Loss of maternal calcitriol reversibly alters early offspring growth and skeletal development in mice
Sarah A Hartery1, Beth J Kirby1, Emma C Walker2
1Faculty of Medicine - Endocrinology, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6, Canada.
Abstract:
Ablation of Cyp27b1 eliminates calcitriol but does not disturb fetal mineral homeostasis or skeletal development. However, independent of fetal genotypes, maternal loss of Cyp27b1 altered fetal mineral and hormonal levels compared to offspring of WT dams. We hypothesized that these maternal influences would alter postnatal skeletal development. Cyp27b1 null and WT females were mated to bear only Cyp27b1+/- offspring. Forty-eight hours after birth, pups were cross-fostered to dams of the same or opposite genotype that bore them. Maternal and offspring samples were collected on days 21 (weaning) and 42. Offspring measurements included minerals and hormones, BMC by DXA, ash weight and mineral content, gene expression, 3-point bending tests, and microCT. Maternal lactational behavior was evaluated. Milk was analyzed for nutritional content. At day 21, offspring fostered by nulls, independent of birth dam, had ~20% lower weight, BMC, ash weight, and ash calcium than pups fostered by WT dams. Adjustment for body weight accounted for the lower BMC but not the lower ash weight and ash calcium. Hormones and serum/urine minerals did not differ across offspring groups. Offspring fostered by nulls had shorter femurs and lower cortical thickness, mean polar moment of inertia, cortical area, trabecular bone volume, and trabecular number. Dam lactational behaviors and milk nutritional content did not differ between groups. At day 42, body weight, ash weight, lengths, BMC, and tibial bone strength were no longer different between pups fostered by null vs WT dams. In summary, pups fostered by Cyp27b1 nulls, regardless of birth dam, have proportionately smaller skeletons at 21 d, impaired microstructure, but normal mineral homeostasis. The skeletal effects are largely recovered by day 42 (3 wk after weaning). In conclusion, maternal loss of calcitriol impairs early postnatal cortical bone growth and trabecular bone mass, but affected offspring catch up after weaning.
Insights
Maternal loss of calcitriol (vitamin D hormone) impairs early postnatal bone development in offspring. However, these skeletal deficits are largely recovered by weaning, indicating resilience in bone growth.
Area of Science:
- Endocrinology
- Developmental Biology
- Bone Biology
Background:
- Calcitriol, the active form of vitamin D, is crucial for mineral homeostasis and skeletal development.
- Maternal deficiency in calcitriol can impact fetal development, but its effects on postnatal skeletal growth require further investigation.
- The enzyme Cyp27b1 is essential for producing calcitriol.
Purpose of the Study:
- To investigate the impact of maternal Cyp27b1 deficiency on postnatal skeletal development in offspring.
- To determine if maternal calcitriol deficiency affects offspring bone mineral content, structure, and strength.
- To assess the recovery of skeletal parameters after weaning in offspring exposed to maternal calcitriol deficiency.
Main Methods:
- Cross-fostering experiments using Cyp27b1 null and wild-type (WT) dams and their offspring.
- Offspring skeletal assessment at weaning (day 21) and post-weaning (day 42) using DXA, microCT, and biomechanical testing.
- Analysis of offspring mineral and hormone levels, gene expression, and maternal milk composition.
Main Results:
- Offspring fostered by Cyp27b1 null dams exhibited reduced body weight, bone mineral content, and bone size at weaning.
- Impaired cortical thickness and trabecular bone microarchitecture were observed in offspring of null dams.
- Skeletal deficits were largely resolved by day 42, indicating significant catch-up growth after weaning.
Conclusions:
- Maternal loss of calcitriol impairs early postnatal skeletal growth and bone microarchitecture, independent of offspring genotype.
- Despite initial deficits, offspring demonstrate catch-up bone growth and recovery of skeletal strength post-weaning.
- This study highlights the critical role of maternal calcitriol during early development and the adaptive capacity of the offspring skeleton.
