Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic inflammation, pain and joint remodeling. Existing RA therapies such analgesics and anti-inflammatories can treat symptoms. More recent strides in disease modifying anti-rheumatic drugs (DMARDs) can slow progression of disease. However, there is still no therapeutic that can reverse disease damage and there is no cure for RA. Resolvin E1 (RvE1) is an endogenous lipid initially identified as a key pro-resolving mediator. By tamping down expression of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), RvE1 is able to down-modulate inflammation and return an inflamed tissue to a homeostatic state. More recently, RvE1 has been shown to act directly to inhibit inflammatory pain through central and peripheral nervous system mechanisms. RvE1 has also been shown to restore bone homeostasis by balancing osteoclast and osteoblast activity. In contrast to current therapeutics that treat symptoms and slow disease progression, a RvE1 pathway agonist has the potential to reverse RA by resolving inflammation, reversing bone remodeling and returning joints to normal homeostasis.

Periodontal disease is initiated by bacterial plaque that induces a chronic inflammatory condition with subsequent leukocyte infiltration, osteoclast activation and alveolar bone resorption. The ideal treatment for periodontal disease is the complete regeneration of the lost periodontium. Resolvin E1 (RvE1) is an endogenous anti-inflammatory lipid mediator derived from omega-3 fatty acids. Animal studies showed that topical treatment of periodontitis with RvE1 significantly decreased osteoclast counts, prevented alveolar bone loss, and restored lost periodontal tissues including bone. It is not known if RvE1 directly impacts osteoblast functions and bone formation. The objective of this study was to determine RvE1 mechanism of action on osteoblasts. Results showed that topical RvE1 treatment prevented the progression of ligature-induced periodontitis in mice compared to the vehicle. RvE1 receptor, chemR23, was expressed in murine calvaria osteoblasts and the expression was not changed in the inflammatory environment with or without RvE1 treatment. RvE1 treatment resulted in a significant increase in the ALP activity after 2 and 7 days of treatment compared to the control as well as in the inflammatory milieu. Similarly, RvE1 treatment enhanced murine calvaria osteoblasts mineralization in vitro compared to the inflammatory environment. The proliferation of mouse calvaria osteoblasts was significantly increased with RvE1 treatment after 2 and 10 days of treatment compared to the control. Results for evaluating the impact of RvE1 on OPG/RANKL axis showed that RvE1 treatment markedly elevated OPG production compared to the IL-6/IL-6R treatment and decreased RANKL. Overall, RvE1 increased the OPG/RANKL ratio to favor bone formation. RvE1 treatment resulted in a significant increase in the phosphorylation of AKT, ERK1/2 and ribosomal S6 (rS6) kinase. Those pathways were further confirmed via using specific pharmacological inhibitors which showed a significant reduction in OPG production and in the osteoblast proliferation as well. In conclusion, RvE1 has a positive anabolic impact in ligature-induced periodontitis model via direct actions on osteoblasts. RvE1 increases the OPG/RANKL production ratio favoring the bone formation through a pathway that includes phosphorylation of AKT, ERK1/2 and rS6 kinase. The data suggest that RvE1 stimulates bone formation in inflammatory conditions by directly modulating both the osteoclast and osteoblast functions.