Local production of parathyroid hormone-related protein (PTHrP, gene name Pthlh) is required for normal bone formation since heterozygous Pthlh null mice and mice with conditional Pthlh deletion in osteoblasts had low bone formation and were osteopenic in adulthood. In addition, Dmp1Cre.Pthlh^f/f (f/f^het) mice with conditional deletion of PTHrP in late osteoblasts and osteocytes exhibited low trabecular bone mass, impaired bone formation and reduced bone strength. These studies were carried out on mice from heterozygous breeding pairs to exclude any effect of parental genotype. Herein, we studied the influence of parental genotype on the skeleton of pups.

When f/f mice were generated from homozygote breeders (f/f^hom), they showed a phenotype opposite to the low bone mass of f/f^het mice. At 14, 16 and 26 weeks of age, male f/f^hom mice had significantly higher trabecular bone volume and number in femora (about 140% and 133% of cousin-bred Dmp1Cre+ controls (w/w), respectively, p<0.01) and L5 spine (n=9-10/group). Adult f/f^hom mice also had significantly wider femora in both mediolateral and anteroposterior dimensions (about 11% higher at 26 weeks of age), but no change in cortical thickness.

Since maternal milk PTHrP deficiency has been reported to result in increased ash calcium content of pups, we extracted genomic DNA from tissues and found that Pthlh was excised not only in long bones, but also in mammary glands of adult female f/f mice. To determine whether this might lead to a difference in the shape of f/f^hom offspring, we collected 12 day-old suckling mice. At this age, f/f^het exhibited normal bone mass, but bone width was significantly greater in f/f^hom.

These results indicate that maternal PTHrP controls trabecular bone mass, bone geometry and strength, not only of neonatal mice, but also of adult Dmp1Cre.Pthlh^f/f mice, and suggest this may result from a reduction in milk PTHrP content.