Spaceflight and the rodent skeleton: A perspective

Adaptations to extreme environments, such as spaceflight, are often studied using model organisms. Beyond basic science goals, validated model organisms are used to better understand human responses. The skeleton, the topic of this perspective, is an important gravity-sensitive organ with structure-to-function relationships that are altered during spaceflight. Here we describe how small rodents have been used during the past 5 decades to understand the skeletal response to spaceflight with an emphasis on changes in bone mass, architecture and quality, and the cellular mechanisms mediating these changes. Additionally, we consider the strengths and limitations of rodents for modeling human response and the unique challenges of the spaceflight environment for designing experiments and collecting and interpreting data. We also evaluate the extent to which these model organisms have increased our understanding of skeletal adaptation to microgravity. Taken together, there is strong evidence that spaceflight influences bone accrual and turnover, often resulting in lower bone mass compared to age-matched ground-based controls. However, the skeletal response to spaceflight is not uniform, the cellular mechanisms for observed changes remain elusive, and the molecular mechanisms are largely unknown. Importantly, it is difficult to distinguish the specific skeletal effects of weightlessness (microgravity) from those associated with the spacecraft environment. Since microgravity during orbital spaceflight is constant, the differences across studies are likely due to coexisting intrinsic and extrinsic factors, including species, sex, age, duration of flight, and housing conditions. While rodent studies provide novel insight into adaptation of the mammalian skeleton to microgravity, because of important species differences in skeletal maturation, metabolism and bone physiology, comparisons of rodents to astronauts should currently be made with caution. • We discuss how rodents are used to understand skeletal response to spaceflight. • Identifying the specific skeletal effects of microgravity is difficult. • Spaceflight influences bone metabolism, but the response is not uniform. • Coexisting intrinsic and extrinsic factors alter the skeletal response to microgravity. • Limitations of the rodent models preclude most direct comparisons to astronauts.