Early life influences on skeletal growth - effects of vitamin D and mechanical loading

生命早期对骨骼生长的影响——维生素 D 和机械负荷的影响

• 批准号: MR/L002191/1
• 负责人: Stephanie Borg
• 金额: $ 35.52万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL002191%2F1
• 关键词: Early; life; influences; skeletal; growth

I propose to determine whether early life vitamin D deficiency alters later skeletal responsiveness to loading in a model system.Fractures in childhood are common and their incidence is increasing. Fractures are more common in children with smaller, narrower bones and lower bone mass for body size. Tracking of fracture risk would be a logical consequence of bone size tracking into adult life. Some studies show evidence of earlier fracture being associated with later bone size and mass. Other studies based on adult recall of childhood fracture do not support the tracking of fracture risk, but those studies recalled rates of fracture are much lower (4-5 fold) than those now reported in the UK in children. Regular loading of bone during childhood, particularly before puberty, has been shown to produce a sustained increase in bone mass and may reduce the risk of fracture both in childhood and in later life. Studies in both those participating in regular sporting activities such as gymnastics that create large strains, and in school-based exercise programmes, have shown biologically relevant increases in bone size and mass at the hip, in the spine and in the whole body. Such increases persist from childhood into post-pubertal life and have biological relevance in the prevention of adult osteoporotic disease.The contribution of vitamin D to fracture rates during childhood has been difficult to assess; a recent study of vitamin D supplementation in infancy showed a trend towards increased bone volume with higher vitamin D doses up to age 3 months. Current Department of Health advice is targeted at the prevention of rickets, rather than altering fracture risk either during childhood or later. The traditional view of vitamin D in relation to skeletal health is that it enhances the absorption of calcium. Lower calcium intake is associated with an increased risk of fracture. The roles of both diet and mechanical loading are therefore of considerable interest in respect of determining their likely contribution to skeletal health and the prevention of fracture in childhood. The timing of loading interventions is thought to be important - prepubertal loading may result in post-pubertal benefit for bone size and mass. What has not been addressed is the impact of the timing of interventions in respect of vitamin D.The suggestion that early life events could influence later growth and development was first advanced by McCance in the early 1960s. The concept has developed further and is now an established field of investigation - the Developmental Origins of Adult Health and Disease. Observational studies in humans suggest that infants of mothers with lower vitamin D levels during pregnancy may have narrower bones, and that this alteration in bone size persists into later childhood, increasing their risk of fracture. The persistence of the effects of lower vitamin D in pregnancy on the skeleton at least to age 8-9 years suggests that the normal response of the skeleton to factors likely to influence its size and shape post-natally is abrogated to some extent. The periods of pregnancy and early post-natal life represent an important opportunity for intervention that could improve skeletal health across the life course.I therefore propose to study the effect of reducing vitamin D intake during pregnancy and early life on the skeleton's response to mechanical loading using an animal model system. The study will help us understand the extent to which diet in early life affects our body's ability to respond appropriately later on, and if successful, may help us reduce the risk of fractures both in childhood and later years.

我建议在模型系统中确定早期维生素D缺乏是否会改变后来骨骼对负荷的反应。骨折更常见于骨骼较小、较窄和骨量较低的儿童。跟踪骨折风险将是骨骼尺寸跟踪到成年生活的逻辑结果。一些研究表明早期骨折与后期骨大小和质量有关。其他基于成人回忆儿童骨折的研究不支持跟踪骨折风险，但这些研究回忆的骨折率远低于英国儿童的骨折率（4-5倍）。在儿童时期，特别是青春期之前，定期对骨骼进行负荷，已被证明可持续增加骨量，并可降低儿童时期和以后生活中骨折的风险。对那些经常参加体育活动（如体操）和参加学校锻炼计划的人进行的研究表明，臀部、脊柱和全身的骨骼尺寸和质量都有生物学相关的增加。这种增加持续从童年到青春期后的生活，并在预防成人骨质疏松症的生物学意义上的贡献，维生素D的骨折率在儿童时期一直难以评估;最近的一项研究维生素D补充在婴儿期显示出增加骨体积的趋势与更高的维生素D剂量，直到年龄3个月。目前卫生部的建议是针对预防佝偻病，而不是改变儿童时期或以后的骨折风险。维生素D与骨骼健康关系的传统观点是，它可以增强钙的吸收。低钙摄入量与骨折风险增加有关。因此，饮食和机械负荷的作用在确定其对骨骼健康的可能贡献和预防儿童骨折方面具有相当大的意义。负荷干预的时机被认为是重要的-青春期前负荷可能会导致青春期后骨骼大小和质量的好处。尚未解决的是维生素D方面的干预措施的时机的影响。早期生活事件可能影响以后的生长和发育的建议是由McCance在20世纪60年代初首先提出的。这一概念得到了进一步发展，现在已成为一个既定的调查领域-成人健康和疾病的发展起源。对人类的观察性研究表明，怀孕期间维生素D水平较低的母亲所生的婴儿可能骨骼较窄，这种骨骼大小的变化持续到童年后期，增加了他们骨折的风险。怀孕期间维生素D含量较低对骨骼的影响至少持续到8-9岁，这表明骨骼对可能影响其出生后大小和形状的因素的正常反应在某种程度上被取消。怀孕期间和出生后早期的生活是一个重要的干预机会，可以改善骨骼健康的整个生命courses.I因此建议研究的影响，减少维生素D的摄入量在怀孕期间和生命早期的骨骼的机械负荷的反应，使用动物模型系统。这项研究将帮助我们了解生命早期的饮食在多大程度上影响我们身体以后做出适当反应的能力，如果成功，可能会帮助我们降低儿童和晚年骨折的风险。

项目成果

Maternal vitamin D deficiency alters later skeletal responsiveness to mechanical loading in a model system

母体维生素 D 缺乏会改变模型系统中后期骨骼对机械负荷的反应

• DOI: 10.1530/boneabs.4.oc21
• 发表时间: 2015
• 期刊: Bone Abstracts
• 作者: Borg S

Maternal vitamin D depletion disrupts neonatal skeletal development in mice

母体维生素 D 缺乏会扰乱小鼠新生儿骨骼发育

• DOI: 10.1530/boneabs.4.lb1
• 发表时间: 2015
• 期刊: Bone Abstracts
• 作者: Buckley H

Early life vitamin D depletion alters the postnatal response to skeletal loading in growing and mature bone.

早期生命维生素D耗竭改变了生长和成熟骨骼骨骼负荷的产后反应。

• DOI: 10.1371/journal.pone.0190675
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Borg SA;Buckley H;Owen R;Marin AC;Lu Y;Eyles D;Lacroix D;Reilly GC;Skerry TM;Bishop NJ
• 通讯作者: Bishop NJ

New diagnostic modalities and emerging treatments for neonatal bone disease

• DOI: 10.1016/j.earlhumdev.2018.08.014
• 发表时间: 2018-11-01
• 期刊: EARLY HUMAN DEVELOPMENT
• 影响因子: 2.5
• 作者: Borg, Stephanie A.;Bishop, Nicholas J.
• 通讯作者: Bishop, Nicholas J.

Early life vitamin D depletion and mechanical loading determine methylation changes in the RUNX2, RXRA, and osterix promoters in mice.

• DOI: 10.1186/s12263-022-00711-0
• 发表时间: 2022-05-26
• 期刊: GENES AND NUTRITION
• 影响因子: 3.5
• 作者: Krstic, Nevena;Bishop, Nick;Curtis, Beth;Cooper, Cyrus;Harvey, Nick;Lilycrop, Karen;Murray, Robert;Owen, Robert;Reilly, Gwen;Skerry, Tim;Borg, Steph
• 通讯作者: Borg, Steph