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. Project Narrative Bone is a dynamic tissue whose formation and breakdown are precisely controlled by mechanical, hormonal and growth factor stimulation. This laboratory discovered a novel pathway involving mitogen-activated protein kinase (MAPK) phosphorylation of a bone-specific gene regulatory factor known as RUNX2. This pathway links external signals to induction of a family of genes that are required for bone formation. This project seeks to gain a mechanistic understanding of this pathway by conducting detailed biochemical and genetic studies in mice. Therapeutic manipulation of the MAPK pathway has the potential to augment bone anabolic therapies such as weight-bearing exercise to prevent or reverse the deleterious effects of osteoporosis.
|Lino, Marsel; Wan, Mark H; Rocca, Antonio S et al. (2018) Diabetic Vascular Calcification Mediated by the Collagen Receptor Discoidin Domain Receptor 1 via the Phosphoinositide 3-Kinase/Akt/Runt-Related Transcription Factor 2 Signaling Axis. Arterioscler Thromb Vasc Biol 38:1878-1889|
|Ge, Chunxi; Zhao, Guisheng; Li, BinBin et al. (2018) Genetic inhibition of PPAR? S112 phosphorylation reduces bone formation and stimulates marrow adipogenesis. Bone 107:1-9|
|Ge, C; Mohamed, F; Binrayes, A et al. (2018) Selective Role of Discoidin Domain Receptor 2 in Murine Temporomandibular Joint Development and Aging. J Dent Res 97:321-328|
|Franceschi, Renny T; Ge, Chunxi (2017) Control of the Osteoblast Lineage by Mitogen-Activated Protein Kinase Signaling. Curr Mol Biol Rep 3:122-132|
|Li, Yan; Ge, Chunxi; Franceschi, Renny T (2017) MAP Kinase-Dependent RUNX2 Phosphorylation Is Necessary for Epigenetic Modification of Chromatin During Osteoblast Differentiation. J Cell Physiol 232:2427-2435|
|Mohamed, Fatma F; Franceschi, Renny T (2017) Skeletal Stem Cells: Origins, Functions and Uncertainties. Curr Mol Biol Rep 3:236-246|
|Gonzalez, Maria E; Martin, Emily E; Anwar, Talha et al. (2017) Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth. Cell Rep 18:1215-1228|
|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 PPAR? Transcription Factors. J Cell Physiol 231:587-96|
|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|
|Ge, Chunxi; Wang, Zhengyan; Zhao, Guisheng et al. (2016) Discoidin Receptor 2 Controls Bone Formation and Marrow Adipogenesis. J Bone Miner Res 31:2193-2203|
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