Inflammation and skeletal homeostasis are closely intertwined. Inflammatory diseases are associated with local and systemic bone loss, and post-menopausal osteoporosis is linked to low-level chronic inflammation. Phosphoinositide-3-kinase signalling is a pivotal pathway modulating immune responses and controlling skeletal health. Mice deficient in Src homology 2-containing inositol phosphatase 1 (SHIP1), a negative regulator of the phosphoinositide-3-kinase pathway, develop systemic inflammation associated with low body weight, reduced bone mass, and changes in bone microarchitecture. To elucidate the specific role of the immune system in skeletal development, a genetic approach was used to characterise the contribution of SHIP1-controlled systemic inflammation to SHIP1-dependent osteoclastogenesis. Lymphocyte deletion entirely rescued the skeletal phenotype in Rag2 ^-/- /Il2rg ^-/- /SHIP1 ^-/- mice. Rag2 ^-/- /Il2rg ^-/- /SHIP1 ^-/- osteoclasts, however, displayed an intermediate transcriptomic signature between control and Rag2 ^+/+ /Il2rg ^+/+ /SHIP1 ^-/- osteoclasts while exhibiting aberrant in vitro development and functions similar to Rag2 ^+/+ /Il2rg ^+/+ /SHIP1 ^-/- osteoclasts. These data establish a cell-intrinsic role for SHIP1 in osteoclasts, with inflammation as the key driver of the skeletal phenotype in SHIP1-deficient mice. Our findings demonstrate the central role of the immune system in steering physiological skeletal development.

中文翻译：

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SHIP1 缺陷会导致炎症依赖性骨骼生长迟缓。

炎症和骨骼稳态密切相关。炎症性疾病与局部和全身骨质流失有关，绝经后骨质疏松症与低水平的慢性炎症有关。磷酸肌醇 3 激酶信号传导是调节免疫反应和控制骨骼健康的关键途径。含有 Src 同源性 2 的肌醇磷酸酶 1 (SHIP1)（磷酸肌醇 3 激酶途径的负调节因子）缺陷的小鼠会出现与低体重、骨量减少和骨微结构变化相关的全身炎症。为了阐明免疫系统在骨骼发育中的具体作用，采用遗传学方法来表征 SHIP1 控制的全身炎症对 SHIP1 依赖性破骨细胞生成的贡献。淋巴细胞删除完全挽救了Rag2 ^-/- /Il2rg ^-/- /SHIP1 ^-/-小鼠的骨骼表型。然而， Rag2 ^-/- /Il2rg ^-/- /SHIP1 ^-/-破骨细胞表现出介于对照和Rag2 ^+/+ /Il2rg ^+/+ /SHIP1 ^-/-破骨细胞之间的中间转录组特征，同时表现出异常的体外发育和相似的功能至Rag2 ^+/+ /Il2rg ^+/+ /SHIP1 ^-/-破骨细胞。这些数据确定了 SHIP1 在破骨细胞中的细胞内在作用，炎症是 SHIP1 缺陷小鼠骨骼表型的关键驱动因素。我们的研究结果证明了免疫系统在指导生理骨骼发育中的核心作用。