The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

Abstract

The balance between bone formation and bone resorption is closely related to bone homeostasis. Osteoclasts, originating from the monocyte/macrophage lineage, are the only cell type possessing bone resorption ability. Osteoclast overactivity is thought to be the major reason underlying osteoclast‐related osteolytic problems, such as Paget's disease, aseptic loosening of prostheses and inflammatory osteolysis; therefore, disruption of osteoclastogenesis is considered a crucial treatment option for these issues. WKYMVm, a synthetic peptide, which is a potent FPR2 agonist, exerts an immunoregulatory effect. This peptide inhibits the production of inflammatory cytokines, such as (IL)‐1β and TNF‐α, thus regulating inflammation. However, there are only few reports on the role of WKYMVm and FPR2 in osteoclast cytology. In the current study, we found that WKYMVm negatively regulates RANKL‐ and lipopolysaccharide (LPS)‐induced osteoclast differentiation and maturation in vitro and alleviates LPS‐induced osteolysis in animal models. WKYMVm down‐regulated the expression of osteoclast marker genes and resorption activity. Furthermore, WKYMVm inhibited osteoclastogenesis directly through reducing the phosphorylation of STAT3 and NF‐kB and indirectly through the CD9/gp130/STAT3 pathway. In conclusion, our findings demonstrated the potential medicinal value of WKYMVm for the treatment of inflammatory osteolysis.

The Effect of WKYMVm Peptide on Promoting mBMSCs Secrete Exosomes to Make M2 Macrophages Polarization Through FPR2 Pathway

“…According to our previous study, WKYMVm peptide could activate the FPR2 pathway in MSCs [20]. In this study, we found that when the FPR2 pathway was activated, the expression of ISG15 in mBMSCs was decreased signi cantly compared with the control group without WKYMVm peptide (Figure 2A,2B).…”

“…Furthermore, exosomes containing many biological molecules, such as proteins, enzymes and miRNAs, which have important physiological or pathological effects [24]. On the other hand, according to our previous studies, WKYMVm peptide, as a powerful activator of FPR2 pathway, can activate the FPR2 pathway in MSCs [20]. However, when the FPR2 pathway of MSCs is activated, what kind of changes will take place, and what impact on the secreted exosomes of MSCs, and what effects of secreted exosomes on the differentiation of macrophages are rarely reported.…”

“…The murine bone marrow-derived macrophage cell line RAW264.7 cells were purchased from American Type Culture Collection (ATCC). According to our team's previous research results [20], we choose WKYMVm peptide as the activator of FPR2 pathway. The WKYMVm peptide with purity more than 95% was synthesized by GL Biochem company and dissolved in acetonitrile.…”

Effect of RvD1/FPR2 on inflammatory response in chorioamnionitis

“…To address the question of how FPR2 plays a role in women with CAM, we detected the location and expression of its downstream target proteins. It was reported that FPR2 was closely associated with inflammation and pregnancy immunity adaptation through NF‐κB pathway 20,21 . Accordingly, we hypothesized that FPR2 participated in the process of CAM through PPARγ/NF‐κB pathway.…”

Activation of the pro-resolving receptors Fpr2/3 attenuate lipopolysaccharide-induced inflammatory microglial activation

“…Our data moreover, indicate an important role for Fpr2/3 in restraining NFκB signalling via inhibition of IκBα degradation, extending our understanding of the receptor’s intracellular signalling pathways (Cooray et al, 2013), as well as highlighting its potential to modulate pro-inflammatory signalling. The modulation of LPS-induced NFκB by Fpr2/3 stimulation has been reported recently in both monocyte (de Gaetano et al, 2019) and osteoclast (Hu et al, 2020) cell lines, suggesting it may be a common feature of macrophage-lineage cells. As microglia are known to rapidly upregulate Fpr2/3 expression following inflammatory insult (Kirkley et al, 2017), this serves as a further indication for the importance of this receptor in inflammatory regulation, emphasising the concept that inflammatory resolution is an intrinsic, programmed part of the inflammatory response (Serhan and Savill, 2005).…”