Genome wide screening of human growth plates during early and progressed stage puberty in one patient

In progressed puberty, estrogen is responsible for the deceleration of growth by stimulating growth plate maturation. The mechanism of action is largely unknown. We obtained pubertal growth plate specimens of the same girl at Tanner stage B2 and Tanner stage B3, which allowed us to address this issue in more detail. Histological analysis showed that progression of puberty coincided with characteristic morphological changes associated with growth plate maturation, such as decreases in total growth plate height (p=0.002), height of the individual zones (p<0.001) and a increase in intercolumnar space (p<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated, 28% downregulated) changing with progression of puberty. Overall changes in gene expression were small (average 1.1 fold change). The 394 genes mapped to 13 significantly changing pathways (p<0.05) in majority belonging to extracellular matrix, cell cycle and cell death, which are all related to growth plate maturation. We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionary conserved binding sites for transcription factors implemented in growth plate maturation such as Estrogen Receptor, Androgen Receptor, Elk1, Stat5b, CREBP and Runx2. Runx2 and Elk1, but not estrogen receptor binding sites were enriched and were present in 87 and 43 out of the 394 genes, respectively.In conclusion, our data suggest a role for Runx2 and Elk1 in growth plate maturation and provides suggestive evidence that the effect of estrogen on growth plate maturation is not mediated by activating genomic estrogen signalling in growth plate chondrocytes.

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Emons J, Dutilh BE, Decker E, Pirzer H, Sticht C, Gretz N, Rappold G, Cameron ER, Neil JC, Stein GS, van Wijnen AJ, Wit JM, Post JN, Karperien M