Icariin attenuates thioacetamide‑induced bone loss via the RANKL‑p38/ERK‑NFAT signaling pathway

Abstract

There is an increasing incidence of destructive bone disease caused by osteoclast proliferation. This is characterized by reduced bone mass and imbalance of bone homeostasis. Icariin (ICA), a flavonoid compound isolated from Epimedium , has anti-osteoporosis activity and inhibits the formation of osteoclasts and bone resorption. The purpose of the present study was to investigate the protective effect of ICA on osteoclastic differentiation induced by thioacetamide (TAA) and its possible mechanism in Sprague Dawley (SD) rats. In the present study, SD rats were intraperitoneally injected with TAA (300 mg/kg) for the bone loss model, treated with ICA (600 mg/kg, intragastric gavage) in the ICA group and TAA+ICA group for treatment of bone loss for 6 weeks. Indexes associated with bone metabolism, such as alkaline phosphatase, N-terminal telopeptide of type-I collagen (NTX–I), calcium (Ca), phosphorus (P) and magnesium (Mg) in the serum, were detected. Osteoclast differentiation of femoral tissues was detected by hematoxylin and eosin and tartrate-resistant acid phosphatase staining. The femoral bone mass was evaluated using a three-point bending test and micro computed tomography. Western blotting was used to detect the expression levels of osteoclast-related proteins in each group. In the rats treated with TAA, the serum concentrations of Ca, P and Mg were decreased, the serum concentration of NTX–I was increased, osteoclast differentiation of the femur was increased, femur bone stress and bone mass were decreased and the bone loss and osteoclast formation were reduced after ICA treatment. In addition, ICA inhibited the protein expression of receptor activator of nuclear factor κ-Β ligand (RANKL), receptor activator of nuclear factor κ-B (RANK), p38, ERK, c-Fos and nuclear factor of activated T cells 1 (NFATc1) in the femur of rats treated with TAA. The results suggested that ICA may inhibit osteoclast differentiation by downregulating the RANKL-p38/ERK-NFAT signaling pathway and prevent TAA-induced bone loss. The results are helpful to understand the mechanism of osteoclast differentiation induced by TAA, as well as the antiresorptive activity and molecular mechanism of ICA, and to provide new ideas for the treatment of osteolytic diseases.

Regulatory Roles of Flavonoids in Caspase-11 Non-Canonical Inflammasome-Mediated Inflammatory Responses and Diseases

“…Icariin is a natural flavonoid found in several plant species belonging to the Epimedium genus. Icariin has biological roles and pharmacological activities, including antiaging, antiosteoporosis, antioxidative, antiatherosclerotic, and anticancer activities [ 161 , 162 , 163 , 164 , 165 ]. Additionally, icariin exerts anti-inflammatory effects by inhibiting the priming step and canonical inflammasomes in inflammatory responses and diseases [ 166 , 167 , 168 , 169 , 170 , 171 ].…”

Icariin regulates RANKL-induced osteoclast differentiation via the ERα/c-Src/RANK signaling

“…A recent study suggested that ICA exerted an estrogenic effect in bones and activated the phosphorylation of estrogen receptor α (ERα) in osteoblasts [12]. In addition, ICA may indirectly regulate bone cell differentiation through the RANK/RANKL signaling [13]. How ERα and the RANK signaling are involved in ICA-mediated osteoclast differentiation warrants further investigation.…”

Oridonin Attenuates Thioacetamide-Induced Osteoclastogenesis Through MAPK/NF-κB Pathway and Thioacetamide-Inhibited Osteoblastogenesis Through BMP-2/RUNX2 Pathway

“…Interestingly, Nakano [ 20 ] also found decreased bone volume and increased bone resorption in TAA-induced cirrhotic rats. Our previous research found that intraperitoneal injection of TAA can induce cortical bone damage and increase trabecular separation in SD rats [ 21 – 23 ]. In addition, TAA, which has the same effect as the classical osteoclast inducers RANKL and M-CSF, can induce BMMs differentiate into osteoclasts in vitro by inducing phosphorylation of PI3K, AKT, p38 and JNK and upregulating the expression of osteoclast specific proteins TRAP and cathepsin K [ 23 ].…”

“…In addition, TAA, which has the same effect as the classical osteoclast inducers RANKL and M-CSF, can induce BMMs differentiate into osteoclasts in vitro by inducing phosphorylation of PI3K, AKT, p38 and JNK and upregulating the expression of osteoclast specific proteins TRAP and cathepsin K [ 23 ]. TAA can also enhance the activity of osteoclasts and promote bone resorption [ 21 ]. However, the effect of TAA on osteogenic differentiation is still unclear.…”