Lim mineralization protein is involved in the premature calvarial ossification in sporadic craniosynostoses

Sporadic mono-sutural craniosynostosis represents a highly prevalent regional bone\r\ndisorder, where a single cranial suture undergoes premature ossification due to a\r\ngenerally unclear etiopathogenesis. The LIM mineralization protein (LMP) was recently\r\ndescribed as an efficient osteogenic molecule involved in osteoblast differentiation,\r\nexpressed in calvarial tissues upon corticosteroid-osteogenic induction and used as a\r\npotent inducer of bone formation in several animal models. In this study, calvarial cells\r\nisolated from both prematurely fused and physiologically patent sutures of children with\r\nsporadic craniosynostosis, were used as an in vitro paradigmatic model for the study of the\r\nmolecular events involved in calvarial osteogenesis, focusing on the possible role of the\r\nLMP-related osteogenic signaling. Calvarial cells isolated from both patent and fused\r\nsutures expressed a mesenchymal-like immunophenotype. Cells isolated from fused\r\nsutures displayed an increased osteogenic potential, being able to undergo spontaneous\r\nmineralization and premature response to osteogenic induction, leading to in vitro bone\r\nnodule formation. The expression of LMP and its target genes (bone morphogenetic\r\nprotein-2, osteocalcin and Runt-related transcription factor 2) was significantly upregulated\r\nin cells derived from the fused sutures. Upon silencing the expression of LMP in\r\nfused suture-derived cells, the osteogenic potential along with the expression of osteospecific\r\ntranscription factors decreased, restoring the “physiologic” cell behavior. These\r\nresults suggested that: 1. mesenchymal cells residing in fused sutures display a\r\nconstitutionally active osteogenic disposition leading to the premature suture ossification;\r\n2. the molecular basis of the overactive osteogenic process may at least in part involve a\r\nderegulation of the LMP-related pathway in calvarial cells.