Abstract
Background: Irisin, a novel exercise-induced myokine, was shown to mediate beneficial effects of exercise in osteoporosis. Microgravity is a major threat to bone homeostasis of astronauts during long-term spaceflight, which results in decreased bone formation. Methods: The hind-limb unloading mice model and a random position machine are respectively used to simulate microgravity in vivo and in vitro. Results: We demonstrate that not only are bone formation and osteoblast differentiation decreased, but the expression of fibronectin type III domain-containing 5 (Fdnc5; irisin precursor) is also downregulated under simulated microgravity. Moreover, a lower dose of recombinant irisin (r-irisin) (1 nM) promotes osteogenic marker gene (alkaline phosphatase (Alp), collagen type 1 alpha-1(ColIα1)) expressions, ALP activity, and calcium deposition in primary osteoblasts, with no significant effect on osteoblast proliferation. Furthermore, r-irisin could recover the decrease in osteoblast differentiation induced by simulated microgravity. We also find that r-irisin increases β-catenin expression and partly neutralizes the decrease in β-catenin expression induced by simulated microgravity. In addition, β-catenin overexpression could also in part attenuate osteoblast differentiation reduction induced by simulated microgravity. Conclusions: The present study is the first to show that r-irisin positively regulates osteoblast differentiation under simulated microgravity through increasing β-catenin expression, which may reveal a novel mechanism, and it provides a prevention strategy for bone loss and muscle atrophy induced by microgravity.
Highlights
Disuse osteoporosis is a worldwide clinically relevant problem for those with a lack of mechanical load [1,2,3,4]
We investigated the inhibitory effects of simulated microgravity (SM) on osteoblast differentiation using a random position machine (RPM) which rotated biological samples along two independent axes to change their orientation in random modes [6]
We found that the decrease of β‐catenin messenger RNA (mRNA) and protein levels induced by simulated microgravity was partly prevented by r‐irisin (Figures 5e,f)
Summary
Disuse osteoporosis is a worldwide clinically relevant problem for those with a lack of mechanical load (e.g., bedridden, microgravity, aging) [1,2,3,4]. Many studies demonstrated that simulated microgravity leads to decreased osteoblast differentiation or bone formation [8,9,10], while the cellular and molecular mechanisms are not yet completely understood. The mechanism of irisin in osteoblast differentiation and bone formation under microgravity warrants an investigation. The hind-limb unloading mice model and a random position machine (RPM) were used to simulate microgravity in vivo and in vitro, respectively. We firstly identified that Fdnc (irisin precursor) expression was decreased and positively correlated with osteoblast differentiation and bone formation under simulated microgravity environment. We demonstrated the mechanism of r-irisin preventing reduction of osteoblast differentiation induced by simulated microgravity through increasing β-catenin expression after treatment with r-irisin. Simulated Microgravity Inhibits Irisin Precursor Expression, Bone Formation, and Osteoblast Differentiation. Statitsetsitc; a*lpd
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