Role of ADAMTS4 in Meningioma Bone Invasion

Introduction: ADAMTS4 (aggrecanase-1), a secreted enzyme belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family, is considered to play a key role in the degradation of cartilage proteoglycan (aggrecan) in osteoarthritis and rheumatoid arthritis. Here, we report, for the first time, the role of ADAMTS4 in bone invasion of meningioma. Although meningiomas are considered as benign primary brain tumors, a subset invades bone and soft tissues and causes hyperostosis or osteolysis. Skull base bone-invading meningiomas represent a significant clinical challenge because complete surgical resection is often impossible, resulting in higher recurrence rates and repeat surgeries. We identified ADAMTS4 as a deferentially expressed gene by mRNA microarray between the bone-invasive meningioma group and noninvasive group, and analyzed the function in bone invasion of meningioma.

Methods: Archived tumor specimens of patients with either bone-invading or non-invading meningiomas were selected, and mRNA microarrays were performed. The results of the array data were verified using real-time PCR analysis. Meningioma cell lines (IOMM-Lee, CH157-MN, and F5) were used for in vitro and in vivo functional studies. Boyden chamber Matrigel invasion assay, wound-healing assay, immunostaining, real-time PCR, and Western blotting were used to characterize the behavior of these cells in vitro.

Results: RNA microarray data identified 222 differentially expressed genes, of which ADAMTS4 were selected as novel matrix remodeling metalloproteinases involved in bone invasion. Real-time PCR analysis confirmed the high expression of these genes in bone-invading meningiomas, as well as all cell lines. All ADAMTS4 knock-down cells show significantly reduced migration capacity in Boyden chamber Matrigel invasion assays. Cell proliferation assays showed no significant difference. The conditioned medium of corresponding meningioma cells, but not knocked-down cells, rescued invasion phenotype.

Discussion: These results suggest that aberrant expression of ADAMTS4 can acquire invasion capacity, and suppression of single gene shows great reduction of invasion capacity. It is known that several oncogenes can acquire invasive phenotype in meningiomas, but they also grade up tumor malignancy. The facts suggest that those genes are not responsible for invasive phenotype of grade I meningiomas. In our study, considering our microarray analysis is limited to grade I meningiomas, our findings suggest that ADAMTS4 has an important role in invasive capacity of grade I meningiomas.

Conclusion: We newly identified ADAMTS4 that play an important contributory role to bone invasion in meningiomas. These results provide the possibility of future studies to explore potential targeting therapy of ADAMTS4 in bone-invading meningiomas.