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Development. 2016 Dec 1;143(23):4352-4367. Epub 2016 Oct 17.

Specification of osteoblast cell fate by canonical Wnt signaling requires Bmp2.

Author information

1
Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
2
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
3
Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, Rua Talim, 330, São José dos Campos, São Paulo, CEP 12231-280, Brazil.
4
Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA Vicki_Rosen@hsdm.harvard.edu.

Abstract

Enhanced BMP or canonical Wnt (cWnt) signaling are therapeutic strategies employed to enhance bone formation and fracture repair, but the mechanisms each pathway utilizes to specify cell fate of bone-forming osteoblasts remain poorly understood. Among all BMPs expressed in bone, we find that singular deficiency of Bmp2 blocks the ability of cWnt signaling to specify osteoblasts from limb bud or bone marrow progenitors. When exposed to cWnts, Bmp2-deficient cells fail to progress through the Runx2/Osx1 checkpoint and thus do not upregulate multiple genes controlling mineral metabolism in osteoblasts. Cells lacking Bmp2 after induction of Osx1 differentiate normally in response to cWnts, suggesting that pre-Osx1+ osteoprogenitors are an essential source and a target of BMP2. Our analysis furthermore reveals Grainyhead-like 3 (Grhl3) as a transcription factor in the osteoblast gene regulatory network induced during bone development and bone repair, which acts upstream of Osx1 in a BMP2-dependent manner. The Runx2/Osx1 transition therefore receives crucial regulatory inputs from BMP2 that are not compensated for by cWnt signaling, and this is mediated at least in part by induction and activation of Grhl3.

KEYWORDS:

BMP; Dlx5; Grhl3; Mouse MLB13 cells; Osteoblast; Osx1; Sp7; Wnt

PMID:
27802170
PMCID:
PMC5201040
DOI:
10.1242/dev.136879
[Indexed for MEDLINE]
Free PMC Article

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