Insight into the roles of melatonin in bone tissue and bone‑related diseases (Review)

Abstract

Bone‑related diseases comprise a large group of common diseases, including fractures, osteoporosis and osteoarthritis (OA), which affect a large number of individuals, particularly the elderly. The progressive destruction and loss of alveolar bone caused by periodontitis is a specific type of bone loss, which has a high incidence and markedly reduces the quality of life of patients. With the existing methods of prevention and treatment, the incidence and mortality of bone‑related diseases are still gradually increasing, creating a significant financial burden to societies worldwide. To prevent the occurrence of bone‑related diseases, delay their progression or reverse the injuries they cause, new alternative or complementary treatments need to be developed. Melatonin exerts numerous physiological effects, including inducing anti‑inflammatory and antioxidative functions, resetting circadian rhythms and promoting wound healing and tissue regeneration. Melatonin also participates in the health management of bone and cartilage. In the present review, the potential roles of melatonin in the pathogenesis and progression of bone injury, osteoporosis, OA and periodontitis are summarized. Furthermore, the high efficiency and diversity of the physiological regulatory effects of melatonin are highlighted and the potential benefits of the use of melatonin for the clinical prevention and treatment of bone‑related diseases are discussed.

Keywords: melatonin; bone injury; osteoporosis; osteoarthritis; periodontitis.

Figure 1

Melatonin contributes to bone repair. Melatonin reduces bone resorption by decreasing the levels of ROS and RANKL, which represent the decreased oxidative stress and osteoclastogenesis, respectively. Melatonin increases new bone regeneration by promoting the proliferation and migration, as well as the chondrogenic and osteogenic differentiation of MSCs. Melatonin also increases the level of VEGF and contributes to angiopoiesis at the site of bone injury, further promoting healing and preventing ischemic injuries. In surgeries following bone injuries, the application of melatonin helps to improve the sleep quality of patients and relieve pain. The combined application of melatonin and bone graft materials also has certain value. ROS, reactive oxygen species; RANKL, receptor activator of NF-κB ligand; MSCs, mesenchymal stem cells; VEGF, vascular endothelial growth factor.

Figure 2

Positive effects of melatonin on osteoporosis. Osteoporosis often occurs in elderly and menopausal women. Melatonin production decreases in both groups and MTNR1A on the surface of osteoblasts decreases in elderly. Exogenous melatonin supplementation is effective and safe, bringing more osteoblasts and less osteoclasts. Melatonin application can reduce the high levels of the NLRP3 inflammasome in subjects suffering from estrogen deficiency. Melatonin also attenuates the autophagy of osteoblasts in patients with DM, which is considered to be beneficial in reducing bone loss. In addition, melatonin regulates calcium metabolism and prevents osteoporosis. MTNR1A, melatonin receptor 1A; NLRP3, nucleotide-binding domain and the leucine-rich repeat pyrin 3 domain; DM, diabetes mellitus.

Figure 3

Pathogenesis of OA and potential roles of melatonin. The direct cause of OA is the decrease of cartilage ECM. Inflammation and strenuous exercise lead to an increased ROS production, activating oxidative stress, inhibiting chondrocytes viability, and decreasing the production of ECM components. Pro-inflammatory cytokines promote chondrocytes hypertrophy and then reduce ECM synthesis. Additionally, pro-inflammatory cytokines decrease miR-140 production in chondrocytes, inhibit the viability and chondrogenic differentiation of MSCs and increase the production of ECM degradation enzymes. All these mechanisms promote the loss of ECM. Oxidative stress also leads to decreased viscosity of synovial fluid. Pro-inflammatory cytokines are also associated with pain and hyperalgesia. The abnormal expression of clock-related genes, such as the decrease in Bmal1 expression and the increase in Per2 expression, is also considered to be related to the occurrence of OA. Melatonin application can effectively antagonize the above-mentioned processes, reducing the level of oxidative stress and inflammation and restoring the normal expression of clock genes. Moreover, melatonin can upregulate TGF-β expression to increase ECM synthesis. Intra-articular injections of glucocorticoids can relieve inflammation and pain, but may also be associated with the risk of aggravating ECM loss. Melatonin can alleviate this adverse reaction. In addition, melatonin treatment combined with mild to moderate exercise may do better in OA therapeutic process. OA, osteoarthritis; ECM, extracellular matrix; ROS, reactive oxygen species; Bmal1, brain and muscle ARNT-like 1; Per2, period circadian regulator 2; TGF-β, transforming growth factor β.

Figure 4

Melatonin promotes periodontal healing. Melatonin is considered to have the properties of antibiosis, regulating of the balance of RANKL and OPG, and reducing pro-inflammatory factors and ROS production in periodontal tissues. Melatonin cannot only reduce the number of osteoclasts and increase that of osteoblasts in alveolar bone, but can also increase that of cementoblasts. The ability of melatonin to restore lipid metabolism is also beneficial to periodontal healing because of the mutual promotion of obesity and periodontitis. In addition, the improvement of sleep quality is helpful. On the whole, melatonin application can effectively improve CAL and reduce PD, further promote periodontal healing. RANKL, receptor activator of NF-κB ligand; OPG, osteoprotegerin; ROS, reactive oxygen species; CAL, clinical attachment level; PD, probing depth.

Figure 5

Roles of melatonin in bone tissue and bone-related diseases. Melatonin plays an important role in bone health. Melatonin promotes the proliferation, osteogenic and chondrogenic differentiation of MSCs, accelerating cartilage and bone formation. Moreover, melatonin inhibits osteoclasts production and prevents bone loss. The level of ROS is significantly inhibited by melatonin, which is associated with a decreased level of oxidative stress. In particular, melatonin can increase VEGF and promote angiopoiesis at the sites of bone injury, avoiding ischemic injury. The melatonin properties of reducing the level of NLRP3 inflammasome helps restore bone metabolic balance. In patients with DM, autophagy of osteoblasts is inhibited by melatonin and this effect is participated in the protection of bone health in DM patients. When used in OA, melatonin can reduce the adverse effects of intra-articular GC injection. In addition, melatonin also has an antibacterial effect on periodontitis bacteria. Metabolism of bone and cartilage is closely associated with circadian rhythm. As an important hormone regulating circadian rhythm, melatonin helps restore the circadian rhythm and this also exerts a positive effect on bone tissue and bone disease. MSCs, mesenchymal stem cells; ROS, reactive oxygen species; NLRP3, nucleotide-binding domain and the leucine-rich repeat pyrin 3 domain; VEGF, vascular endothelial growth factor; DM, diabetes mellitus; OA, osteoarthritis; GC, glucocorticoid.