High dietary intake of retinol leads to bone marrow hypoxia and diaphyseal endosteal mineralization in rats

Lind, Thomas; Lind, P. Monica; Jacobson, Annica; Hu, Lijuan; Sundqvist, Anders; Risteli, Juha; Yebra‐Rodríguez, África; Rodríguez‐Navarro, Alejandro B.; Andersson, Göran; Melhus, Håkan

doi:10.1016/j.bone.2010.10.169

Cited by 52 publications

(86 citation statements)

References 52 publications

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“…These different paradigms for bone fragility may help explain some of the differing outcomes in studies evaluating vitamin A intake and fracture risk. In support of this view, a recent hypervitaminosis A study in rodents has suggested that increased bone fragility associated with thinning of cortical bone may occur with little decrease in bone mass (61).…”

Section: Discussionmentioning

confidence: 68%

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

Conaway

Pirhayati

Persson

et al. 2011

Journal of Biological Chemistry

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Increased vitamin A (retinol) intake has been suggested to increase bone fragility. In the present study, we investigated effects of retinoids on bone resorption in cultured neonatal mouse calvarial bones and their interaction with glucocorticoids (GC). All-trans-retinoic acid (ATRA), retinol, retinalaldehyde, and 9-cis-retinoic acid stimulated release of 45 Ca from calvarial bones. The resorptive effect of ATRA was characterized by mRNA expression of genes associated with osteoclast differentiation, enhanced osteoclast number, and bone matrix degradation. In addition, the RANKL/OPG ratio was increased by ATRA, release of 45 Ca stimulated by ATRA was blocked by exogenous OPG, and mRNA expression of genes associated with bone formation was decreased by ATRA. All retinoid acid receptors (RAR␣/␤/␥) were expressed in calvarial bones. Agonists with affinity to all receptor subtypes or specifically to RAR␣ enhanced the release of 45 Ca and mRNA expression of Rankl, whereas agonists with affinity to RAR␤/␥ or RAR␥ had no effects. Stimulation of Rankl mRNA by ATRA was competitively inhibited by the RAR␣ antagonist GR110. Exposure of calvarial bones to GC inhibited the stimulatory effects of ATRA on 45 Ca release and Rankl mRNA and protein expression. This inhibitory effect was reversed by the glucocorticoid receptor (GR) antagonist RU 486. Increased Rankl mRNA stimulated by ATRA was also blocked by GC in calvarial bones from mice with a GR mutation that blocks dimerization (GR dim mice). The data suggest that ATRA enhances periosteal bone resorption by increasing the RANKL/OPG ratio via RAR␣ receptors, a response that can be inhibited by monomeric GR.

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Section: Discussionmentioning

confidence: 68%

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

Conaway

Pirhayati

Persson

et al. 2011

Journal of Biological Chemistry

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“…The necessity of understanding these is increasing with the usage of nutritional vitamin supplements containing vitamin A, as there is clinical evidence that hypervitaminosis A is associated with increased fracture risk in humans [14][15][16]. A negative influence of retinoids on skeletal integrity has also been reported in various animal studies, most of them demonstrating that increased periostal bone resorption is an underlying cause [7,[37][38][39]. Since similar observations were made in organ cultures, it was hypothesized that osteoclasts are the main cells responsible for the effects of retinoids on bone [40][41][42][43][44].…”

Section: Discussionmentioning

confidence: 95%

“…Despite the fact that various effects of vitamin A on skeletal development and remodeling have been described over recent decades, the underlying mechanisms have not been fully clarified to date [7,[37][38][39]. The necessity of understanding these is increasing with the usage of nutritional vitamin supplements containing vitamin A, as there is clinical evidence that hypervitaminosis A is associated with increased fracture risk in humans [14][15][16].…”

Section: Discussionmentioning

confidence: 95%

“…Second, there was an induction of Tnfsf11 expression with a simultaneous repression of Tnfrsf11b expression. Although the kinetics of these latter regulations suggests that they rather represent secondary transcriptional events, they provide a likely explanation for the increased osteoclastogenesis observed in animals with hypervitaminosis A [7,[37][38][39]. More specifically, the proosteoclastogenic cytokine Rankl (encoded by the Tnfsf11 gene) is generally considered to represent the major positive regulator of bone resorption in mice and humans, and a monoclonal antibody neutralizing RANKL has been established for the treatment of osteoporosis [50,51].…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2015

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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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“…Furthermore, in a recent one week study where rats were fed increased vitamin A, increased cortical osteoclasts and cortical bone thinning were also observed; however, in these animals, endosteal osteoclasts disappeared because of impaired endosteal/marrow blood flow, which resulted in hypoxia and pathological endosteal mineralization [Lind et al 2011]. This resulted in thinner, more brittle bones with little apparent affect on bone mass.…”

Section: Retinoids and Bone Resorption In Vivomentioning

confidence: 96%

Retinoids and Bone

Conaway¹,

Lerner²

2011

Contemporary Aspects of Endocrinology

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High dietary intake of retinol leads to bone marrow hypoxia and diaphyseal endosteal mineralization in rats

Cited by 52 publications

References 52 publications

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

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

Retinoids and Bone

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