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Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders.
Am J Pathol. 1999 May; 154(5):1465-77.AJ

Abstract

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 Calpha and protein kinase Cepsilon 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 Czeta 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.

Authors+Show Affiliations

Laboratorio di Biologia Cellulare, Istituto Superiore di Sanità, Rome, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10329600

Citation

Fragale, A, et al. "Decreased Proliferation and Altered Differentiation in Osteoblasts From Genetically and Clinically Distinct Craniosynostotic Disorders." The American Journal of Pathology, vol. 154, no. 5, 1999, pp. 1465-77.
Fragale A, Tartaglia M, Bernardini S, et al. Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders. Am J Pathol. 1999;154(5):1465-77.
Fragale, A., Tartaglia, M., Bernardini, S., Di Stasi, A. M., Di Rocco, C., Velardi, F., Teti, A., Battaglia, P. A., & Migliaccio, S. (1999). Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders. The American Journal of Pathology, 154(5), 1465-77.
Fragale A, et al. Decreased Proliferation and Altered Differentiation in Osteoblasts From Genetically and Clinically Distinct Craniosynostotic Disorders. Am J Pathol. 1999;154(5):1465-77. PubMed PMID: 10329600.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders. AU - Fragale,A, AU - Tartaglia,M, AU - Bernardini,S, AU - Di Stasi,A M, AU - Di Rocco,C, AU - Velardi,F, AU - Teti,A, AU - Battaglia,P A, AU - Migliaccio,S, PY - 1999/5/18/pubmed PY - 1999/5/18/medline PY - 1999/5/18/entrez SP - 1465 EP - 77 JF - The American journal of pathology JO - Am J Pathol VL - 154 IS - 5 N2 - 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 Calpha and protein kinase Cepsilon 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 Czeta 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. SN - 0002-9440 UR - https://www.unboundmedicine.com/medline/citation/10329600/Decreased_proliferation_and_altered_differentiation_in_osteoblasts_from_genetically_and_clinically_distinct_craniosynostotic_disorders_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(10)65401-6 DB - PRIME DP - Unbound Medicine ER -