Piperlongumine Inhibits Titanium Particles-Induced Osteolysis, Osteoclast Formation, and RANKL-Induced Signaling Pathways.

Xuan Liu,Mei Liu,Yudie Zhang,Li Diao,Xiaotian Shi,Yuhang Mao,Xue Yang,Fuli Zhao,Junnan Zhou

doi:10.3390/ijms23052868

Abstract

Wear particle-induced aseptic loosening is the most common complication of total joint arthroplasty (TJA). Excessive osteoclast formation and bone resorptive activation have been considered to be responsible for extensive bone destruction and prosthesis failure. Therefore, identification of anti-osteoclastogenesis agents is a potential therapy strategy for the treatment of aseptic loosening and other osteoclast-related osteolysis diseases. In the present study, we reported, for the first time, that piperlongumine (PL), a key alkaloid compound from Piper longum fruits, could significantly suppress the formation and activation of osteoclasts. Furthermore, PL effectively decreased the mRNA expressions of osteoclastic marker genes such as tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), and cathepsin K (CTSK). In addition, PL suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced activations of MAPKs (ERK, JNK and p38) and NF-κB, which down-regulated the protein expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Using a titanium (Ti) particle-induced calvarial osteolysis model, we demonstrated that PL could ameliorate Ti particle-induced bone loss in vivo. These data provide strong evidence that PL has the potential to treat osteoclast-related diseases including periprosthetic osteolysis (PPO) and aseptic loosening.

Highlights

The results showed that concentration of PL at and below 1 μM did not affect the viab of bone marrow-derived macrophage (BMM) cells, and the calculated IC50 for this effect was 6.35 μM (Figure 2A)
To investigate the effect of PL on RANKL-induced osteoclast formation, BMMs treated with different doses of PL in the presence of RANKL
The result showed that concentrations of PL that inhibited osteoclast formation (0.25~1 μM) had little effect on the expression of Alkaline phosphatase (ALP) (Figure 2G)

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Total joint replacement (TJR) is an effective clinical treatment for treating end-stage joint diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and femoral head necrosis [1]. With the number of patients receiving this surgery constantly increasing, particle-induced periprosthetic osteolysis (PPO) and subsequent aseptic loosening have attracted more and more attention [2]. Much research has focused on improving the implant designs [3], perfecting surgical techniques, and searching for better biomaterials

Methods

Results

Conclusion