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FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation.
J Bone Miner Metab. 2012 Jan; 30(1):19-30.JB

Abstract

To examine the roles of FGF and ERK MAPK signaling in osteocyte differentiation and function, we performed microarray analyses using the osteocyte cell line MLO-Y4. This experiment identified a number of mineralization-related genes that were regulated by FGF2 in an ERK MAPK-dependent manner. Real-time PCR analysis indicated that FGF2 upregulates Ank, Enpp1, Mgp, Slc20a1, and Dmp1 in MLO-Y4 cells. Consistent with this observation, the selective FGF receptor inhibitor PD173074 decreased Ank, Enpp1, Slc20a1, and Dmp1 mRNA expression in mouse calvaria in organ culture. Since Dmp1 plays a central role in osteocyte differentiation and mineral homeostasis, we further analyzed FGF regulation of Dmp1. Similar to FGF2, FGF23 upregulated Dmp1 expression in MLO-Y4 cells in the presence of Klotho. Furthermore, increased extracellular phosphate levels partially inhibited FGF2-induced upregulation of Dmp1 mRNA expression, suggesting a coordinated regulation of Dmp1 expression by FGF signaling and extracellular phosphate. In MLO-Y4 osteocytes and in MC3T3E1 and primary calvaria osteoblasts, U0126 strongly inhibited both basal expression of Dmp1 mRNA and FGF2-induced upregulation. Consistent with the in vitro observations, real-time PCR and immunohistochemical analysis showed a strong decrease in Dmp1 expression in the skeletal elements of ERK1(-/-); ERK2(flox/flox); Prx1-Cre mice. Furthermore, scanning electron microscopic analysis revealed that no osteocytes with characteristic dendritic processes develop in the limbs of ERK1(-/-); ERK2 (flox/flox); Prx1-Cre mice. Collectively, our observations indicate that FGF signaling coordinately regulates mineralization-related genes in the osteoblast lineage and that ERK signaling is essential for Dmp1 expression and osteocyte differentiation.

Authors+Show Affiliations

Department of Orthopaedics, Case Western Reserve University, 2109 Adelbert Road BRB 329, Cleveland, OH 44106, 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

21678127

Citation

Kyono, Ai, et al. "FGF and ERK Signaling Coordinately Regulate Mineralization-related Genes and Play Essential Roles in Osteocyte Differentiation." Journal of Bone and Mineral Metabolism, vol. 30, no. 1, 2012, pp. 19-30.
Kyono A, Avishai N, Ouyang Z, et al. FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation. J Bone Miner Metab. 2012;30(1):19-30.
Kyono, A., Avishai, N., Ouyang, Z., Landreth, G. E., & Murakami, S. (2012). FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation. Journal of Bone and Mineral Metabolism, 30(1), 19-30. https://doi.org/10.1007/s00774-011-0288-2
Kyono A, et al. FGF and ERK Signaling Coordinately Regulate Mineralization-related Genes and Play Essential Roles in Osteocyte Differentiation. J Bone Miner Metab. 2012;30(1):19-30. PubMed PMID: 21678127.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation. AU - Kyono,Ai, AU - Avishai,Nanthawan, AU - Ouyang,Zhufeng, AU - Landreth,Gary E, AU - Murakami,Shunichi, Y1 - 2011/06/17/ PY - 2010/12/28/received PY - 2011/05/16/accepted PY - 2011/6/17/entrez PY - 2011/6/17/pubmed PY - 2012/5/15/medline SP - 19 EP - 30 JF - Journal of bone and mineral metabolism JO - J. Bone Miner. Metab. VL - 30 IS - 1 N2 - To examine the roles of FGF and ERK MAPK signaling in osteocyte differentiation and function, we performed microarray analyses using the osteocyte cell line MLO-Y4. This experiment identified a number of mineralization-related genes that were regulated by FGF2 in an ERK MAPK-dependent manner. Real-time PCR analysis indicated that FGF2 upregulates Ank, Enpp1, Mgp, Slc20a1, and Dmp1 in MLO-Y4 cells. Consistent with this observation, the selective FGF receptor inhibitor PD173074 decreased Ank, Enpp1, Slc20a1, and Dmp1 mRNA expression in mouse calvaria in organ culture. Since Dmp1 plays a central role in osteocyte differentiation and mineral homeostasis, we further analyzed FGF regulation of Dmp1. Similar to FGF2, FGF23 upregulated Dmp1 expression in MLO-Y4 cells in the presence of Klotho. Furthermore, increased extracellular phosphate levels partially inhibited FGF2-induced upregulation of Dmp1 mRNA expression, suggesting a coordinated regulation of Dmp1 expression by FGF signaling and extracellular phosphate. In MLO-Y4 osteocytes and in MC3T3E1 and primary calvaria osteoblasts, U0126 strongly inhibited both basal expression of Dmp1 mRNA and FGF2-induced upregulation. Consistent with the in vitro observations, real-time PCR and immunohistochemical analysis showed a strong decrease in Dmp1 expression in the skeletal elements of ERK1(-/-); ERK2(flox/flox); Prx1-Cre mice. Furthermore, scanning electron microscopic analysis revealed that no osteocytes with characteristic dendritic processes develop in the limbs of ERK1(-/-); ERK2 (flox/flox); Prx1-Cre mice. Collectively, our observations indicate that FGF signaling coordinately regulates mineralization-related genes in the osteoblast lineage and that ERK signaling is essential for Dmp1 expression and osteocyte differentiation. SN - 1435-5604 UR - https://www.unboundmedicine.com/medline/citation/21678127/FGF_and_ERK_signaling_coordinately_regulate_mineralization_related_genes_and_play_essential_roles_in_osteocyte_differentiation_ L2 - https://dx.doi.org/10.1007/s00774-011-0288-2 DB - PRIME DP - Unbound Medicine ER -