Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: involvement of circadian clock genes

Abstract

Rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most prevalent joint diseases. A such, they are important causes of pain and disability in a substantial proportion of the human population. A common characteristic of these diseases is the erosion of articular cartilage and consequently joint dysfunction. Melatonin has been proposed as a link between circadian rhythms and joint diseases including RA and OA. This hormone exerts a diversity of regulatory actions through binding to specific receptors and intracellular targets as well as having receptor-independent actions as a free radical scavenger. Cytoprotective effects of melatonin involve a myriad of prominent receptor-mediated pathways/molecules associated with inflammation, of which the role of omnipresent NF-κB signalling is crucial. Likewise, disturbance of circadian timekeeping is closely involved in the aetiology of inflammatory arthritis. Melatonin is shown to stimulate cartilage destruction/regeneration through direct/indirect modulation of the expression of the main circadian clock genes, such as BMAL, CRY and/or DEC2. In the current article, we review the effects of melatonin on RA and OA, focusing on its ability to regulate inflammatory pathways and circadian rhythms. We also review the possible protective effects of melatonin on RA and OA pathogenesis.

Melatonin attenuates TNF‐α and IL‐1β expression in synovial fibroblasts and diminishes cartilage degradation: Implications for the treatment of rheumatoid arthritis

“…Anti‐inflammatory effects of melatonin involve several signaling pathways and molecules, such as MAPK, NF‐κB, arachidonic acid, toll‐like receptors, amongst others . These wide‐spectrum anti‐inflammatory actions of melatonin eventually lead to the blockade of the NF‐κB signaling pathway . In osteoarthritis, a low‐grade inflammatory arthritis, the anti‐inflammatory activities of melatonin, occur through the inhibition of proinflammatory cytokines and blockade of the PI3K/AKT, p38, ERK, and NF‐κB cascades .…”

“…15 However, the role of melatonin in RA is controversial. Evidence suggests that melatonin may promote the progression of RA through proinflammatory activities [16][17][18] and dysregulation of circadian clock genes, 19 whereas other investigations have demonstrated that melatonin possesses anti-inflammatory responses in adjuvant-induced arthritis rats 20 and antiproliferative effects in human rheumatoid fibroblast-like synoviocytes (FLS). 21 Notably, on the strength of its antioxidant effects in clinical investigations, 22 researchers have suggested that melatonin is appropriate as adjunctive therapy in the treatment of RA.…”

Melatonin in macrophage biology: Current understanding and future perspectives

“…53 Another melatonin-related player to be considered in the future is SIRT1, which is upregulated in nontumor cells by melatonin and shares with melatonin several anti-inflammatory properties by inhibiting or downregulating several factors discussed in this review, such as HMGB1, TLR4, mTORC1, NLRP3, and NF-κB, as recently summarized. 16 Considering that circadian rhythms govern immune cell function (eg, cytokines production and clearance of bacterial or viral pathogens), 270,271 its disruption gives rise to the occurrence of diverse inflammatory diseases [272][273][274] ; therefore, it is necessary to further investigate the potential effects of melatonin in synchronizing peripheral macrophage rhythms. Melatonin has beneficial effects on macrophage-associated diseases (eg, cancer and parasite infections) by regulating macrophage responses.…”

The roles of Wnt/β‐catenin pathway in tissue development and regenerative medicine

“…Therefore, regenerative medicine has become the center of attention in recent decades and opens new avenues in the offering therapies for patients with end‐stage organ failure. Since Wnt/β‐catenin signaling pathway has essential roles in the regulation of the progenitor cell fate, developmental decisions, proliferation during embryonic development, and adult tissue homeostasis, it has been the subject of a huge number of researches for investigating its possible role in progenitor cell function during regeneration (Badalzadeh et al, ; Jahanban‐Esfahlan, Mehrzadi et al, ). Multiple studies have reported the expression of Wnt ligands and components of the β‐catenin signaling pathway in regenerating amphibian and fish appendages, and other studies have documented that Wnt/β‐catenin signaling is functionally contributed in the proliferation of cells during regeneration of mammalian muscle, liver, and bone (Stoick‐Cooper, Weidinger et al, ).…”