Abstract
Angulated femurs are present prenatally both in CYP26B1 deficient humans with a reduced capacity to degrade retinoic acid (RA, the active metabolite of vitamin A), and mice overexpressing vascular endothelial growth factor a (Vegfa). Since excessive ingestion of vitamin A is known to induce spontaneous fractures and as the Vegfa-induced femur angulation in mice appears to be caused by intrauterine fractures, we analyzed bones from a CYP26B1 deficient human and rats with hypervitaminosis A to further explore Vegfa as a mechanistic link for the effect of vitamin A on bone. We show that bone from a human with CYP26B1 mutations displayed periosteal osteoclasts in piles within deep resorption pits, a pathognomonic sign of hypervitaminosis A. Analysis of the human angulated fetal femur revealed excessive bone formation in the marrow cavity and abundant blood vessels. Normal human endothelial cells showed disturbed cell-cell junctions and increased CYP26B1 and VEGFA expression upon RA exposure. Studies in rats showed increased plasma and tissue Vegfa concentrations and signs of bone marrow microhemorrhage on the first day of excess dietary vitamin A intake. Subsequently hypervitaminosis A rats displayed excess bone formation, fibrosis and an increased number of megakaryocytes in the bone marrow, which are known characteristics of Vegfa overexpression. This study supports the notion that the skeletal phenotype in CYP26B1 deficient human bone is caused by excess RA. Our findings suggest that an initial part of the vitamin A mechanism causing bone alterations is mediated by excess Vegfa and disturbed bone marrow microvessel integrity.
Highlights
In humans, biallelic mutations in CYP26B1, the gene encoding the major enzyme responsible for degradation of excess intracellular retinoic acid (RA), that lead to a substantial reduction in enzyme activity result in severe skeletal anomalies demonstrating the importance of strict regulation of intracellular RA levels for human bone health (Laue et al, 2011) The major skeletal defects were angulated femora, joint synostosis, advanced bone age and calvarial bone hypoplasia
It has been shown that mutations in the RA catabolizing enzyme CYP26B1 lead to effects on long bone development but direct evidence to implicate excessive levels of RA on bone mineralization is incomplete
We show that CYP26B1 insufficiency induces local pathological accumulation of bone resorbing osteoclasts in the periosteum, similar to that consistently observed in hypervitaminosis A
Summary
Biallelic mutations in CYP26B1, the gene encoding the major enzyme responsible for degradation of excess intracellular retinoic acid (RA), that lead to a substantial reduction in enzyme activity result in severe skeletal anomalies demonstrating the importance of strict regulation of intracellular RA levels for human bone health (Laue et al, 2011) The major skeletal defects were angulated femora, joint synostosis, advanced bone age and calvarial bone hypoplasia. Unrestricted chondrogenesis and aberrant osteoblast-osteocyte transitioning were proposed as the mechanisms behind the joint synostosis and craniosynostosis (a phenotypic feature associated with a hypomorphic CYP26B1 mutations), respectively (Laue et al, 2011). High intake and elevated serum concentrations of vitamin A in humans have been associated with an increased risk of hip fracture (Melhus et al, 1998; Michaëlsson et al, 2003).
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