Background

Cellular senescence is an important process related to the pathogenic mechanism of different disorders, especially bone loss. During senescence, bone marrow stromal cells (BMSCs) lose their self-renewal and functional differentiation abilities. Therefore, finding signals opposing the osteogenic differentiation of BMSCs within bone marrow microenvironment is the important for elucidating these above-mentioned mechanisms. Inflammatory cytokines affect bone physiology and remodeling. However, the function of interleukin-19 (IL-19) in skeletal system remains unclear.

Methods

The mouse model of IL-19 knockout was established through embryonic stem cell injection for analyzing how IL-19 affected bone formation. Micro-CT examinations were performed to evaluate bone microstructures. We performed a three-point bending test to measure bone stiffness and the ultimate force. Antibody arrays were performed to detect interleukin family members in bone marrow aspirates. BMSCs were cultured and induced for osteogenic differentiation.

Results

According to our findings, there was increased IL-19 accumulation within bone marrow in old mice relative to that in their young counterparts, resulting in bone loss via the inhibition of BMSCs osteogenic differentiation. Among Wnt/β-catenin pathway members, IL-19 strongly upregulated sFRP1 via STAT3 phosphorylation. The inhibition of STAT3 and sFRP1 abolished IL-19’s inhibition against the BMSCs osteogenic differentiation.

Conclusion

To sum up, IL-19 inhibited BMSCs osteogenic differentiation in old mice. Our findings shed novel lights on pathogenic mechanism underlying age-related bone loss and laid a foundation for further research on identifying novel targets to treat senile osteoporosis.

Graphical Abstract

中文翻译：

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骨髓中的白细胞介素 19 通过抑制老年小鼠 BMSC 的成骨分化潜力而导致骨质流失

背景

细胞衰老是与不同疾病尤其是骨丢失的发病机制相关的重要过程。在衰老过程中，骨髓基质细胞（BMSC）失去自我更新和功能分化能力。因此，寻找骨髓微环境中反对BMSCs成骨分化的信号对于阐明上述机制具有重要意义。炎症细胞因子影响骨生理和重塑。然而，白介素19（IL-19）在骨骼系统中的功能仍不清楚。

方法

通过胚胎干细胞注射建立IL-19敲除小鼠模型，用于分析IL-19如何影响骨形成。进行显微 CT 检查以评估骨微结构。我们进行了三点弯曲测试来测量骨骼刚度和极限力。进行抗体阵列检测骨髓抽吸物中的白细胞介素家族成员。培养并诱导BMSCs进行成骨分化。

结果

根据我们的研究结果，与年轻小鼠相比，老年小鼠骨髓内 IL-19 积累增加，通过抑制 BMSC 成骨分化导致骨质流失。在 Wnt/β-catenin 通路成员中，IL-19 通过 STAT3 磷酸化强烈上调 sFRP1。STAT3和sFRP1的抑制消除了IL-19对BMSC成骨分化的抑制作用。

结论

综上所述，IL-19抑制老年小鼠BMSCs成骨分化。我们的研究结果为年龄相关性骨质流失的致病机制提供了新的线索，并为进一步研究确定治疗老年骨质疏松症的新靶点奠定了基础。

图形概要