Martin, T. J. | Search bioRxiv

bioRxiv2020

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

Parathyroid hormone related-protein (PTHrP) is a pleiotropic regulator of tissue homeostasis. In bone, knockdown in osteocytes by Dmp1Cre-targeted deletion causes osteopenia and impaired strength. We report that this outcome depends on parental genotype. Adult Dmp1Cre.Pthlhf/f mice 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 female Dmp1Cre.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 of Dmp1Cre.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 that Dmp1Cre leads 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.

cell biology↗

bioRxiv2018

Increased autophagy in ephrinB2 deficient osteocytes is associated with hypermineralized, brittle bones

Mineralized bone forms when collagen-containing osteoid accrues hydroxyapatite crystals. This process has two phases: a rapid initiation (primary mineralization), followed by slower accrual of mineral (secondary mineralization) that continues until that portion of bone is renewed by remodelling. Within the bone matrix is an interconnected network of cells termed osteocytes. These cells are derived from bone-forming osteoblasts. Osteoblast differentiation requires expression of ephrinB2, and we were intrigued about why ephrinB2 continues to be expressed in mature osteocytes. To determine its function in osteocytes, we developed an osteocyte-specific ephrinB2 null mouse and found they exhibited a brittle bone phenotype. This was not caused by a change in bone mass, but by an intrinsic defect in the strength of the bone material. Although the initiation of osteoid mineralization occurred at a normal rate, the process of secondary mineralization was accelerated in these mice. The maturing mineralized bone matrix incorporated mineral and carbonate more rapidly than controls, indicating that osteocytic ephrinB2 suppresses mineral accumulation in bone. No known regulators of mineralization were modified in the bone of these mice. However, RNA sequencing showed differential expression of a group of autophagy-associated genes, and increased autophagic flux was confirmed in ephrinB2 knockdown osteocytes. This indicates that the process of secondary mineralization in bone makes use of autophagic machinery in a manner that is limited by ephrinB2 in osteocytes, and that this process may be disrupted in conditions of bone fragility.

cell biology↗