Role of Mineral Nutrition in Neonatal Bone Health: Effects on Porcine Mesenchymal Stem Cells
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2009-12-03
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MAHAJAN, AVANIKA. Role of Mineral Nutrition in Neonatal Bone Health: Effects on
Porcine Mesenchymal Stem Cells. (Under the direction of Chad H. Stahl).
Both calcium and phosphorus tremendously impact bone health, and their deficiencies are
associated with reduced bone parameters in growing mammals due to altered levels of
calcitropic hormones (Parathyroid hormone (PTH) and 1,25(OH)2D3). However, effects of
mineral deficiency on bone during the neonatal period are less characterized. Mesenchymal
stem cell (MSC) differentiation into osteoblasts and adipocytes is a major determinant of
bone quality and quantity. The aim of this research was to examine the effects of mineral
nutrition and calcitropic hormones on MSC activity, bone parameters and gene expression
during the neonatal period using pig as the model system. In the first study, 1,25(OH)2D3 was
found to stimulate adipocytic differentiation of MSC isolated from 2-week old piglet based
on dose-dependent increase in adipogenic (PPARG, LPL and AP2) expression and lipid accumulation (Oil Red O staining) in cells treated in vitro for a period of 12 days. A trend for reduced Runx2 (osteogenic transcription factor) expression and a significant reduction in
alkaline phosphatase (ALP) activity suggested inhibition of osteogenesis, however, the
effects were unclear due to a dose-dependent increase in osteogenic marker osteocalcin
expression with 1,25(OH)2D3. Stimulatory effects of 1,25(OH)2D3 were also found to be
altered in the presence of physiologically relevant electrical stimulation. Elevated levels of 1,25(OH)2D3 during P deficiency seen in older animals could impact bone by altering MSC
activity. In the second study, dietary P deficiency during the neonatal period (d0-d15)
resulted in dramatically reduced in vivo MSC proliferation accompanied by increased
adipogenic markers (PPARG and LPL) and reduced osteocalcin expression in the bone
marrow. Although the reduction in growth performance, bone growth and reduced PTH
levels associated with classical P deficiency were observed, unlike older animals, circulating
levels of 1,25(OH)2D3 did not change. The reduced PTH levels seen with P deficiency could
impact MSC activity. In the third study, PTH was found to alter MSC activity depending on
the mode of treatment as it caused increased adipogenic expression (PPARG, LPL) and lipid
accumulation (Oil Red O) with continuous treatment and increased osteogenic expression
(ALP, Runx2) and ALP activity by both continuous and intermittent treatment. Also, PTH
and 1,25(OH)2D3 acted antagonistically when added together as the ability of 1,25(OH)2D3 to
stimulate adipogenesis was partly inhibited by PTH while the ability of PTH to cause
osteogenic expression was partly inhibited by 1,25(OH)2D3. Since both calcitropic hormones
affect MSC activity, dietary calcium deficiency may alter developmental programming of
bone during the neonatal period. In the fourth study, dietary Ca deficiency during neonatal
period (d0-d18) caused a dramatic reduction in the in vivo MSC proliferation. Although bone
quality and quantity were significantly reduced, unlike older animals, the circulating levels of
Ca, P and 1,25(OH)2D3 were unaltered and PTH levels were increased only by end of the
study with calcium deficiency. In vitro studies utilizing homologous sera demonstrated that
MSC activity was affected by both the calcium status of the animal and the sera, as well as
by their interaction Altered MSC activity maybe attributed to one or more of the 22
differentially expressed serum proteins identified by proteomic analysis of homologous sera. Overall, the data from these studies indicates that neonatal mineral nutrition is crucial for bone integrity and suggests that early life Ca and P restriction may have long-term effects on bone integrity via programming of MSC. Also, the circulating levels of calcitropic hormones may affect in vivo bone development based on their ability to alter MSC differentiation potential in vitro as seen in these studies.
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parathyroid hormone, phosphorus, vitamin D, calcium, neonate, pig, adipocytes, osteoblasts
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Degree
PhD
Discipline
Animal Science
Poultry Science
Poultry Science
