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，并将其应用于改善 肌肉骨骼组织的再生和愈合。为了这个目标，我们有了一个新的发现， 软骨细胞和成骨细胞系细胞表达被称为GIRK的离子通道，控制钾的运输 在G蛋白偶联受体激活后，跨细胞膜激活细胞内程序。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 破骨细胞。缺乏Girk2和GIRK3的动物的骨骼明显更长、更致密，这表明 当Girk2和GIRK3缺失或失活时，更多的软骨和骨形成。的中心假说 本项目是Girk2和GIRK3共同调控软骨细胞和成骨细胞的存活、增殖 和/或在软骨内骨发育过程中成熟。我们的具体目标是：1)确定Girk2 和GIRK3调节生长板软骨细胞成熟，2)确定Girk2和GIRK3如何参与 成骨细胞系成熟和骨密度，以及3)决定由Girk2和GIRK3形成的通道是否 在软骨细胞和成骨细胞中阿片类药物诱导反应所必需的。这项工作的意义在于 Girk2和GIRK3是潜在的药物靶点，其活性和/或表达可以被控制到 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.