The ERK mitogen activated protein kinases (MAPK) pathway has been implicated in a number of skeletal disorders. Our recent genetic experiments in mice have indicated that the ERK MAPK pathway plays critical roles in the regulation of chondrocyte differentiation and osteoblast differentiation. We hypothesize that 1) Krox20 expression is regulated by ERK1/ERK2 through its MAPK response element via DNA binding complex containing direct ERK1/ERK2 substrates, 2) ERK1 and ERK2 regulate differentiation of perichondrial/periosteal cells in a cell autonomous manner, 3) ERK1 and ERK2 in the perichondrium/periosteum and osteoblasts regulate chondrocyte phenotype in the adjacent epiphyseal cartilage. We will test these hypotheses by pursuing the following Specific Aims:
Aim 1. Identify mechanisms whereby ERK1 and ERK2 regulate Krox20 expression in skeletal cells, Aim 2. Determine whether the effect of ERK1 and ERK2 inactivation on the perichondrium/periosteum is cell autonomous, Aim 3. Determine how loss of ERK1 and ERK2 in committed osteoblasts affects skeletal development. These experiments will provide novel insights into the roles of ERK1 and ERK2 in mesenchymal cell differentiation and skeletal development.

Public Health Relevance

Human mutations in the molecules in the ERK MAPK pathway have been identified in a number of skeletal syndromes. This study identifies novel regulatory mechanisms of bone formation by ERK1 and ERK2. The identification of the regulatory mechanisms will provide much needed information for controlling bone formation in various skeletal disorders such as osteoporosis and genetic skeletal syndromes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055556-04
Application #
8289660
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Tyree, Bernadette
Project Start
2009-08-10
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$335,729
Indirect Cost
$121,889
Name
Case Western Reserve University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Kyono, Ai; Avishai, Nanthawan; Ouyang, Zhufeng et al. (2012) FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation. J Bone Miner Metab 30:19-30
Sebastian, Arjun; Matsushita, Takehiko; Kawanami, Aya et al. (2011) Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal. J Orthop Res 29:375-9
Krejci, Pavel; Murakami, Shunichi; Prochazkova, Jirina et al. (2010) NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells. J Biol Chem 285:20644-53
Matsushita, Takehiko; Chan, Yuk Yu; Kawanami, Aya et al. (2009) Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol Cell Biol 29:5843-57