Icariin ameliorates dexamethasone‑induced bone deterioration in an experimental mouse model via activation of microRNA‑186 inhibition of cathepsin K

Abstract

The present study aimed to investigate bone deterioration in glucocorticoid-induced osteoporosis (GIOP) mice, and the anti-osteoporosis effect and underlying molecular mechanism of icariin. Dexamethasone (DSM) treatment was demonstrated to facilitate the induction of hypercalciuria in GIOP mice. Icariin treatment reversed the dexamethasone (DXM)-induced disequilibrium of calcium homeostasis and bone resorption, and increased serum alkaline phosphatase, tartrate resistant acid phosphatase, osteocalcin and deoxypyridinoline. Haematoxylin and eosin staining revealed an increase in disconnections and separation in the trabecular bone network of the tibial proximal metaphysis, in the GIOP group. Icariin treatment reversed the DXM-induced trabecular deleterious effects, and stimulated bone remodeling in GIOP mice. Furthermore, the results demonstrated that the mRNA and protein expression of cathepsin K were significantly increased in GIOP mice, compared with the control group. Icariin treatment may suppress the expression of cathepsin K in the tibia of GIOP mice. The levels of microRNA (miR)-186 were markedly reduced in the tibia of GIOP mice compared with control group; however, this was inhibited by icariin treatment. Bioinformatics analysis demonstrated that miR-186 regulates cathepsin K via binding to the upstream 3′-untranslated region. Furthermore, transfection with miR-186 mimics resulted in inhibition of cathepsin K expression, whereas miR-186 inhibitors facilitated cathepsin K expression in osteoclasts. In conclusion, the present study demonstrated the protective effects of icariin against bone deteriorations in the experimental GIOP mice, and the underlying mechanism was mediated, at least partially, via activation of miR-186-mediated suppression of cathepsin K. These results provide evidence to support the use of icariin as a therapeutic approach in the management of glucocorticoid-induced bone loss, and the disequilibrium of calcium homeostasis.

Therapeutic Anabolic and Anticatabolic Benefits of Natural Chinese Medicines for the Treatment of Osteoporosis

“…Liu et al found that icariin had beneficial effects for osteoporotic rats via the inhibition of peroxisome proliferator-activated receptor γ (PPARγ) and Notch2 mRNA expression (Liu et al, 2017a). And Ma et al found that icariin appears to be a therapeutic drug to manage glucocorticoid-induced bone loss via the activation of microRNA-186-mediated suppression on cathepsin K (Ma et al, 2018). Additionally, icariin could significantly reduce particle-induced bone resorption by suppressing osteoclast formation (Shao et al, 2015).…”

miRNA Mechanisms Underlying the Association of Beta Blocker Use and Bone Mineral Density

“…( 54 ) miR‐186 has been shown to inhibit cathepsin K and the PI3K‐AKT pathway in mice, affecting osteoarthritis and drug‐induced bone deterioration. ( 55,56 ) miR‐19a‐3p and miR‐186‐5p are expressed in bone, brain, and spinal cord tissue as well as in whole blood, ( 57 ) so it is reasonable that these miRNAs may be acting on bone or the SNS (Supplemental Fig. S4 A ).…”

Icariin Attenuates Amyloid-β (Aβ)-Induced Neuronal Insulin Resistance Through PTEN Downregulation

“…For example, both of miR-186 and miR-21 can negatively regulate gene expression by binding to the 3′-untranslated region (3′-UTR) of PTEN mRNAs, leading to mRNA degradation or translational repression (Bermúdez Brito et al, 2015;Feng et al, 2019). Interestingly, icariin can upregulate these miRNAs (Lian et al, 2018;Ma et al, 2018), suggesting a possibility of that miR-186 or miR-21 may mediate the inhibitory effects of icariin on PTEN. However, our RT-qPCR results revealed that neither Ab nor icariin affected the expression levels of miR-186 and miR-21 in SK-N-MC cells (data not shown).…”