Department of Orthopedic Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
J Cell Biochem. 2019 Sep;120(9):15007-15017. doi: 10.1002/jcb.28762. Epub 2019 May 5.
Although congenital scoliosis is defined as a genetic disease characterized by a congenital and abnormal curvature of the spinal vertebrae, our knowledge of the genetic underpinnings of the disease is insufficient. We herein show that the downregulation of the retinol-retinoic acid metabolism pathway is involved in the pathogenesis of congenital scoliosis. By analyzing DNA microarray data, we found that the expression levels of genes associated with the retinol metabolism pathway were decreased in the lumbar spine of Ishibashi rats (IS), a rat model of congenital kyphoscoliosis. The expression of Adh1 and Aldh1a2 (alcohol dehydrogenase), two enzymes that convert retinol to retinoic acid in this pathway, were decreased at both the gene and protein levels. Rarα, a receptor of retinoic acid and bone morphogenetic protein 2, which play a central role in bone formation and are located downstream of this pathway, were also downregulated. Interestingly, the serum retinol levels of IS rats were higher than those of wild-type control rats. These results indicate that the adequate conversion from retinol to retinoic acid is extremely important in the regulation of normal bone formation and it may also be a key factor for understanding the pathogenesis of congenital scoliosis.
虽然先天性脊柱侧凸被定义为一种以脊柱先天性和异常弯曲为特征的遗传病，但我们对该病遗传基础的了解还不够。我们在此表明，视黄醇-视黄酸代谢途径的下调与先天性脊柱侧凸的发病机制有关。通过分析 DNA 微阵列数据，我们发现 Ishibashi 大鼠（IS），一种先天性脊柱后凸的大鼠模型，其腰椎中与视黄醇代谢途径相关的基因表达水平降低。该途径中两个将视黄醇转化为视黄酸的酶 Adh1 和 Aldh1a2（醇脱氢酶）的基因和蛋白表达均降低。视黄酸和骨形态发生蛋白 2 的受体 Rarα也下调，这两种物质在骨形成中起核心作用，位于该途径的下游。有趣的是，IS 大鼠的血清视黄醇水平高于野生型对照大鼠。这些结果表明，视黄醇向视黄酸的充分转化对视黄醇在正常骨形成中的调节至关重要，它可能也是理解先天性脊柱侧凸发病机制的关键因素。
