Jatrorrhizine Hydrochloride Suppresses RANKL-Induced Osteoclastogenesis and Protects against Wear Particle-Induced Osteolysis

Abstract

Wear particle-induced aseptic prosthetic loosening is a major complication associated with total joint arthroplasty (TJA). A growing body of evidence suggests that receptor activator of nuclear factor κ-B ligand (RANKL)-stimulated osteoclastogenesis and bone resorption are responsible for peri-implant loosening. Thus, agents which attenuate excessive osteoclast differentiation and function have been considered to offer therapeutic potential for prolonging the life of TJA implants. Jatrorrhizine hydrochloride (JH), a major protoberberine alkaloid isolated from the traditional Chinese herb Coptis chinensis, has been reported to have antimicrobial, antitumor, and antihypercholesterolemic and neuroprotective activities. However, its effects on osteoclast biology remain unknown. Here, we found that JH inhibited RANKL-induced osteoclast formation and bone resorption in vitro and exerted protection against titanium (Ti) particle-induced osteolysis in vivo. Biochemical analysis demonstrated that JH suppressed RANKL-induced activation of MAPKs (p38 and ERK) which down-regulated the production of NFATc1 and NFATc1-regulated osteoclastic marker genes, such as TRAP, CTR and CTSK. Collectively, our findings suggest that JH may be a promising anti-osteoclastogenesis agent for treating periprosthetic osteolysis or other osteoclast-related osteolytic diseases.

IL-35 and RANKL Synergistically Induce Osteoclastogenesis in RAW264 Mouse Monocytic Cells

“…It has been reported that specific genes, such as cathepsin K, MMP-9, and TRAP, are upregulated in response to RANKL [25][26][27]. Our results demonstrated that the expression of these osteoclastspecific genes was increased by RANKL, and IL-35 enhanced such gene expression similarly to other cytokines including IL-17 and IL-15 [28,29].…”

Phillyrin Attenuates Osteoclast Formation and Function and Prevents LPS-Induced Osteolysis in Mice

“…However, the number and area of osteoclast were significantly suppressed by Phil treatment in a dose-dependent manner ( Figures 2B, C ). To determine at which stages Phil suppressed osteoclast formation, 10µM Phil was added at different differentiation time points, as our previous report (Li et al, 2018). As shown in Figures 2D, E , Phil treatment on day 3 of the 5-day culture (late treatment) had little effect on osteoclast formation.…”

“…BMM cells were isolated, purified, and cultured as our previous reports (Liu et al, 2015; Li et al, 2018). These cells were plated into 96-well plates at a density of 8×10 3 per well (in triplicate) and treated with various doses of Phil (0, 2.5, 5, 10, and 20µM) in the presence of M-CSF (30 ng/ml) and RANKL (100 ng/ml) for 5 days.…”

“…F-actin ring-formation assay was performed according to our previous report (Li et al, 2018). In brief, after pretreating with varying doses of Phil for 2 days, the mature osteoclasts cultured on bone slices were fixed with 4% paraformaldehyde for 15 min and then permeabilized with 0.5% Triton X-100 for 10 min.…”

Potential Advantages of Bioactive Compounds Extracted From Traditional Chinese Medicine to Inhibit Bone Destructions in Rheumatoid Arthritis

“…on the other hand, it can directly inhibit osteoclast-mediated bone resorption ( Bao et al., 2017 ; Liu et al., 2018 ). NFATc1 is one of the important transcription factors that induce osteoclast differentiation, and it can induce the formation of osteoclast specific genes such as TRAP, CTR and CTSK ( Li H. et al., 2018 ). Recent studies have shown that NFATc1 is mainly activated through NF-κB and Ca 2+ signaling pathways ( Bendickova et al., 2017 ).…”