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Osteoblast proliferation or differentiation is regulated by relative strengths of opposing signaling pathways.
J Cell Physiol. 2008 May; 215(2):442-51.JC

Abstract

Skeletal development requires the correct balance of osteoblast proliferation, survival, and differentiation which is modulated by a network of signaling pathways and transcription factors. We have examined the role of the AKT (PKB), and ERK1/2 signaling pathways in the osteoblast response to FGFs, which inhibit differentiation, and to IGF-1 and Wnt signaling, which promote it. Using osteoblastic cell lines as well as primary calvarial osteoblasts, we show that ERK1/2 and AKT have distinct effects in FGF-induced osteoblast proliferation and differentiation. ERK1/2 is a primary mediator of FGF-induced proliferation, but also contributes to osteoblast differentiation, while AKT is important for osteoblast survival. Signaling by IGF-1, that promotes osteoblast differentiation, strongly activates AKT and weakly ERK1/2, while the opposite results are obtained with FGF, which inhibits differentiation. By introducing a constitutively active form of AKT, we found that increased AKT activity drives osteoblasts to differentiation. Increasing the AKT signal in osteoblasts that harbor FGFR2 activating mutations, found in Crouzon (342Y) and Apert (S22W) syndromes, is also able to drive differentiation in these cells, that normally fail to differentiate. Wnt signals, that promotes differentiation, also induce AKT phosphorylation, and cells expressing active AKT have increased levels of stabilized beta-catenin, a central molecule in Wnt signaling. Our results indicate that the relative strengths of ERK and AKT signaling pathways determine whether osteoblasts are driven into proliferation or differentiation, and that the effects of AKT may be due, in part, to synergy with the Wnt pathway as well as with the Runx2 transcription factor.

Authors+Show Affiliations

Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17960591

Citation

Raucci, Angela, et al. "Osteoblast Proliferation or Differentiation Is Regulated By Relative Strengths of Opposing Signaling Pathways." Journal of Cellular Physiology, vol. 215, no. 2, 2008, pp. 442-51.
Raucci A, Bellosta P, Grassi R, et al. Osteoblast proliferation or differentiation is regulated by relative strengths of opposing signaling pathways. J Cell Physiol. 2008;215(2):442-51.
Raucci, A., Bellosta, P., Grassi, R., Basilico, C., & Mansukhani, A. (2008). Osteoblast proliferation or differentiation is regulated by relative strengths of opposing signaling pathways. Journal of Cellular Physiology, 215(2), 442-51.
Raucci A, et al. Osteoblast Proliferation or Differentiation Is Regulated By Relative Strengths of Opposing Signaling Pathways. J Cell Physiol. 2008;215(2):442-51. PubMed PMID: 17960591.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Osteoblast proliferation or differentiation is regulated by relative strengths of opposing signaling pathways. AU - Raucci,Angela, AU - Bellosta,Paola, AU - Grassi,Roberta, AU - Basilico,Claudio, AU - Mansukhani,Alka, PY - 2007/10/26/pubmed PY - 2008/3/26/medline PY - 2007/10/26/entrez SP - 442 EP - 51 JF - Journal of cellular physiology JO - J. Cell. Physiol. VL - 215 IS - 2 N2 - Skeletal development requires the correct balance of osteoblast proliferation, survival, and differentiation which is modulated by a network of signaling pathways and transcription factors. We have examined the role of the AKT (PKB), and ERK1/2 signaling pathways in the osteoblast response to FGFs, which inhibit differentiation, and to IGF-1 and Wnt signaling, which promote it. Using osteoblastic cell lines as well as primary calvarial osteoblasts, we show that ERK1/2 and AKT have distinct effects in FGF-induced osteoblast proliferation and differentiation. ERK1/2 is a primary mediator of FGF-induced proliferation, but also contributes to osteoblast differentiation, while AKT is important for osteoblast survival. Signaling by IGF-1, that promotes osteoblast differentiation, strongly activates AKT and weakly ERK1/2, while the opposite results are obtained with FGF, which inhibits differentiation. By introducing a constitutively active form of AKT, we found that increased AKT activity drives osteoblasts to differentiation. Increasing the AKT signal in osteoblasts that harbor FGFR2 activating mutations, found in Crouzon (342Y) and Apert (S22W) syndromes, is also able to drive differentiation in these cells, that normally fail to differentiate. Wnt signals, that promotes differentiation, also induce AKT phosphorylation, and cells expressing active AKT have increased levels of stabilized beta-catenin, a central molecule in Wnt signaling. Our results indicate that the relative strengths of ERK and AKT signaling pathways determine whether osteoblasts are driven into proliferation or differentiation, and that the effects of AKT may be due, in part, to synergy with the Wnt pathway as well as with the Runx2 transcription factor. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/17960591/Osteoblast_proliferation_or_differentiation_is_regulated_by_relative_strengths_of_opposing_signaling_pathways_ L2 - https://doi.org/10.1002/jcp.21323 DB - PRIME DP - Unbound Medicine ER -