Maternal high-cholesterol diet negatively programs offspring bone development and downregulates hedgehog signaling in osteoblasts.

Cholesterol is one of the essential intrauterine factors
required for fetal growth and development. Maternal high
cholesterol levels are known to be detrimental for offspring
health. However, its long-term effect on offspring skeletal
development remains to be elucidated. We performed our
studies in two strains of mice (C57BL6/J and Swiss Albino) and
human subjects (65 mother–female newborn dyads) to under�stand the regulation of offspring skeletal growth by maternal
high cholesterol. We found that mice offspring from high�cholesterol-fed dams had low birth weight, smaller body
length, and delayed skeletal ossification at the E18.5 embryonic
stage. Moreover, we observed that the offspring did not recover
from the reduced skeletal mass and exhibited a low bone mass
phenotype throughout their life. We attributed this effect to
reduced osteoblast cell activity with a concomitant increase in
the osteoclast cell population. Our investigation of the mo�lecular mechanism revealed that offspring from high�cholesterol-fed dams had a decrease in the expression of li�gands and proteins involved in hedgehog signaling. Further,
our cross-sectional study of human subjects showed a signifi�cant inverse correlation between maternal blood cholesterol
levels and cord blood bone formation markers. Moreover, the
bone formation markers were significantly lower in the female
newborns of hypercholesterolemic mothers compared with
mothers with normal cholesterolemic levels. Together, our
results suggest that maternal high cholesterol levels deleteri�ously program offspring bone mass and bone quality and
downregulate the hedgehog signaling pathway in their
osteoblasts.