髓巨噬细胞分泌 reticulocalbin-2 以启动骨髓脂肪分解。鉴于脂肪分解在运动刺激的成骨和淋巴细胞生成中的关键作用，这些发现表明 reticulocalbin-2 是局部脂肪-成骨/免疫轴的关键调节剂。从机制上讲，reticulocalbin-2 与由神经素 2 和整合素 beta-1 组成的功能性受体复合物结合，激活 cAMP-PKA 信号通路，通过脂解动员骨​​髓脂肪，促进间充质和造血细胞的分化和功能。干细胞。尤其，在悬尾小鼠和老年小鼠中施用重组网状蛋白-2可显着减少骨髓脂肪积累并促进成骨和淋巴细胞生成。这些发现将 reticulocalbin-2 确定为一种新的机械敏感性脂解因子，可维持骨驻留细胞的能量稳态，它为骨骼和免疫健康提供了一个有希望的目标。