ERK Mitogen Activated Protein Kinases in Skeletogenesis

描述（由申请人提供）：ERK有丝分裂原活化蛋白激酶（MAPK）途径与许多骨骼疾病有关。我们最近在小鼠身上进行的基因实验表明，ERK MAPK通路在调节软骨细胞分化和成骨细胞分化中起着关键作用。我们假设1)Krox20的表达是由ERK1/ERK2通过其MAPK响应元件通过含有ERK1/ERK2直接底物的DNA结合复合体调控的，2)ERK1和ERK2以细胞自主的方式调节硬骨膜/骨膜细胞的分化，3)硬骨膜/骨膜和成骨细胞中的ERK1和ERK2调节相邻骺软骨中的软骨细胞表型。我们将通过追求以下具体目标来检验这些假设：目标1。确定ERK1和ERK2调节骨骼细胞中Krox20表达的机制，目的2。确定ERK1和ERK2失活对硬骨膜/骨膜的影响是否是细胞自主的，Aim 3。确定固定成骨细胞中ERK1和ERK2的缺失如何影响骨骼发育。这些实验将为ERK1和ERK2在间充质细胞分化和骨骼发育中的作用提供新的见解。公共卫生相关性：在许多骨骼综合征中已经确定了ERK MAPK通路中分子的人类突变。本研究确定了ERK1和ERK2对骨形成的新调控机制。调控机制的确定将为控制骨质疏松症和遗传性骨骼综合征等各种骨骼疾病的骨形成提供急需的信息。

DESCRIPTION (provided by applicant): 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.