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Immediate effects of retinoic acid on gene expression in primary murine osteoblasts

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Abstract

Consistent with clinical observations demonstrating that hypervitaminosis A is associated with increased skeletal fracture risk, we have previously found that dietary retinol deprivation partially corrects the bone mineralization defects in a mouse model of X-linked hypophosphatemic rickets. That retinol-dependent signaling pathways impact the skeleton is further supported by various findings demonstrating a negative influence of retinoic acid (RA) on bone-forming osteoblasts. We hypothesized that RA would directly regulate the expression of specific target genes in osteoblasts, and we aimed to identify these by genome-wide expression analyses. Here we show that high dietary retinol intake in mice causes low bone mass associated with increased osteoclastogenesis and decreased osteoblastogenesis, but intact bone matrix mineralization. We additionally found that short-term treatment of primary osteoblasts with RA causes a rapid induction of specific genes involved in either retinol-dependent signaling (i.e. Rara, Crabp2) or skeletal remodeling (i.e. Twist2, Tnfsf11). In contrast, neither expression of established osteoblast differentiation markers nor the proliferation rate was immediately affected by RA administration. Collectively, our data suggest that the negative effects of vitamin A on skeletal integrity are explainable by an immediate influence of RA signaling on specific genes in osteoblasts that in turn influence bone remodeling.

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Acknowledgments

This work was supported by the German Federal Ministry of Education and Research within the framework of the project “Molecular Pathology of Osteoporosis” (OsteoPath).

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All authors have no conflicts of interest.

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    Authors and Affiliations

    1. Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg, Germany

      Timur A. Yorgan, Timo Heckt, Carsten Rendenbach, Christina Helmis, Sebastian Seitz, Michael Amling & Thorsten Schinke

    2. Department of Clinical Chemistry, University Medical Center Hamburg Eppendorf, Hamburg, Germany

      Thomas Streichert

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    1. Timur A. Yorgan
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    Correspondence to Thorsten Schinke.

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    T. Yorgan, T. Heckt and C. Rendenbach contributed equally to this work.

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    Supplementary material 1 (PDF 17 kb) Supplementary Table 1. ATRA-induced genes in primary osteoblasts. The results of genome-wide expression analysis in primary osteoblasts following treatment with ATRA for 6 h are shown. The signal intensities and the logarithmic ratios of signal intensities (signal log ratio, SLR) are given. The table includes all genes with a signal intensity >100 and an SLR >2.0

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    Yorgan, T.A., Heckt, T., Rendenbach, C. et al. Immediate effects of retinoic acid on gene expression in primary murine osteoblasts. J Bone Miner Metab 34, 161–170 (2016). https://doi.org/10.1007/s00774-015-0666-2

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