Daphnetin attenuates LPS‐induced osteolysis and RANKL mediated osteoclastogenesis through suppression of ERK and NFATc1 pathways

Abstract

Aseptic prosthetic loosening and periprosthetic infection resulting in inflammatory osteolysis is a leading complication of total joint arthroplasty (TJA). Excessive bone destruction around the bone and prosthesis interface plays a key role in the loosening prostheses leading to revision surgery. The bacterial endotoxins or implant‐derived wear particles‐induced inflammatory response is the major cause of the elevated osteoclast formation and activity. Thus, agents or compounds that can attenuate the inflammatory response and/or inhibit the elevated osteoclastogenesis and excessive bone resorption would provide a promising therapeutic avenue to prevent aseptic prosthetic loosening in TJA. Daphnetin (DAP), a natural coumarin derivative, is clinically used in Traditional Chinese Medicine for the treatment of rheumatoid arthritis due to its anti‐inflammatory properties. In this study, we report for the first time that DAP could protect against lipopolysaccharide‐induced inflammatory bone destruction in a murine calvarial osteolysis model in vivo. This protective effect of DAP can in part be attributed to its direct inhibitory effect on RANKL‐induced osteoclast differentiation, fusion, and bone resorption in vitro. Biochemical analysis found that DAP inhibited the activation of the ERK and NFATc1 signaling cascades. Collectively, our findings suggest that DAP as a natural compound has potential for the treatment of inflammatory osteolysis.

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

“…LPS-induced calvarial osteolysis model was established as the previous studies (Fu et al, 2019; Wu et al, 2019). In brief, the animals were randomly divided into four groups (n = 10): PBS control (sham), LPS injection (5 mg/kg body weight) (vehicle), and LPS together with different concentrations of Phil (5 and 10mg/kg).…”

[Retracted] Exosome: Function and Application in Inflammatory Bone Diseases

“…Then, kinases, such as NF- κ B, extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38 are activated [ 66 ]. Eventually, osteoclast precursor cells differentiate into osteoblasts by expressing c-Fos and nuclear factor of activated T cells (NFATc1), transcription factors of specific genes, such as tartrate-resistant acid phosphatase (TRAP), and cathepsin K, for osteoclast differentiation [ 67 , 68 ]. As in inflammation, exosomes are involved in several processes, such as promoting osteolysis and inhibition of osteolysis ( Figure 3 ).…”

Pregnenolone Inhibits Osteoclast Differentiation and Protects Against Lipopolysaccharide-Induced Inflammatory Bone Destruction and Ovariectomy-Induced Bone Loss

“…The importance of these signaling molecules and transcription factors in osteoclast biology are exemplified by numerous genetic and pharmacological studies. Genetic deficiency of NF-kB, MAPK, c-Fos, and NFATc1 have led to osteopetrotic phenotypes in mice (Iotsova et al, 1997;Matsuo et al, 2000;Klein et al, 2006;Thouverey and Caverzasio, 2012), whereas pharmacological inhibition studies that impairs the activation of these signaling cascades show promise as therapeutic agents against osteolytic conditions (Zhang et al, 2018;Xiao et al, 2019;Wu et al, 2019).…”