The Mechanism of Osteoprotegerin-Induced Osteoclast Pyroptosis In Vitro

Abstract

Osteoprotegerin (OPG) is a new member of the tumor necrosis factor (TNF) receptor superfamily, which can inhibit the differentiation and activity of osteoclasts by binding to nuclear factor kappa B receptor activator (RANK) competitively with nuclear factor kappa B receptor activator ligand (RANKL). The previous experiments found that OPG can induce apoptosis of mature osteoclasts in vitro, which can inhibit the activity of mature osteoclasts, thereby exerting its role in protecting bone tissue. In addition, pyroptosis is a new type of cell death that is different from apoptosis. It is unclear whether OPG can induce mature osteoclast pyroptosis and thereby play its role in protecting bone tissue. In this study, the results showed that compared with the control group, the survival rate of osteoclasts in the OPG group was significantly reduced, and the contents of IL-1β, IL-18, and LDH in the supernatant both increased. Many osteoclast plasma membranes were observed to rupture in bright fields, and OPG induced loss of their morphology. Flow cytometry was used to analyze the pyroptosis rate; OPG significantly increased the osteoclast pyroptosis rate. To further reveal the mechanism of OPG-induced osteoclast pyroptosis, we examined the expression level of pyroptosis-related genes and proteins, and the results found that OPG increased the expression of NLRP3, ASC, caspase-1, and GSDMD-N compared with the control group. In summary, OPG can induce osteoclast pyroptosis, and its mechanism is related to the expression levels of ASC, NLRP3, caspase 1 and GSDMD, which were included in the classical pathway of pyroptosis.

Identification of pyroptosis-associated genes with diagnostic value in calcific aortic valve disease

“…TREM1, TNFRSF11B and PGF were positively correlated with caspase-1-induced pyroptosis genes (CASP1, NLRP3, PYCARD, IL1B and IL18). Previous studies also reported that these three diagnostic genes increased the expression of NLRP3 and promoted several diseases, such as septic cardiomyopathy via pyroptosis ( 29 , 39 , 43 ). Five pyroptosis-related genes were positively correlated with IL6 and TNF, but negatively correlated with SOX9.…”

“…TNFRSF11B, also known as osteoprotegerin (OPG), is a secretory protein that interacts with receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL) ( 29 , 30 ). TNFRSF11B was associated with increased expression of NLRP3, caspase 1 and GSDMD, and induced osteoclast pyroptosis to protect the bone tissues ( 29 ). TNFRSF11B plays a significant role in several cardiovascular diseases, including coronary artery syndromes and myocardial infarction ( 31 ).…”

Programmed cell death of periodontal ligament cells

“…Exposure of murine long bone osteocyte‐Y4 bone cells to fluid shear stress (FSS) led to an increase in OPG expression (Liu, Tang, et al, 2022). OPG not only induced osteoclast apoptosis but also significantly increased the rate of pyroptosis in osteoclastse, which is related to the expression levels of apoptosis‐associated speck‐like protein containing a CARD, pyrin domain‐containing 3 (Pyrin domain containing protein 3 [NLRP3]), caspase‐1, and GSDMD‐N in the classic pyroptosis pathway (Zhu et al, 2023).…”

C-C Motif Chemokine Ligand 5 (CCL5) Promotes Irradiation-Evoked Osteoclastogenesis

“…The expression profile of 110+ SASP components secreted by IR-induced senescent OCYs was established in our laboratory previously using a cellular multifactor antibody microarray assay [8,17]. Based on the results of previous experiments, in conjunction with the bioinformatic analysis and literature search, in this study, we focus on the C-C motif chemokine ligand 5 (CCL5), which plays a regulatory role in osteoclastogenesis [18][19][20][21], given the fact that CCL5 promotes the migration of OC precursor cells in a concentration-dependent manner, enhancing osteoclastogenesis. Accordingly, CCL5 can not only stimulate the elevated intracellular Ca 2+ concentrations and prolonged calcium flow, which results in hyperphosphorylation and extensive cellular activation, but it can also activate the JAK1/STAT3 pathway, which is a stressful inflammatory signaling pathway that has the ability to cascade the production and secretion of key SASP factors, especially CCL5, that regulate bone metabolism.…”