Icariin Treatment Enhanced the Skeletal Response to Exercise in Estrogen-Deficient Rats

Abstract

Estrogen deficiency frequently leads to a fall in estrogen receptor-α (ERα) numbers and then reduces the skeletal response to mechanical strain. It, however, is still unclear whether phytoestrogen administration will enhance the effects of exercise on the estrogen-deficient bone loss. This study aimed to determine the effect of Icariin treatment on the response of osteogenic formation to exercise in ovariectomized (OVX) rats. Thirty-two 3-month old female Sprague–Dawley rats were randomly allocated into four groups: (1) Sham-operated (SO); (2) OVX; (3) OVX plus exercise (EX); and (4) OVX plus exercise and Icariin (EI). After 8-week interventions, the rats were killed and samples were collected for bone morphometry, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. EI interventions showed a greater improvement for the OVX-induced bone loss and the elevated serum tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) compared with EX only. Both EX and EI interventions bettered the OVX-related reduction of BV/TV and trabecular number and thickness, and decreased the enlargement of trabecular bone separation (Tb. Sp); the improvement for BV/TV and Tb. Sp was greater in EI group. Furthermore, EX and EI treatment significantly increased the number of ALP+ cells and mineralized nodule areas compared with OVX group; the change was higher in EI group. Additionally, in comparison to OVX rats, the protein and mRNA expression of β-catenin, phosphorylated-Akt (p-Akt) or Akt, ERα, and Runt-related transcription factor 2 (Runx2) in osteoblasts were elevated in EX and EI intervention rats, with greater change observed in EI group. The upregulated β-catenin and Akt mRNA levels in EX and EI groups was depressed by ICI182780 treatment, and the difference in β-catenin and Akt mRNA levels between EX and EI groups was no longer significant. Conclusively, the combination of Icariin and exercise significantly prevent OVX-induced bone loss and increase osteoblast differentiation and the ability of mineralization compared with exercise alone; the changes might be regulated partly by ERα/Akt/β-catenin pathway.

The Potential Mechanism of Exercise Combined with Natural Extracts to Prevent and Treat Postmenopausal Osteoporosis

“…It was reported that β-catenin, Akt, ERα, and Runx2 expression were significantly increased in OB in the treadmill-bound Epimedii intervention group, compared with exercise alone. Combination treatment significantly prevented OVX-induced bone loss and increased OB differentiation and mineralization ability, some of which may be regulated by the ERα/Akt/β-catenin pathway, but whether combination intervention affected OC differentiation remains unclear [77]. In vitro experiments by domestic scholars have shown icariin combined with exercise coupling stimulation may inhibit bone resorption by regulating NF-κB signaling and influence the upregulation of OB proliferation by the classical Wnt/β-catenin pathway.…”

Icariin: A Potential Alternative Against Osteoporosis

“…Exercise-induced skeletal adaptation to ICA therapy was enhanced in part by the ER/AKT/β-catenin pathway. 66 ICA promotes bone formation in osteoblasts in rats by activating the cAMP pathway, which is localized to osteoblast primary cilia, as demonstrated by siRNA suppression of a protein involved in cilium assembly. 54 This research strengthened the link between cAMP-mediated signaling and osteogenesis and provided fresh insights into the mechanism and function of ICA.…”

“…89 Exercise enhanced this process via upregulating the expression of ERα and then strengthening the Akt/β-catenin pathway. 66 Specific MAPK inhibitors, including the JNK inhibitor SP600125 and the ERK inhibitor U0126, reduced the effects of ICA on osteoblast differentiation. ICI182780, an ER antagonist, decreased ICA-mediated effects and prevented ERK and JNK phosphorylation, indicating that ICA's activation of the ER signaling pathway also activates the ERK and JNK pathways.…”