The extracellular signal-regulated kinase (ERK)/MAP kinase pathway is a major control point for mesenchymal differentiation. In bone, this pathway is a major conduit for conveying information about the extracellular environment to the nucleus and has been implicated in the response of bone to a variety of signals including cell adhesion, hormone/growth factor stimulation and mechanical loading. As shown by this laboratory, ERK/MAPK signaling is necessary for osteoblast differentiation and in vivo skeletal development. Furthermore, actions of this pathway on osteoblast differentiation are mediated by phosphorylation and activation of the bone-related transcription factor, RUNX2, at 2 critical serine residues. Goals for this renewal are to understand how phosphorylation controls RUNX2 transcriptional activity and establish the physiological significance of MAPK signaling and RUNX2 phosphorylation during development and post-natal life.
Aims are: 1. Establish the importance of MAPK phosphorylation to the biological activity of RUNX2 in vitro and the underlying mechanism of transcriptional activation. 2. Evaluate the role of the ERK/MAPK pathway in osteoblast/osteocyte function in adult mice. 3. Evalulate the in vivo role of RUNX2 phosphorylation in skeletal development and homeostasis. These studies will establish the significance of a novel pathway for controlling gene expression in bone. Mechanisms defined in this project have the potential to explain how bone responds to a number of primary extracellular stimuli including ECM and mechanical signals and may serve as the basis for new therapeutic approaches targeting MAPK signaling.7.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011723-14
Application #
8015287
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Wan, Jason
Project Start
1995-09-01
Project End
2012-11-30
Budget Start
2011-02-01
Budget End
2012-11-30
Support Year
14
Fiscal Year
2011
Total Cost
$382,545
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Stechschulte, Lance A; Ge, Chunxi; Hinds Jr, Terry D et al. (2016) Protein Phosphatase PP5 Controls Bone Mass and the Negative Effects of Rosiglitazone on Bone through Reciprocal Regulation of PPARγ (Peroxisome Proliferator-activated Receptor γ) and RUNX2 (Runt-related Transcription Factor 2). J Biol Chem 291:24475-24486
Ge, Chunxi; Cawthorn, William P; Li, Yan et al. (2016) Reciprocal Control of Osteogenic and Adipogenic Differentiation by ERK/MAP Kinase Phosphorylation of Runx2 and PPARγ Transcription Factors. J Cell Physiol 231:587-96
Li, Yan; Ge, Chunxi; Franceschi, Renny T (2016) MAP Kinase-Dependent RUNX2 Phosphorylation Is Necessary for Epigenetic Modification of Chromatin During Osteoblast Differentiation. J Cell Physiol :
Ge, C; Zhao, G; Li, Y et al. (2016) Role of Runx2 phosphorylation in prostate cancer and association with metastatic disease. Oncogene 35:366-76
Lee, Eunsohl; Wang, Jingcheng; Yumoto, Kenji et al. (2016) DNMT1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cells, Which Promotes Prostate Cancer Metastasis. Neoplasia 18:553-66
Park, Y; Hosomichi, J; Ge, C et al. (2015) Immortalization and characterization of mouse temporomandibular joint disc cell clones with capacity for multi-lineage differentiation. Osteoarthritis Cartilage 23:1532-42
McElderry, John-David P; Zhao, Guisheng; Khmaladze, Alexander et al. (2013) Tracking circadian rhythms of bone mineral deposition in murine calvarial organ cultures. J Bone Miner Res 28:1846-54
Danciu, Theodora E; Li, Yan; Koh, Amy et al. (2012) The basic helix loop helix transcription factor Twist1 is a novel regulator of ATF4 in osteoblasts. J Cell Biochem 113:70-9
Wang, Weizhuo; Olson, Douglas; Liang, Gang et al. (2012) Collagen XXIV (Col24α1) promotes osteoblastic differentiation and mineralization through TGF-β/Smads signaling pathway. Int J Biol Sci 8:1310-22

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