Recombinant Irisin Prevents the Reduction of Osteoblast Differentiation Induced by Stimulated Microgravity through Increasing β-Catenin Expression

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.

Silencing of miR-138-5p sensitizes bone anabolic action to mechanical stimuli

“…The hindlimb unloaded mouse model was constructed using 8-week-old male C57BL/6 mice according to previous reports 14 . Briefly, a clip-shaped holder was reformed to secure the tail of each mouse, and the mice were then suspended with a chain at a degree of 30° in a custom-made suspension cage.…”

“…A desktop random positioning machine (RPM, the Center for Space Science and Applied Research of Chinese Academy of Sciences, China) was used to simulate mechanical unloading conditions for the cell culture, as described previously 14 . The cell culture vessel was fixed on the inner frame and the RPM was placed inside a 37 °C incubator.…”

Bone and Muscle Crosstalk in Aging

“…Consistent with that, Colaianni et al (2015) reported that irisin enhances ERK phosphorylation in cultured osteoblasts. Furthermore, irisin can reduce the number of apoptotic osteoblasts in an osteoporosis rat model, and protect against decreased osteoblast differentiation by increasing β-catenin levels ( Chen et al, 2020 ; Xu et al, 2020 ). Except for its direct effect on osteoblasts, irisin can indirectly promote osteogenesis by polarizing macrophages to the M2 phenotype via the adenosine monophosphate-activated protein kinase (AMPK) pathway ( Ye et al, 2020 ).…”

Role of the Myokine Irisin on Bone Homeostasis: Review of the Current Evidence

“…Hindlimb unloaded mice, as a model to stimulate microgravity effects on bone in vivo, had increased femur bone loss, and reduced mineral apposition rates of trabecular and cortical bone (Table 5) [76]. Additionally, Fndc5 mRNA levels and mRNA levels of the osteogenesis markers (Alp, ColIa1) were reduced.…”