The retinol‐retinoic acid metabolic pathway is impaired in the lumbar spine of a rat model of congenital kyphoscoliosis

Abstract

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.

Spinal malformation − A biochemical analysis using congenital kyphosis rats

“…The mRNA and protein expression of TrkC in ISRs was lower than that in Wt rats by 54% and 27%, respectively 9 . Similarly, the expression of BMP‐2 mRNA and protein was lower than in Wt rats by 71% and 35%, respectively 8 . Taken together, these findings strongly suggest that the breakdown of BMP‐2‐mediated crosstalk between RA‐Rarα and NT3‐TrkC is the cause of spinal malformation (Figure 2).…”

“…7 Our study is the first to perform a DNA microarray analysis as a comprehensive analysis of the gene expression in congenital kyphosis. [8][9][10] For the DNA microarray analysis, total RNA was extracted from the third to fifth lumbar spine segments, which are the most common areas of deformity in male ISRs, on postnatal Day 4. RNA samples from ISRs and wild-type (Wt) rats were labeled with Cy3 and Cy5 fluorescent dye, respectively.…”

“…We adopted a DNA microarray for this purpose 7 . Our study is the first to perform a DNA microarray analysis as a comprehensive analysis of the gene expression in congenital kyphosis 8–10 …”

“…Furthermore, the expression of retinol metabolism‐related enzymes (alcohol dehydrogenase I [Adh1] and aldehyde dehydrogenase 1 family member A2 [Aldh 1a2]) and retinoic acid (RA) receptor α (Rarα) was significantly decreased (Table 1). 8 …”

“…Furthermore, the expression of retinol metabolismrelated enzymes (alcohol dehydrogenase I [Adh1] and aldehyde dehydrogenase 1 family member A2 [Aldh 1a2]) and retinoic acid (RA) receptor α (Rarα) was significantly decreased (Table 1). 8 RA regulates the expression of the Hox genes that control the formation of the lumbar and sacral vertebrae. 20 Hox 10 and 11 regulate the formation of the lumbar and sacral vertebrae.…”