Table 5 Studies of bone loss in animal and cellular models subjected to simulated microgravity.
From: The effects of microgravity on bone structure and function
Cell type/species | Technique | Duration (days) | µG-related observations | Refs. |
|---|---|---|---|---|
Preosteoblasts/Mice | HLU | 28 | • IL-6 expression increased in both sera and femurs of mice • IL-6-neutralising treatment alleviated bone loss reflected by increased BMD of tibia, trabecular thickness and number, bone volume fraction and load and stiffness of femur • IL-6 treatment increased mRNA expression of ALP, osteopontin, Runx2 and decreased NFkB ligand protein in MC3T3-E1 cells | He et al.103 |
Osteoclast/mice | HLU | 28 | • Decreased femur BMD • Increased stimulation of osteoclastogenesis • Increased RANKL-stimulated osteoclastogenesis from precursors removed from tibia | Saxena et al.126 |
Osteoclast/mice | HLU | 18 | • Increased osteoclast numbers and resorptive activity following osteocyte apoptosis • Decreased bone density and compressive resistance | Aguirre et al.127 |
Osteoblasts/mice | HLU | 14 | • Reduced bone formation and osteocyte/osteoblast viability from decreased Wnt/β-catenin signalling • Increased sclerostin production, which inhibits bone growth by antagonising Wnt/β-catenin signalling | Lin et al.107 |
Preosteoblasts/rat | HLU Clinostat | 28 | • Increased bone loss in femurs, with decreased expression of transcription factors critical to osteoblast differentiation and increased mRNA expression of apoptotic proteins • Decreased cell activity and increased apoptosis in MC3T3-E1 cells | Dong et al.100 |
Preosteoblast/rat | HLU RWV | 42 | • Reduced BMD, trabecular thickness, trabecular number, ultimate load and stiffness in tibiae • Enhanced IL-6 in sera, skeletal muscle and tibiae • Hydrogen sulfide donor (GYY4137) treatment preserved bone structure in rats • GYY4137 stimulated expression of genes for osteoblastic differentiation and activity in MC3T3-E1 cells | Yang et al.155 |
MSC/mice | HLU | 28 | • Decreased osteogenic potential with reduced Runx2 expression • Enhanced adipogenic potential with increased PPARγ expression | Pan et al.105 |
Mice | HLU | 28 | • Elevated glucocorticoid signalling in osteoblasts, leading to cortical tibia bone loss • Osteoblast activity and bone formation inhibited • Osteoclast activity and bone resorption promoted • Increased sclerostin and RANKL-positive osteocytes, and apoptotic osteoblasts and osteocytes • Blocking glucocorticoid signalling prevents osteoblast cell death | Yang et al.156 |
Mice | HLU | 28 | • Reduced trabecular bone volume, surface area of cortical bone, maximum load and stiffness in tibia • Treatment with alendronate and anti-RANKL antibody inhibited bone resorption and restored bone mass close to control • Treatment with bortezomib increased whole bone mass by inhibiting bone resorption and promoting bone formation | Ding et al.157 |
Rat | HLU | 14 | • 66% increase in percentage of apoptosis in osteocytes • 14% increase in osteoclast number • 48% decrease in bone volume • Reloading returned apoptotic osteocytes and bone volume to baseline | Basso et al.132 |
Mice | HLU | 3 | • Increased osteocyte apoptosis in both trabecular and cortical bone, sequestered in endosteal cortical bone • Increased osteoclast number and cortical porosity • Decreased spinal BMD and vertebral strength | Aguirre et al.127 |
Rat | HLU | 28 | • Metaphyseal bone density reduced in hindlimb, but not in the proximal humerus • Opposite response of osteocyte proteins and osteoblast surface in hindlimb and forelimb bones within the same unloaded rat | Metzger et al.136 |
Mice | HLU | 14 | • Decreased Wnt/β-catenin signalling and upregulated Sost expression • Sclerostin suppressed osteoblast activity and viability of osteoblasts and osteocytes • Sost-ablated mice were resistant to HLU-induced bone loss and Wnt/β-catenin signalling was unaffected | Lin et al.107 |
Mice | HLU | 7 | • Osteocyte-ablated mice (with 20–30% remaining osteocytes) had fragile bone, osteoblastic dysfunction, and trabecular bone loss with microstructural deterioration • “Osteocyte-less” mice were resistant to HLU-induced bone loss | Tatsumi et al.142 |
Mice | HLU | 28 | • Preventative irisin treatment during unloading prevented bone loss in hindlimb • Irisin treatment following bone loss induced recovery of bone mass | Colaianni et al.147 |
Rat | HLU | 28 | • Decreased cancellous bone volume, higher osteoclast surfaces and lower bone formation rate in hindlimb and 4th lumbar vertebrae • Higher bone formation rate and lower osteoclast surfaces in proximal humerus • Osteocyte RANKL and sclerostin elevated in distal femur, but lowered in proximal humerus • Irisin treatment increased bone formation rate, lowered osteoclast surfaces and osteocyte RANKL and sclerostin | Metzger et al.130 |
Osteosarcoma/human | Clinostat | 2 | • Microgravity inhibited Runx2 activity and its responsiveness to BMP2 • Linked to actin microfilament disruption | Dai et al.158 |
Osteoblasts/human | RPM | 1, 4.58 | • Osteoblasts dedifferentiated assuming a spindle-shape and had decreased production of mineralisation crystals • Osteoblastic differentiation markers ALP, Runx2, BMP2 downregulated | Gioia et al.94 |
MSC/human | RCC | 7 | • Inhibition of osteogenic markers: ALP, collagen type 1, osteocalcin and Runx2 • Enhanced expression of adipogenic markers: adipsin, leptin, glut4 and PPARγ | Saxena et al.159 |
BMSC/human | RPM | 4, 10 | • Induced overexpression of Runx2, osterix, osteopontin and osteocalcin in non-osteogenic media • COL1A1 was upregulated, but only in the presence of osteogenic media | Cazzaniga et al.115 |
Osteoblasts/human | RPM | 7, 14 | • Cytoskeletal changes resulted in some cells detaching from the culture surface and forming multicellular spheroids • Increased expression of Sox9 and osteopontin after 7 and 14 days • Increased expression of osteocalcin and collagen type 1 after 14 days | Mann et al.108 |
Osteoblasts/human | Clinostat | 20 | • Inhibited calcium deposition with a complete absence of bone nodules compared to ground control • Cytoskeleton disruption and cells taking on a bulging morphology • Osteoblast inhibition in microgravity linked to repression of p38 phosphorylation | Yuge et al.106 |
Osteoblasts/mice | Clinostat | 1 | • Arrest of osteoblast cell cycle in the G2 phase due to a decrease in cyclin B1 expression associated with miRNA (specifically miR-181c-5p) inhibitory activity | Sun et al.102 |
Preosteoblasts/mice | RPM | 1 | • Inhibition of ALP, Runx2, osteocalcin, type 1 collagen and BMP expression • No changes in cell morphology | Hu et al.96 |
Preosteoblasts/mice | RPM | 1 | • Downregulation of ALP, osteocalcin, COL1A1, DMP1 and Runx2 gene expression | Hu et al.160 |
Osteoblasts/mice | RWV | 1 | • Decreased ALP, osteocalcin, AP-1 and Runx2 expression | Ontiveros and McCabe97 |
Preosteoblasts/mice | RWV | 3 | • Decreased ALP activity and inhibited RUNX2, BMP4, PthR1 and osteomodulin gene expression | Patel et al.18 |
Preosteoblasts/mice | RPM | 3-9 | • Inhibition of ALP activity and downregulated ALP, RUNX2, osteomodulin, PthR1 gene expression • Upregulation of Cathepsin K | Pardo et al.99 |
Osteoblasts Osteoclasts/mice | RPM | 1 | • Enhanced osteoclastogenesis by decreasing osteoblast production of OPG (increasing RANKL/OPG ratios) | Rucci et al.121 |
Preosteoblasts/mice | RWV | 1 | • Increased osteoclastogenesis and upregulated production/expression of factors involved in osteoclastogenesis e.g. cytokines, growth factors, proteases, signalling proteins and transcription factors c-Jun, MITF and CREB compared to ground control | Sambandam et al.122 |
Preosteoblasts Preosteoclasts/mice | RPM | 7 | • Inhibited expression of Runx2, Osterix, type I collagen α1 chain, RANKL and OPG genes in MCT3T3-E1 cells, which prevents osteoblast differentiation • Suppressed RANKL-dependent maturation of preosteoclasts | Makihira et al.101 |
Osteocyte / Mice | RWV | 3 | • Increased expression of SOST, sclerostin and RANK/OPG ratio | Spatz et al.135 |
Osteocyte-like/immortalised | RWV | 5 | • Disassembly of F-actin filaments and short dendritic processes at cell periphery • Increased Wnt1 and Sost expression • Reduced gene and protein level of β-catenin, with no nuclear translocation • Sclerostin antibody inhibited µG-induced down regulation of Wnt target genes and sclerostin protein expression | Yang et al.140 |
