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Sustained platelet-derived growth factor receptor alpha signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase C-gamma pathway.
Mol Cell Biol 2009; 29(3):881-91MC

Abstract

The development and growth of the skull is controlled by cranial sutures, which serve as growth centers for osteogenesis by providing a pool of osteoprogenitors. These osteoprogenitors undergo intramembranous ossification by direct differentiation into osteoblasts, which synthesize the components of the extracellular bone matrix. A dysregulation of osteoblast differentiation can lead to premature fusion of sutures, resulting in an abnormal skull shape, a disease called craniosynostosis. Although several genes could be linked to craniosynostosis, the mechanisms regulating cranial suture development remain largely elusive. We have established transgenic mice conditionally expressing an autoactivated platelet-derived growth factor receptor alpha (PDGFRalpha) in neural crest cells (NCCs) and their derivatives. In these mice, premature fusion of NCC-derived sutures occurred at early postnatal stages. In vivo and in vitro experiments demonstrated enhanced proliferation of osteoprogenitors and accelerated ossification of osteoblasts. Furthermore, in osteoblasts expressing the autoactivated receptor, we detected an upregulation of the phospholipase C-gamma (PLC-gamma) pathway. Treatment of differentiating osteoblasts with a PLC-gamma-specific inhibitor prevented the mineralization of synthesized bone matrix. Thus, we show for the first time that PDGFRalpha signaling stimulates osteogenesis of NCC-derived osteoblasts by activating the PLC-gamma pathway, suggesting an involvement of this pathway in the etiology of human craniosynostosis.

Authors+Show Affiliations

Department of Developmental Pathology, Institute of Pathology, University of Bonn, Bonn, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19047372

Citation

Moenning, Anne, et al. "Sustained Platelet-derived Growth Factor Receptor Alpha Signaling in Osteoblasts Results in Craniosynostosis By Overactivating the Phospholipase C-gamma Pathway." Molecular and Cellular Biology, vol. 29, no. 3, 2009, pp. 881-91.
Moenning A, Jäger R, Egert A, et al. Sustained platelet-derived growth factor receptor alpha signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase C-gamma pathway. Mol Cell Biol. 2009;29(3):881-91.
Moenning, A., Jäger, R., Egert, A., Kress, W., Wardelmann, E., & Schorle, H. (2009). Sustained platelet-derived growth factor receptor alpha signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase C-gamma pathway. Molecular and Cellular Biology, 29(3), pp. 881-91. doi:10.1128/MCB.00885-08.
Moenning A, et al. Sustained Platelet-derived Growth Factor Receptor Alpha Signaling in Osteoblasts Results in Craniosynostosis By Overactivating the Phospholipase C-gamma Pathway. Mol Cell Biol. 2009;29(3):881-91. PubMed PMID: 19047372.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sustained platelet-derived growth factor receptor alpha signaling in osteoblasts results in craniosynostosis by overactivating the phospholipase C-gamma pathway. AU - Moenning,Anne, AU - Jäger,Richard, AU - Egert,Angela, AU - Kress,Wolfram, AU - Wardelmann,Eva, AU - Schorle,Hubert, Y1 - 2008/12/01/ PY - 2008/12/3/pubmed PY - 2009/2/5/medline PY - 2008/12/3/entrez SP - 881 EP - 91 JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 29 IS - 3 N2 - The development and growth of the skull is controlled by cranial sutures, which serve as growth centers for osteogenesis by providing a pool of osteoprogenitors. These osteoprogenitors undergo intramembranous ossification by direct differentiation into osteoblasts, which synthesize the components of the extracellular bone matrix. A dysregulation of osteoblast differentiation can lead to premature fusion of sutures, resulting in an abnormal skull shape, a disease called craniosynostosis. Although several genes could be linked to craniosynostosis, the mechanisms regulating cranial suture development remain largely elusive. We have established transgenic mice conditionally expressing an autoactivated platelet-derived growth factor receptor alpha (PDGFRalpha) in neural crest cells (NCCs) and their derivatives. In these mice, premature fusion of NCC-derived sutures occurred at early postnatal stages. In vivo and in vitro experiments demonstrated enhanced proliferation of osteoprogenitors and accelerated ossification of osteoblasts. Furthermore, in osteoblasts expressing the autoactivated receptor, we detected an upregulation of the phospholipase C-gamma (PLC-gamma) pathway. Treatment of differentiating osteoblasts with a PLC-gamma-specific inhibitor prevented the mineralization of synthesized bone matrix. Thus, we show for the first time that PDGFRalpha signaling stimulates osteogenesis of NCC-derived osteoblasts by activating the PLC-gamma pathway, suggesting an involvement of this pathway in the etiology of human craniosynostosis. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/19047372/Sustained_platelet_derived_growth_factor_receptor_alpha_signaling_in_osteoblasts_results_in_craniosynostosis_by_overactivating_the_phospholipase_C_gamma_pathway_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=19047372 DB - PRIME DP - Unbound Medicine ER -