Increased bone formation and osteoblastic cell phenotype in premature cranial suture ossification (craniosynostosis)

Abstract

Craniosynostosis is a heterogeneous disorder characterized by premature fusion of the skull bone sutures. To evaluate the pathogenesis of premature cranial suture ossification in craniosynostosis, we have evaluated the histologic indices of bone formation and the characteristics of osteoblastic cells derived from normal and affected cranial sutures in 47 infants and children, aged 3-18 months, with nonsyndromic craniosynostosis. The histomorphometric analysis of normal and fused sutures showed an age-related decline in the extent of endosteal bone surface covered with osteoid and osteoblasts during postnatal suture ossification. Bone formation was 20-50% higher at 3-6 months of age in fused sutures compared with normal sutures in the same patients. Cells derived from normal and fused sutures displayed characteristics of the osteoblast phenotype in culture. Analysis of [3H]thymidine incorporation into DNA from 1-14 days of culture showed an age-related decrease in osteoblastic cell growth in both normal and affected sutures. The proliferation of osteoblastic cells isolated from fused sutures was similar at all ages to that of cells isolated from normal sutures in the same patients. In contrast, alkaline phosphatase activity and osteocalcin production by osteoblastic cells cultured in basal conditions and after stimulation with 1,25-dihydroxyvitamin D (1,25[OH]2D3), were 53-74% higher in fused sutures compared with cells isolated from normal sutures in the same patients. The results indicate that bone formation activity at the suture site is locally increased in craniosynostosis, and this disorder is associated with increased in vitro parameters of osteoblastic cell differentiation, suggesting that an increased maturation of osteoblastic cells at the site of the suture leads to the premature ossification in nonsyndromic craniosynostosis.