Abstract
Osteolysis is an osteolytic lesion featured by enhanced osteoclast formation and potent bone erosion. Lacking of effective regimen for treatment of the pathological process highlights the importance of identifying agents that can suppress the differentiation and function of osteoclast. Artemether is a natural compound derived from Artemisia annua L. and it is popularized for the treatment of malaria. In present study, we demonstrated that artemether could suppress RANKL-induced osteoclastogenesis and expression of osteoclast marker genes such as tartrate-resistant acid phosphatase, cathepsin K, matrix metalloproteinase 9, nuclear factor of activated T-cell cytoplasmic 1, and dendritic cell-specific transmembrane protein. It inhibited the osteoclastic bone resorption in a dose-dependent manner in vitro. Furthermore, artemether attenuated RANKL-induced MAPKs (ERK, JNK, p-38) activity. In addition, we have showed that artemether was able to mitigate bone erosion in a murine model of LPS-induced inflammatory bone loss. Taken together, these findings suggest that artemether reduces inflammatory bone loss via inhibition of MAPKs activation during osteoclast differentiation, and it might be a potential candidate for the treatment of osteoclast-related disorders.
Highlights
Total joint arthroplasty is a routine orthopedic procedure for pain relief and mobility restoration to patients with end-stage joint diseases
The formation of osteoclast was almost completely suppressed at high concentration (10 μM) of artemether, whereas the survival of Bone marrow-derived macrophages (BMMs) were not affected at same concentration (Fig. 1h, i), indicating that these concentrations of artemether could attenuate osteoclast formation without interfering cell viability
The major reason for the longterm failure is aseptic loosening owning to periprosthetic osteolysis[26], which is mainly triggered by an inflammatory response to wear particles generated from implant
Summary
Total joint arthroplasty is a routine orthopedic procedure for pain relief and mobility restoration to patients with end-stage joint diseases. The interaction between RANKL and its receptor RANK recruits adaptor molecules TNF receptorassociated factors (TRAFs) and activates several downstream signal pathways, including MAPKs, NF-κB, PI3K/Akt, followed by the activation of transcription factors like activator protein 1 (AP-1) and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1)[12,13]. Activation of these downstream factors triggers osteoclast differentiation and function by inducing specific genes, including TRAP, cathepsin K (CTSK), matrix metalloproteinase 9 (MMP-9), and resulting in the formation of mature osteoclasts[12,13]
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