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(American Journal of Pathology. 1999;154:1465-1477.)
© 1999 American Society for Investigative Pathology

Regular Articles

Decreased Proliferation and Altered Differentiation in Osteoblasts from Genetically and Clinically Distinct Craniosynostotic Disorders

Alessandra Fragale^*, Marco Tartaglia^*, Silvia Bernardini, A.M. Michela Di Stasi^*, Concezio Di Rocco^§, Francesco Velardi^§, Anna Teti^¶, Piero A. Battaglia^* and Silvia Migliaccio

From the Laboratorio di Biologia Cellulare,^*
Istituto Superiore di Sanità, Rome, Italy; Dipartimento di Istologia e Embriologia Medica
and Dipartimento di Fisiopatologia Medica,
Università "La Sapienza," Rome, Italy; Sezione Autonoma di Neurochirurgia Infantile,^§
Policlinico Universitario "Agostino Gemelli," Rome, Italy; and Dipartimento di Medicina Sperimentale,^¶
Università dell'Aquila, L'Aquila, Italy

Craniosynostoses are a heterogeneous group of disorders characterized by premature fusion of cranial sutures. Mutations in fibroblast growth factor receptors (FGFRs) have been associated with a number of such conditions. Nevertheless, the cellular mechanism(s) involved remain unknown. We analyzed cell proliferation and differentiation in osteoblasts obtained from patients with three genetically and clinically distinct craniosynostoses: Pfeiffer syndrome carrying the FGFR2 C342R substitution, Apert syndrome with FGFR2 P253R change, and a nonsyndromic craniosynostosis without FGFR canonic mutations, as compared with control osteoblasts. Osteoblasts from craniosynostotic patients exhibited a lower proliferation rate than control osteoblasts. P253R and nonsyndromic craniosynostosis osteoblasts showed a marked differentiated phenotype, characterized by high alkaline phosphatase activity, increased mineralization and expression of noncollagenous matrix proteins, associated with high expression and activation of protein kinase C and protein kinase C isoenzymes. By contrast, the low proliferation rate of C342R osteoblasts was not associated with a differentiated phenotype. Although they showed higher alkaline phosphatase activity than control, C342R osteoblasts failed to mineralize and expressed low levels of osteopontin and osteonectin and high protein kinase C levels. Stimulation of proliferation and inhibition of differentiation were observed in all cultures on FGF2 treatment. Our results suggest that an anticipated proliferative/differentiative switch, associated with alterations of the FGFR transduction pathways, could be the causative common feature in craniosynostosis and that mutations in distinct FGFR2 domains are associated with an in vitro heterogeneous differentiative phenotype.

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