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RESEARCH SUMMARY:
Age-related bone loss is a major health problem in both men
and women. The main focus of our research has been to determine
how calcium homeostasis changes with age and how this contributes
to age-related bone loss. We have used the F344 rat as an
animal model in which to study changes in calcium homeostasis
with age. The F344 rat shows changes in calcium homeostasis
which are similar to those seen in humans.
We have investigated three major findings with regard to calcium
homeostasis in the F344 rat:
1. There is decreased capacity of 1,25-dihydroxyvitamin
D3 (1,25(OH)2D), the active metabolite of vitamin D3, to stimulate
intestinal calcium absorption with age. In both young
and adult rats, 1,25(OH)2D stimulates active calcium transport
in the duodenum as measured by in vitro assays. However, the
maximal stimulation is much less in the adult compared to
the young. With regard to mechanisms, the capacity of 1,25(OH)2D
to increase the protein levels of intestinal calbindin and
the intestinal calcium pump declines with age. These two proteins
are thought to be involved in the movement of calcium across
the intestine. However, the capacity of 1,25(OH)2D to increase
calbindin and calcium pump mRNA levels does not decline with
age. This suggests that suggests that there is an age-related
defect in the translation of these mRNAs into functional protein
in the intestine.
2. There is decreased capacity of parathyroid hormone (PTH)
to stimulate renal production of 1,25(OH)2D with age.
In the rat, PTH stimulates renal production of 1,25(OH)2D
when given to young parathyroidectomized rats but not when
given to adult rats. This effect of PTH has also been studied
in isolated renal slices. PTH stimulates production of 1,25(OH)2D
by renal slices from young rats but not in renal slices from
adult rats. With regard to mechanisms, the capacity of PTH
to increase cAMP levels and increase protein kinase A activity
does not change with age in the kidney. In addition, the capacity
of PTH to increase mRNA levels of the 1-hydroxylase enzyme,
which synthesizes the 1,25(OH)2D in the kidney, does not decline
with age. This suggests that there may be a defect in the
translation of the 1-hydroxylase mRNA into functional protein
in the kidney.
3. There is decreased sensitivity of the parathyroid glands
to serum calcium with age. Studies in rats have found
an increase in PTH secretion with age. However, it was not
clear whether this increase was due to an increase in the
set point or an increase in maximal secretion with age. To
clarify this, PTH secretion has been studied as a function
of age by incubating thyroparathyroid gland complexes in vitro.
There is no change in maximal secretion with age, but the
capacity of calcium to suppress PTH secretion declines with
age. This suggests a change in the sensitivity of the parathyroid
glands to calcium with age.
Future studies will focus on
why there is an age-related decrease in the expression of
key proteins in response to hormonal stimulation. These include
calbindin and the calcium pump in the intestine and the 1-hydroxylase
enzyme in the kidney. Possible mechanisms to be investigated
include decreased translation of mRNA, increased protein degradation,
and decreased protein functionality due to oxidative damage.
With the continuing increase
in the elderly population, these studies have growing clinical
relevance. The age-related changes in calcium homeostasis
seen in the F344 rat are also seen in humans. These changes
tend to diminish the role of dietary calcium and increase
the role of bone calcium in maintaining calcium homeostasis.
Over time, this may result in the gradual loss of calcium
from bone and an increase in the risk of bone fracture.
For a more detailed discussion
with references, see "Altered Calcium Homeostasis and
Age-Related Bone Loss" by H.J. Armbrecht in The Science
of Geriatrics (Morley et al., eds.) Serti, Paris, 2000, pp.
419-427. |
