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.

Fibroblast-like synoviocytes (FLSs) are the prominent non-immune cells in synovium and play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Searching for natural compounds that may suppress the pathological phenotypes of FLSs is important for the development of RA treatment. Tomatidine (Td), a steroidal alkaloid derived from the solanaceae family, has been reported to have anti-inflammatory, anti-tumor and immunomodulatory effects. However, its effect on RA remains unknown. Here, we examined the inhibitory effect of Td on TNFα-induced arthritic FLSs, and subsequently investigated its therapeutic effect on collagen-induced arthritis (CIA) rats. Our results revealed that Td significantly inhibited TNFα-induced proliferation and migration of arthritic FLSs. In addition, we found that Td treatment could efficaciously ameliorate synovial inflammation and joint destruction of rats with CIA. Both in vitro and in vivo studies showed that Td significantly suppressed the production of pro-inflammatory cytokines including IL-1β, IL-6 and TNFα, and downregulated the expression of MMP-9 and RANKL. Further molecular mechanism studies revealed that the inhibitory effect of Td on RA might attribute to the decreased activations of MAPKs (ERK and JNK) and NF-κB. These findings provide evidence that Td has the potential to be developed into a complementary or alternative agent for RA therapy.

Background: Rheumatoid arthritis (RA) is a chronic joint in ammatory disease that is associated with the aberrant activation of broblast-like synoviocytes (FLSs). Searching for natural compounds that may suppress the activation of FLSs has become a complementary approach for RA treatment. Here, we investigated the effects and mechanisms of imperatorin (IPT) on proliferation, migration, and in ammation in primary cultured arthritic FLSs. Methods: Cell viability was evaluated by an MTS assay. The effects of IPT on FLS proliferation, apoptosis and migration were determined by the EdU incorporation assay, ow cytometry and wound healing assay, respectively. In ammation was assessed by detecting the expression of multiple proin ammatory cytokines using quantitative real-time PCR. Western blot and immuno uorescent staining were used to analyze the potential underlying molecular mechanisms. Statistical comparisons were performed using one-way ANOVA, followed by Tukey's post hoc analysis.Results: we found that IPT signi cantly suppressed TNFα-induced proliferation and migration of arthritic FLSs, but showed little effects on survival and apoptosis. In addition, IPT treatment signi cantly reduced TNFα-induced transcripts of proin ammatory cytokines (IL-1β, TNFα, IL-6 and IL-8) in arthritic FLSs. Further mechanism studies suggested that IPT inhibited the activations of p38 and ERK. Also, IPT blocked NF-κB activation via suppressing degradation of IκBα, and preventing the translocation of p65. Conclusion: Our results demonstrated that IPT could inhibit the over-activated phenotypes of arthritic FLSs via MAPK (p38 and ERK) and NF-KB pathways. These ndings suggested IPT has the potential to be developed as a novel agent for RA treatment.

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