Abstract

Resolvins are endogenous lipid mediators derived from omega-3 fatty acids. Resolvin E1 (RvE1), derived from eicosapentaenoic acid (EPA), modulates osteoclasts and immune cells in periodontal disease models. The direct role of RvE1 in bone remodeling is not well understood. The objective of this study was to determine the impact of RvE1 on bone remodeling under inflammatory conditions. Our working hypothesis is that RvE1 downregulates bone resorption through direct actions on both osteoblast and osteoclast function in inflammatory osteoclastogenesis. A tumor necrosis factor-α induced local calvarial osteolysis model with or without the systemic administration of RvE1 was used. To evaluate osteoclastogenesis and NFκB signaling pathway activity, murine bone tissue was evaluated by Micro CT (μCT) analysis, TRAP staining, and immunofluorescence analysis. Mechanistically, to evaluate the direct role of RvE1 impacting bone cells, primary calvarial mouse osteoblasts were stimulated with interleukin (IL)-6 (10 ng/ml) and IL-6 receptor (10 ng/ml) and simultaneously incubated with or without RvE1 (100 nM). Expression of receptor activator of NFκB ligand (RANKL) and osteoprotegerin (OPG) was measured by ELISA. RNA sequencing (RNA-Seq) and differential expression analysis was performed to determine signaling pathways impacted by RvE1. The systemic administration of RvE1 reduced calvarial bone resorption as determined by µCT. Histologic analysis of calvaria revealed that osteoclastogenesis was reduced as determined by number and size of osteoclasts in TRAP-stained sections (p < 0.05). Immunofluorescence staining of calvarial sections revealed that RvE1 reduced RANKL secretion by 25% (p < 0.05). Stimulation of osteoblasts with IL-6 increased RANKL production by 30% changing the RANKL/OPG to favor osteoclast activation and bone resorption. The ratio changes were reversed by 100 nM RvE1. RvE1 decreased the production of RANKL maintaining an RANKL/OPG more favorable for bone formation. RNA-Seq and transcriptomic pipeline analysis revealed that RvE1 significantly downregulates osteoclast differentiation mediated by differential regulation of NFκB and PI3K–AKT pathways. RvE1 reduces inflammatory bone resorption. This action is mediated, at least in part, by direct actions on bone cells promoting a favorable RANKL/OPG ratio. Mediators of resolution in innate immunity also directly regulate bone cell gene expression that is modulated by RvE1 through at least 14 specific genes in this mouse model.

Highlights

  • The niche mediators and cells shaping metabolic control of bone tissue tightly regulate bone-remodeling circuitry

  • lipid peroxidation products Regulates skeletal myogenesis May act as an adaptor molecule in the JAK

  • STAT signaling pathway Provides protection of neurons against serum deprivation-induced apoptosis The protein encoded by this gene belongs to the glutathione peroxidase family

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Summary

Introduction

The niche mediators and cells shaping metabolic control of bone tissue tightly regulate bone-remodeling circuitry. The coupling activities between mesenchymal origin bone forming cells, osteoblasts, with the myeloid origin bone resorbing cells, osteoclasts, are modulated by receptor activator of NFκB ligand (RANKL) and osteoprotegerin (OPG) biological actions [1, 2]. Inflammatory cytokines produced by osteoblasts and osteoclasts, including interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), activate the bone microenvironment, boosting expression of RANK and bone resorption phenotype [3]. In chronic inflammatory conditions including periodontitis and rheumatoid arthritis, persistent chronic inflammation leads to loss of bone mass and volume, and is consistently accompanied by an increase in local expression of RANKL [4,5,6,7,8]. Understanding activation and resolution (termination) of inflammation has potential impact in bone metabolism and human health

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