Gene Expression in Osteoblasts and Osteoclasts Under Microgravity Conditions: A Systematic Review

Abstract

Background: Microgravity (µG) negatively influences bone metabolism by affecting normal osteoblast and osteoclast function. µG effects on bone metabolism has been an extensive field of study in recent years, due to the challenges presented by space flight. Methods: We systematically reviewed research data from genomic studies performed in real or simulated µG, on osteoblast and osteoclast cells. Our search yielded 50 studies, of which 39 concerned cells of the osteoblast family and 11 osteoclast precursors. Results: Osteoblastic cells under µG show a decreased differentiation phenotype, proved by diminished expression levels of Alkaline Phosphatase (ALP) and Osteocalcin (OCN) but no apoptosis. Receptor Activator of NF-κB Ligand (RANKL)/ Osteoprotegerine (OPG) ratio is elevated in favor of RANKL in a time-dependent manner, and further RANKL production is caused by upregulation of Interleukin- 6 (IL-6) and the inflammation pathway. Extracellular signals and changes in the gravitational environment are perceived by mechanosensitive proteins of the cytoskeleton and converted to intracellular signals through the Mitogen Activated Protein Kinase pathway (MAPK). This is followed by changes in the expression of nuclear transcription factors of the Activator Protein-1 (AP-1) family and in turn of the NF-κB, thus affecting osteoblast differentiation, cell cycle, proliferation and maturation. Pre-osteoclastic cells show increased expression of the marker proteins such as Tryptophan Regulated Attenuation Protein (TRAP), cathepsin K, Matrix Metalloproteinase-9 (MMP-9) under µG conditions and become sensitized to RANKL. Conclusion: Suppressing the expression of fusion genes such as syncytine-A which acts independently of RANKL, could be possible future therapeutic targets for microgravity side effects.

Integrated RNA-seq Analysis Indicates Asynchrony in Clock Genes between Tissues under Spaceflight

“…Rodent models are often used as analogs for estimating biological mechanisms inside human tissues [ 3 , 4 ]. Mice studies under spaceflight conditions have been successfully conducted to elicit molecular mechanisms at the tissue and cellular levels [ 3 , 5 , 6 , 7 , 8 ].…”

Influence of Microgravity on Apoptosis in Cells, Tissues, and Other Systems In Vivo and In Vitro

“…This hypothesis has been supported by several papers, all suggesting that the cellular response to microgravity alters the expression of apoptotic and anti-apoptotic genes [ 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ]. As highlighted by Chatziravdeli et al [ 140 ], several apoptotic genes, including p53 and BAX , were upregulated in osteoblasts under microgravity conditions. Of note, as a response to the upregulation of these two apoptotic genes, there was a concomitant increase in anti-apoptotic genes, such as CDKN1A , BCL2 , and X-linked inhibitor of apoptosis (XIAP ) [ 140 ].…”

“…As highlighted by Chatziravdeli et al [ 140 ], several apoptotic genes, including p53 and BAX , were upregulated in osteoblasts under microgravity conditions. Of note, as a response to the upregulation of these two apoptotic genes, there was a concomitant increase in anti-apoptotic genes, such as CDKN1A , BCL2 , and X-linked inhibitor of apoptosis (XIAP ) [ 140 ]. The researchers obtained these data in normal human osteoblastic (HOB) cells from trabecular bone [ 137 ].…”

“…The authors described that during the early stage of cancer progression, autophagy in ML-1 and ONCO-DG1 thyroid cancer cells significantly increased compared to other cell lines. This could explain the different starting points of apoptosis in microgravity cultures: In ML-1 and ONCO-DG1 thyroid cancer cells, apoptosis increased after 24 h exposure to simulated microgravity [ 6 , 140 ], whereas in MDA-MB-231 breast cancer and SGC-7901 gastric adenocarcinoma cells, apoptosis increased only after 72 h [ 149 , 152 ]. On the other hand, the number of secondary lysosomes also increased in MDA-MB-231 cells cultured in a RCCS [ 160 ].…”

Simulated Microgravity Remodels Extracellular Matrix of Osteocommitted Mesenchymal Stromal Cells

“…This is supported by numerous data from in vitro experiments conducted aboard space vehicles and under ground-based microgravity simulations. The reduced osteogenic potential of osteoblasts and low commitment of stromal progenitors in vitro has been convincingly demonstrated [19][20][21][22]. In addition, a downregulation of osteogenic-associated genes and upstream signaling pathway genes has been observed [23,24].…”