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      The effects of microgravity on bone structure and function

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          Abstract

          Humans are spending an increasing amount of time in space, where exposure to conditions of microgravity causes 1–2% bone loss per month in astronauts. Through data collected from astronauts, as well as animal and cellular experiments conducted in space, it is evident that microgravity induces skeletal deconditioning in weight-bearing bones. This review identifies contentions in current literature describing the effect of microgravity on non-weight-bearing bones, different bone compartments, as well as the skeletal recovery process in human and animal spaceflight data. Experiments in space are not readily available, and experimental designs are often limited due to logistical and technical reasons. This review introduces a plethora of on-ground research that elucidate the intricate process of bone loss, utilising technology that simulates microgravity. Observations from these studies are largely congruent to data obtained from spaceflight experiments, while offering more insights behind the molecular mechanisms leading to microgravity-induced bone loss. These insights are discussed herein, as well as how that knowledge has contributed to studies of current therapeutic agents. This review also points out discrepancies in existing data, highlighting knowledge gaps in our current understanding. Further dissection of the exact mechanisms of microgravity-induced bone loss will enable the development of more effective preventative and therapeutic measures to protect against bone loss, both in space and possibly on ground.

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          Most cited references170

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          Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.

          The ligand for osteoprotegerin has been identified, and it is a TNF-related cytokine that replaces the requirement for stromal cells, vitamin D3, and glucocorticoids in the coculture model of in vitro osteoclastogenesis. OPG ligand (OPGL) binds to a unique hematopoeitic progenitor cell that is committed to the osteoclast lineage and stimulates the rapid induction of genes that typify osteoclast development. OPGL directly activates isolated mature osteoclasts in vitro, and short-term administration into normal adult mice results in osteoclast activation associated with systemic hypercalcemia. These data suggest that OPGL is an osteoclast differentiation and activation factor. The effects of OPGL are blocked in vitro and in vivo by OPG, suggesting that OPGL and OPG are key extracellular regulators of osteoclast development.
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            Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.

            A novel secreted glycoprotein that regulates bone resorption has been identified. The protein, termed Osteoprotegerin (OPG), is a novel member of the TNF receptor superfamily. In vivo, hepatic expression of OPG in transgenic mice results in a profound yet nonlethal osteopetrosis, coincident with a decrease in later stages of osteoclast differentiation. These same effects are observed upon administration of recombinant OPG into normal mice. In vitro, osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG. Furthermore, OPG blocks ovariectomy-associated bone loss in rats. These data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity.
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              From space to Earth: advances in human physiology from 20 years of bed rest studies (1986-2006).

              Bed rest studies of the past 20 years are reviewed. Head-down bed rest (HDBR) has proved its usefulness as a reliable simulation model for the most physiological effects of spaceflight. As well as continuing to search for better understanding of the physiological changes induced, these studies focused mostly on identifying effective countermeasures with encouraging but limited success. HDBR is characterised by immobilization, inactivity, confinement and elimination of Gz gravitational stimuli, such as posture change and direction, which affect body sensors and responses. These induce upward fluid shift, unloading the body's upright weight, absence of work against gravity, reduced energy requirements and reduction in overall sensory stimulation. The upward fluid shift by acting on central volume receptors induces a 10-15% reduction in plasma volume which leads to a now well-documented set of cardiovascular changes including changes in cardiac performance and baroreflex sensitivity that are identical to those in space. Calcium excretion is increased from the beginning of bed rest leading to a sustained negative calcium balance. Calcium absorption is reduced. Body weight, muscle mass, muscle strength is reduced, as is the resistance of muscle to insulin. Bone density, stiffness of bones of the lower limbs and spinal cord and bone architecture are altered. Circadian rhythms may shift and are dampened. Ways to improve the process of evaluating countermeasures--exercise (aerobic, resistive, vibration), nutritional and pharmacological--are proposed. Artificial gravity requires systematic evaluation. This review points to clinical applications of BR research revealing the crucial role of gravity to health.
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                Author and article information

                Contributors
                joey.man@csiro.au
                andrew.laslett@csiro.au
                Journal
                NPJ Microgravity
                NPJ Microgravity
                NPJ Microgravity
                Nature Publishing Group UK (London )
                2373-8065
                5 April 2022
                5 April 2022
                2022
                : 8
                : 9
                Affiliations
                [1 ]GRID grid.1016.6, ISNI 0000 0001 2173 2719, Commonwealth Scientific and Industrial Research Organisation (CSIRO) Manufacturing, ; Clayton, Victoria 3168 Australia
                [2 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Australian Regenerative Medicine Institute, Monash University, ; Melbourne, Victoria 3800 Australia
                [3 ]GRID grid.1016.6, ISNI 0000 0001 2173 2719, Space Technology Future Science Platform, , Commonwealth Scientific and Industrial Research Organisation (CSIRO), ; Clayton, Victoria 3168 Australia
                Author information
                http://orcid.org/0000-0002-7864-3562
                http://orcid.org/0000-0003-4729-8193
                Article
                194
                10.1038/s41526-022-00194-8
                8983659
                35383182
                8349c7d4-5f68-4d0e-af62-a5617b9daa8e
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 27 September 2021
                : 4 March 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000943, Commonwealth Scientific and Industrial Research Organisation (CSIRO);
                Award ID: ST-R2-04
                Award ID: ST-R2-04
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2022

                cell biology,biotechnology
                cell biology, biotechnology

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