Cranial sutures function as growth centers for calvarial bones. Abnormal suture closure will cause permanent cranium deformities. MMP9 is a member of the gelatinases that degrades components of the extracellular matrix. MMP9 has been reported to regulate bone development and remodeling. However, the function of MMP9 in cranial suture development is still unknown. Here, we identified that the expression of Mmp9 was specifically elevated during fusion of posterior frontal (PF) suture compared with other patent sutures in mice. Interestingly, inhibition of MMP9 ex vivo or knockout of Mmp9 in mice (Mmp9-/-) disturbed the fusion of PF suture. Histological analysis showed that knockout of Mmp9 resulted in wider distance between osteogenic fronts, suppressed cell condensation and endocranial bone formation in PF suture. Proliferation, chondrogenesis and osteogenesis of suture cells were decreased in Mmp9-/- mice, leading to the PF suture defects. Moreover, transcriptome analysis of PF suture revealed upregulated ribosome biogenesis and downregulated IGF signaling associated with abnormal closure of PF suture in Mmp9-/- mice. Inhibition of the ribosome biogenesis partially rescued PF suture defects caused by Mmp9 knockout. Altogether, these results indicate that MMP9 is critical for the fusion of cranial sutures, thus suggesting MMP9 as a potential therapeutic target for cranial suture diseases.

中文翻译：

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MMP9 的缺失通过抑制小鼠的细胞增殖、软骨形成和成骨来干扰颅缝融合


颅缝起着颅骨生长中心的作用。缝合线闭合异常会导致永久性颅骨畸形。MMP9 是明胶酶的成员，可降解细胞外基质的成分。据报道，MMP9 可调节骨骼发育和重塑。然而，MMP9 在颅缝发育中的功能仍然未知。在这里，我们发现与小鼠的其他未开缝线相比，Mmp9 的表达在后额缝 （PF） 融合过程中特异性升高。有趣的是，小鼠离体抑制 MMP9 或敲除 Mmp9 （Mmp9-/-） 干扰了 PF 缝合线的融合。组织学分析显示，敲除 Mmp9 导致 PF 缝合线中成骨前沿之间的距离更宽，抑制了细胞浓缩和颅内骨形成。Mmp9-/-小鼠缝合细胞的增殖、软骨生成和成骨减少，导致 PF 缝合缺陷。此外，PF 缝合线的转录组分析显示，与 Mmp9-/- 小鼠 PF 缝合线异常闭合相关的核糖体生物发生上调和 IGF 信号下调。抑制核糖体生物发生部分挽救了由 Mmp9 敲除引起的 PF 缝合缺陷。总之，这些结果表明 MMP9 对颅缝合至关重要，因此表明 MMP9 是颅缝疾病的潜在治疗靶点。