Understanding skeletal development across the life course

Abstract

Health can be influenced by a number of factors and there is evidence to suggest that environmental cues during early-life stages greatly affect disease susceptibility in adulthood. Incidences of bone disease are becoming increasingly prevalent and it is believed that bone health in later life may be determined during foetal and neonatal stages. Currently, surrogate measures of bone strength (bone mineral density and content) are used to assess the risk to fracture, but are acknowledged to predict only a proportion of clinical cases. Therefore, it is important to understand and develop supplementary fracture risk to augment traditional tools.

There has been difficulty in characterising the mechanical strength and toughness of bone due to the complexity of the hierarchical structure and compositional material properties. The bone quality framework describes the material and structural contributions to bone mechanical performance and hence utilisation of parameters associated with these contributors, alongside conventional bone mass measurements through densitometry, may improve the accuracy of fracture risk assessment. A myriad of factors have been suggested to affect bone health and therefore the current challenge is to identify the most influential. At present, there lacks a model that fully describes how material and structural factors act together throughout the bone hierarchy to affect the mechanical properties and fracture toughness of a whole bone, as well as how environmental factors may adapt these features.

Within this project the relationship between biological alterations in bone formation and how this adapts material and microscale architecture are explored, with a view to assess the effect on whole bone mechanics. An initial pilot study on the effect of maternal low dietary protein during pregnancy on second generation female rat bone health was conducted to establish methodological protocol. Specifically, this project investigated the effect of maternal vitamin D, a known contributory factor in bone health, on offspring skeletal development and health. It was hypothesised that cellular activity can influence organ-level bone properties through control of the bone matrix and that subtle environmental assaults, such as low maternal protein or vitamin D, can alter this highly regulated process. Results from measuring bone i) gene expression, ii) micromechanics, iii) composition, iv) architecture, v) fracture toughness and vi) whole-bone mechanics in murine models have shown increased expression levels to be significantly correlated to an increase in microindentation distances at multiple locations along the femur and a reduction in cortical bone thickness and mechanical competence at the femur diaphysis. In particular, Runx2 expression was indicative of bone structure and mechanics, emphasising the importance of exploring the link between biological and mechanical bone environments further to understanding skeletal development and health.

Investigation into the effect of maternal low protein status during pregnancy on female second generation offspring bone health health at 70 days of age demonstrated no significant differences between low protein background and control rats. Although a trend of lower mean osteogenic gene expression levels, lower mean fracture toughness, lower mean maximum load in whole bone mechanical testing and increased micromechanical indentation distances were observed in low protein animals, no significance was reached suggesting no persistent change is present from grand-maternal dietary protein status in second generation offspring. The effect of vitamin D deficiency during in utero life on offspring bone development was subsequently assessed using this multi-disciplinary experiment strategy in rats. Although the importance of vitamin D in childhood and adulthood bone health is established, the role of vitamin D in utero towards post-birth bone health remains contentious. Vitamin D deficient offspring at 21 days of age (childhood) were observed to have reduced diaphyseal cross section area and reduced mechanical capability in males. No further differences were found in gene expression, composition or material properties and no differences were identified in females. At 140 days of age (adulthood), negligible differences were found between control and vitamin D depleted animals in any bone health outcomes.

These results indicate vitamin D depletion during in utero life has limited impact on skeletal health of rats at 140 days old. Critically, the detrimental effects of bone caused by vitamin D depletion at 21 days of age in male rats appears to have been recovered in adulthood after resuming a vitamin D sufficient diet after birth. Therefore, these results suggest vitamin D suffciency during childhood is essential for skeletal development. In summary, these results highlight the importance of the relationship between bone biological mechanisms and bone structure/mechanics across different length scales. Appreciation of this link enables comprehension of how skeletal development is established and the consequent effect of any challenges caused by disease. Furthermore, uncovering the aetiology of bone disease will enable the development of improved prophylactic measures, diagnosis and therapeutic strategies

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Identifiers

ORCID for Philipp Thurner: orcid.org/0000-0001-7588-9041

ORCID for Stuart Lanham: orcid.org/0000-0002-4516-264X

ORCID for Richard Oreffo: orcid.org/0000-0001-5995-6726

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