Girk2/3 channels in cartilage biology and disease

摘要 长骨是通过软骨内骨化过程形成和修复的。我们的目标是 了解软骨内骨生长的分子机制，并应用这些知识来改善 肌肉骨骼组织再生和愈合。为了实现这个目标，我们有了一个新的发现， 软骨细胞和成骨细胞系细胞表达称为GIRKs的离子通道，控制钾离子转运 在G蛋白偶联受体激活后，穿过细胞膜并激活细胞内程序。我们 证明GIRK亚基在软骨细胞和成骨细胞系细胞中表达，但不表达GIRK亚基。 破骨细胞缺乏Girk 2和Girk 3的动物骨骼明显更长更密，这表明 当Girk 2和Girk 3缺失或失活时，软骨和骨形成更大。的中心假设 该项目是Girk 2和Girk 3协同调节软骨细胞和成骨细胞的存活、增殖 和/或在软骨内骨发育期间成熟。我们的具体目标是：1）确定Girk 2 和Girk 3调节生长板软骨细胞成熟，2）定义Girk 2和Girk 3如何有助于 成骨细胞谱系成熟和骨密度，以及3）确定由Girk 2和Girk 3形成的通道是否 软骨细胞和成骨细胞中阿片样物质诱导的反应所需。这项工作的意义在于， Girk 2和Girk 3是潜在的可药物化靶标，其活性和/或表达可以被控制以 加速长骨生长和愈合。

ABSTRACT Long bones are formed and repaired through the process of endochondral ossification. Our goal is to understand molecular mechanisms of endochondral bone growth and apply that knowledge to improve musculoskeletal tissue regeneration and healing. Towards this goal, we made the novel discovery that chondrocyte- and osteoblast-lineage cells express ion channels called GIRKs that control potassium transport across cell membranes and activate intracellular programs after activation of G-protein-coupled receptors. We demonstrate that GIRK subunits are expressed in chondrocyte- and osteoblast-lineage cells, but not osteoclasts. Animals lacking both Girk2 and Girk3 have remarkably longer and denser bones, suggesting greater cartilage and bone formation when Girk2 and Girk3 are absent or inactivated. The central hypothesis of this project is that Girk2 and Girk3 cooperate to regulate chondrocyte and osteoblast survival, proliferation and/or maturation during endochondral bone development. Our specific aims are to: 1) determine how Girk2 and Girk3 regulate growth plate chondrocyte maturation, 2) define how Girk2 and Girk3 contribute to osteoblast-lineage maturation and bone density, and 3) determine if channels formed by Girk2 and Girk3 are required for opioid-induced responses in chondrocytes and osteoblasts. The significance of this work is that Girk2 and Girk3 are potentially druggable targets whose activities and/or expression could be controlled to accelerate long bone growth and healing.