Abstract
The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (µCT) demonstrated that Aldh1a1-deficient (Aldh1a1−/−) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demonstrated significantly higher bone marrow adiposity in Aldh1a1−/− mice. In serum assays, Aldh1a1−/− mice also had higher serum IGF-1 levels. In vitro, primary Aldh1a1−/− mesenchymal stem cells (MSCs) expressed significantly higher levels of bone morphogenetic protein 2 (BMP2) and demonstrated enhanced osteoblastogenesis and adipogenesis versus WT MSCs. BMP2 was also expressed at higher levels in the femurs and tibias of Aldh1a1−/− mice with accompanying induction of BMP2-regulated responses, including expression of Runx2 and alkaline phosphatase, and Smad phosphorylation. In vitro, Rald, which accumulates in Aldh1a1−/− mice, potently induced BMP2 in WT MSCs in a retinoic acid receptor (RAR)-dependent manner, suggesting that Rald is involved in the BMP2 increases seen in Aldh1a1 deficiency in vivo. Collectively, these data implicate Aldh1a1 as a novel determinant of cortical bone density and marrow adiposity in the skeleton in vivo through modulation of BMP signaling.
Highlights
Retinoids - the products of retinol and b carotene metabolism - direct fundamental cellular processes and play a crucial role in limb patterning and skeletal development [1]
We demonstrate here that female Aldh1a12/2 mice have higher cortical bone density and greater marrow adiposity when compared to age and sex matched wild type controls (WT)
We examined Aldh1a1 expression patterns during in vitro mesenchymal stem cells (MSCs) osteoblastogenesis and adipogenesis
Summary
Retinoids - the products of retinol (vitamin A) and b carotene metabolism - direct fundamental cellular processes and play a crucial role in limb patterning and skeletal development [1]. Pre-clinical studies in rodent models linked hypervitaminosis A with skeletal abnormalities and increased bone fragility [2], while human epidemiological studies identify high retinol intake as a risk factor for hip fractures in the elderly [3,4]. Animal studies demonstrate that retinol and its main metabolite all trans retinoic acid (ATRA) consistently increase bone fragility in rodent models by reducing radial bone growth and bone density [5,6,7,8]. In vitro studies of retinoid regulation in bone cells have yielded more conflicting results. Retinoids have been reported to either induce or inhibit in vitro osteoblastogenesis and osteoclastogenesis depending on the differentiation marker examined and the cell system employed [9,10,11,12,13,14,15,16]
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