Microgravity induces inhibition of osteoblastic differentiation and mineralization through abrogating primary cilia

Abstract

It is well documented that microgravity in space environment leads to bone loss in astronauts. These physiological changes have also been validated by human and animal studies and modeled in cell-based analogs. However, the underlying mechanisms are elusive. In the current study, we identified a novel phenomenon that primary cilia (key sensors and functioning organelles) of rat calvarial osteoblasts (ROBs) gradually shrank and disappeared almost completely after exposure to simulated microgravity generated by a random positioning machine (RPM). Along with the abrogation of primary cilia, the differentiation, maturation and mineralization of ROBs were inhibited. We also found that the disappearance of primary cilia was prevented by treating ROBs with cytochalasin D, but not with LiCl or dynein light chain Tctex-type 1 (Dynlt1) siRNA. The repression of the differentiation, maturation and mineralization of ROBs was effectively offset by cytochalasin D treatment in microgravity conditions. Blocking ciliogenesis using intraflagellar transport protein 88 (IFT88) siRNA knockdown inhibited the ability of cytochalasin D to counteract this reduction of osteogenesis. These results indicate that the abrogation of primary cilia may be responsible for the microgravity’s inhibition on osteogenesis. Reconstruction of primary cilia may become a potential strategy against bone loss induced by microgravity.

Osteogenic Stimulation of Human Adipose-Derived Mesenchymal Stem Cells Using a Fungal Metabolite That Suppresses the Polycomb Group Protein EZH2

“…While these findings collectively suggest that cellular tension is important for mediating cell fate decisions, studies by Sen et al recently showed cellular tension transmitted through the actin cytoskeleton (and subsequent bone formation in vitro and in vivo) was not the sole determining factor of deciding cell fate but that the specific control of gene expression was primarily dependent on intranuclear actin transport [24]. In other studies by Shi et al and Chen et al, CytoD has been shown to have reduced the viability and osteogenic differentiation of calvarial osteoblasts and tendon stem cells, in vitro [39,40]. These inhibitory responses could be attributed to cell shape status and confluency conditions before CytoD treatment.…”

Dietary countermeasure mitigates simulated spaceflight-induced osteopenia in mice

“…Together, these events result in bone loss as well as reduced bone mechanical properties in rodents [49][50][51][52] . In addition, exposure to microgravity in mice adversely affects osteoprogenitors 53,54 . The bone marrow niche contains osteoblast progenitors cells 4 and it has been shown that exposure to microgravity alters the cells proliferation capacity and impairs their ability to produce extracellular matrix, in turn inhibiting the maturation of the bone matrix.…”

“…The bone marrow niche contains osteoblast progenitors cells 4 and it has been shown that exposure to microgravity alters the cells proliferation capacity and impairs their ability to produce extracellular matrix, in turn inhibiting the maturation of the bone matrix. Thus, the ability to maintain bone homeostasis is diminished 16,[54][55][56] .…”

Understanding vestibular-related physiological functions could provide clues on adapting to a new gravitational environment

“…A recent study reported that the microgravity-induced effect on syncytin-A expression stimulated osteoclast formation independently of receptor activation of nuclear factor-kappa B ligand (RANKL), a crucial bone resorption factor, in mouse monocytic RAW264.7 cells [34]. Regarding osteoblasts, microgravity suppresses cell metabolism by impairing the cell mitochondrial energy state in human osteoblasts; further, it represses rat osteoblast differentiation by affecting primary cilia, which partly sense mechanical stress [35,36]. Moreover, spaceflight has been reported to result in enhanced bone resorption by inducing osteocyte death and the subsequent bone mass deterioration and microstructure in mice [37].…”