Differential Responsiveness to BMP9 between Patent and Fused Suture Progenitor Cells from Craniosynostosis Patients

Abstract

Several studies have verified that BMPs may be involved in the development of craniosynostosis; little attention has been focused on the role of BMP9 in cranial suture biology. BMP9 is the most osteogenic BMP and promotes the osteoblastic differentiation of mesenchymal stem cells. We investigated the role of BMP9 in suture progenitor cells (SuPs). We isolated and cultured prematurely fused (FSuPs) and internal control patent (PSuPs) suture progenitor cells from patients with nonsyndromic craniosynostosis. Overexpression of BMP9 was mediated by adenoviral vectors. Osteoblast and osteoclast differentiation-related markers were evaluated by staining techniques and TqPCR analysis. In vivo analysis of BMP9-induced SuPs osteogenesis was performed in an ectopic bone formation model. We demonstrated that the prematurely fused sutures have a higher endogenous expression of the osteogenic differentiation-related genes than patent sutures, while the same pattern of gene expression exists between FSuPs and PSuPs. Importantly, both PSuPs and FSuPs undergo osteogenic differentiation and express multiple lineage regulators and NELL-1 upon BMP9 stimulation, while FSuPs have a higher basal osteogenic potential than PSuPs. BMP9 regulates the expression of osteoclast differentiation-related genes in SuPs. Forced BMP9 expression enhances the mineralization and maturity of ectopic bone formation of SuPs implanted in vivo. Our findings suggest that FSuPs have an elevated osteogenic potential. BMP9 could regulate the expression of multiple osteoblast and osteoclast differentiation-related genes, as well as NELL1 in both SuPs, indicating that BMP9 may play a role in craniosynostosis.