Dmp1Cre-directed knockdown of PTHrP in murine decidua is associated with increased bone width and a life-long increase in strength specific to male progeny

Abstract

AbstractParathyroid hormone related-protein (PTHrP) is a pleiotropic regulator of tissue homeostasis. In bone, knockdown in osteocytes byDmp1Cre-targeted deletion causes osteopenia and impaired strength. We report that this outcome depends on parental genotype. AdultDmp1Cre.Pthlhf/fmice from homozygous parents (Dmp1Cre.Pthlhf/f(hom)) have stronger bones, with 40% more trabecular bone mass and 30% greater femoral width than controls. At 12 days old, greater bone width was also found in male and femaleDmp1Cre.Pthlhf/f(hom)mice, but not in gene-matched mice from heterozygous parents, suggesting a maternal influence before weaning. Milk PTHrP levels were normal, but decidua from mothers ofDmp1Cre.Pthlhf/f(hom)mice were smaller, with low PTHrP levels. Moreover,Dmp1Cre.Pthlhf/f(hom)embryonic bone was more mineralized and wider than control. We conclude thatDmp1Creleads to gene recombination in decidua, and that decidual PTHrP influences decidual cell maturation and limits embryonic bone growth. This identifies a maternal-derived developmental origin of adult bone strength.