periplocin and Inflammation

Osteoporosis is a common inflammaging-related condition, where long-term accumulation of pro-inflammatory cytokines causes massive bone loss. Periplocin, a cardiotonic steroid isolated from Periploca forrestii, has been proved to reduce inflammation in several inflammatory diseases, such as rheumatoid arthritis. However, its effect and mechanism of inflammation in osteoporosis, in which pro-inflammatory factors accelerate bone loss, has not been well demonstrated. In this study, periplocin attenuated receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation of bone marrow-derived macrophages (BMMs) and RAW264.7 cells in vitro. It reduced osteoclast numbers and bone resorption in a concentration- and time-dependent manner. Further, periplocin treatment resulted in reduced bone loss on mice with ovariectomy-induced osteoporosis in vivo. By transcriptome sequencing, periplocin was indicated to function through inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways and attenuating interactions between NF-κB and nuclear factor of activated T-cells 1 (NFATc1). It was further detected to bind low density lipoprotein receptor-related protein 4 (LRP4) in osteoclasts to exert anti-inflammatory and anti-osteoclastic effects. Overall, the findings have highlighted a better understanding for the anti-inflammatory and anti-osteoclastic role of periplocin in osteoporosis and its mechanism, bringing new possibilities for osteoporosis treatment.

Topics: Animals; Anti-Inflammatory Agents; Bone Resorption; Cell Differentiation; Female; Inflammation; Mice; NF-kappa B; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Osteoporosis; RANK Ligand; Receptors, LDL

Apoptotic resistance and excessive proliferation of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) stimulated by inflammation could lead to distal joint destruction and bone damage. Periplocin could promote apoptosis, resist proliferation, and reduce inflammation. However, the effect and mechanism toward periplocin in proliferation and inflammation of RA-FLSs remain unclear. The role of tumor necrosis factor (TNF)-α induced proliferation and expression of inflammatory cytokines in RA-FLSs was established. Our studies noted that cell viability of TNF-α-induced RA-FLSs was inhibited in periplocin treatment via dose-response, whereas cell apoptosis of RA-FLSs was triggered by dose-dependent effect of periplocin. Bcl-2 protein, one of the apoptotic regulators, was downregulated, while other regulators of apoptosis, including BAX, cleaved caspase-3, and cleaved caspase-9, were upregulated in RA-FLSs under periplocin treatment. In addition, periplocin decreased the TNF-α-induced mRNA and protein expression levels of interleukin (IL)-1β and IL-6 in RA-FLSs in a dose-dependent way. Finally, the increased levels of phospho (p)-inhibitor of kappa B (IκBα)/IκBα and p-NF (nuclear factor)-κB/nuclear factor kappa B (NF-κB) ratio of RA-FLSs stimulated by TNF-α were decreased by periplocin treatment. Taken together, periplocin treatment decreased cell viability and cytokines expression and promoted cell apoptosis of TNF-α-induced RA-FLSs through inhibition of NF-κB signaling pathway, providing a potential therapeutic approach for RA.

Topics: Apoptosis; Arthritis, Rheumatoid; Cell Movement; Cell Proliferation; Cells, Cultured; Cytokines; Fibroblasts; Humans; Inflammation; NF-kappa B; Saponins; Signal Transduction; Synoviocytes; Tumor Necrosis Factor-alpha