Parathyroid hormone related-protein (PTHrP; gene: Pthlh) acts as an autocrine/paracrine factor to maintain homeostasis of many tissues. Adult mice with conditional deletion of PTHrP in osteocytes, Dmp1Cre.Pthlhf/f (f/f), showed bone loss and fragility, indicating that osteocytic PTHrP is required for maintenance of bone during remodeling. These studies were carried out on mice from heterozygous breeders to exclude any effect of parental genotype. We reported previously at this meeting that adult male f/f mice from homozygous breeders (f/fhom) show a phenotype different from the above heterozygous-bred mice. Here, we report that this phenotype arises in utero, and depends on the parental genotype.
At 14, 16 and 26 weeks of age, male (but not female) f/fhom mice had higher trabecular bone volume in femora (~140% of controls). Male f/fhom mice also had wider femora (50% increase in moment of inertia), but no change in bone length or cortical thickness.
Since Dmp1Cre is expressed in mammary glands, we determined whether this arose in suckling pups, and assessed PTHrP levels in the milk of f/f dams. We then determined whether the phenotype arose in utero. Both male and female f/fhom suckling mice had wider long bones than controls at 12 days of age. This was also observed as early as embryonic day 18.5 when male and female f/fhom embryos had more mineralized and significantly (~10%) wider femora than controls but normal bone length, and normal body weight. While maternal milk PTHrP levels were unchanged, samples containing placenta and decidua from f/f dams had significantly lower PTHrP mRNA levels than controls (57% less, n=6/group).
We conclude that maternal PTHrP limits fetal radial bone growth. This effect became sex-specific after puberty; only adult male mice retained wide long bones, indicating that parental PTHrP overrides the bone loss caused by loss of local osteocytic PTHrP action.