Loss of MMP9 disturbs cranial suture fusion via suppressing cell proliferation, chondrogenesis and osteogenesis in mice

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.

Chondrogenesis; MMP9; Matrix metalloproteinases; Osteogenic differentiation; Posterior frontal suture.