Perinatal Exposure to Vitamin A Differentially Regulates Chondrocyte Growth and the Expression of Aggrecan and Matrix Metalloprotein Genes in the Femur of Neonatal Rats

Abstract

Vitamin A (VA) and its active form, retinoic acid (RA), are regulators of skeletal development. In the present study, we investigated if maternal VA intake during pregnancy and lactation, as well as direct oral supplementation of neonates with VA + RA (VARA) in early life, alters neonatal bone formation and chondrocyte gene expression. Offspring of dams fed 3 levels of VA (marginal, adequate, and supplemented) for 10 wk were studied at birth (P0) and postnatal day 7 (P7). One-half of the newborns received an oral supplement of VARA on P1, P4, and P7. Tissues were collected on P0 and 6 h after the last dose on P7. Pup plasma and liver retinol concentrations were increased by both maternal VA intake and VARA (P < 0.01). Although maternal VA did not affect bone mineralization as assessed by von Kossa staining, newborn femur length was increased with maternal VA (P < 0.05). VARA supplementation of neonates increased the length of the hypertrophic zone only in VA-marginal pups, close to that in neonates from VA-adequate dams, suggesting VARA caused a catching up of growth that was limited by low maternal VA intake. Maternal diet did not alter type X nor type II collagen mRNA. However, VARA-treated pups from VA-supplemented dams had reduced mRNA for aggrecan, a major component of cartilage matrix, and increased mRNA for matrix metalloproteinase (MMP)13, which catalyzes the degradation of aggrecan and collagens. These results suggest that moderately high maternal VA intake combined with neonatal VARA supplementation can reduce the ratio of aggrecan:MMP, which may unfavorably alter early bone development.

Ubiquitination is associated with lysosomal degradation of cell surface-resident ATP-binding cassette transporter A1 (ABCA1) through the endosomal sorting complex required for transport (ESCRT) pathway

“…This suggests that the vulnerable period regarding maternal diet is the period of lactation when VA is transferred in milk to the nursling pups. In recent studies, we have shown that milk total retinol is increased ∼sixfold in the dams fed VA‐supplemented diet, while plasma retinol is also significantly elevated in the pups of VA‐supplemented dams, and nearly doubled after treatment with VARA, regardless of the level of VA in the mother's diet [Zhang and Ross, 2012]. MafB expression also was increased in vivo in a similar dose‐ and time‐dependent manner by RA.…”

Myeloid Zinc Finger 1 (MZF‐1) Regulates Expression of the CCN2/CTGF and CCN3/NOV Genes in the Hematopoietic Compartment

“…Stimulation of marrow stromal cells by ATRA increases their production and secretion of macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), of which GM-CSF has been shown to increase expression of both MZF-1 and CCN3 (Nakajima et al, 1994;Hui et al, 1995;Kimura et al, 2009). Treatment with ATRA causes hypertrophy and terminal differentiation of chondrocytes, and interestingly increases their MMP-13 expression (Oettinger and Pacifici, 1990;Iwamoto et al, 1993;Yasuhara et al, 2010;Zhang et al, 2012). Calcitriol has also been shown to enhance markers of chondrocyte differentiation and activity including BMP-7, Vitamin D receptor, and the previously mentioned FGF-23 (Sanchez and He, 2007).…”

Retinoic acid and the transcription factor MafB act together and differentially to regulate aggrecan and matrix metalloproteinase gene expression in neonatal chondrocytes

“…We next asked whether MafB expression in bone was affected by maternal VA status or by direct oral supplementation with VARA, a combination of VA and RA [Ross et al, 2006]. In a recent study [Zhang and Ross, 2012], we have shown that the varying the VA content of the mother's diet during pregnancy results in different levels of tissue VA in their P0 neonates: the livers of pups from VA‐marginal, VA‐adequate, and VA‐supplemented dams equaled 20 ± 2.1, 32 ± 4.2, and 121 ± 17 nmol/g tissue, respectively, all of which differed ( P < 0.05) from each other. Plasma retinol also differed significantly between P0 neonates from the VA‐supplemented mothers (1.26 ± 0.07 µM) and pups from either the VA‐marginal or VA‐adequate dams (0.81 ± 0.04 and 0.94 ± 0.02 µM).…”

“…For all pups that were supplemented directly with VARA, both liver and plasma retinol were increased significantly, but to the same extent for each maternal diet. Liver total retinol increased by approximately 400 nmol/g and plasma retinol by 2 µM as a result of direct treatment with VARA [Zhang and Ross, 2012].…”