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The role of melatonin in periodontal and periimplant bone homeostasis and regeneration

July 4, 2016 / Categories: Digital Dentistry, Implant Dentistry

Galindo Moreno, Pablo

Avila Ortiz, Gustavo

Wang, Hom-Lay

Padial Molina, Miguel

Ortega Ollera, Inmaculada

O’Valle Ravassa, Francisco

The objectives of this study are to review the properties of melatonin in regulating bone homeostasis; to discuss its direct and indirect effects on bone; and to propose mechanisms for the use of melatonin as an agent to promote alveolar bone regeneration.

Introduction

Numerous systemic hormonal changes are known to be associated with aging.1Morley JE. Hormones and the aging process. → J Am Geriatr Soc. 2003 Jul;51(7 Suppl):S333–7. Some conditions linked to circadian rhythms and age may alter bone metabolism, resulting in changes in immune activity or bone-associated pathologies,2Eastell R, Calvo MS, Burritt MF, Offord KP, Russell RG, Riggs BL. Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. → J Clin Endocrinol Metab. 1992 Mar;74(3):487–94. such as periodontal disease. These disorders may be associated with alterations in normal levels of melatonin.3Cutando A, Galindo P, Gómez-Moreno G, Arana C, Bolaños J, Acuña-Castroviejo D, Wang HL. Relationship between salivary melatonin and severity of periodontal disease. → J Periodontol. 2006 Sep;77(9):1533–8.4Gómez-Moreno G, Cutando-Soriano A, Arana C, Galindo P, Bolaños J, Acuña-Castroviejo D, Wang HL. Melatonin expression in periodontal disease. → J Periodontal Res. 2007 Dec;42(6):536–40.

Melatonin (N-acetyl-5-methoxytryptamine), a hormone that is endogenously synthesized, primarily in the pineal gland, is a molecule with intense antioxidant activity5Reiter RJ, Tan DX, Poeggeler B, Menendez-Pelaez A, Chen LD, Saarela S. Melatonin as a free radical scavenger: implications for aging and age-related diseases. → Ann N Y Acad Sci. 1994 May;719:1–12. and a wide range of biological actions, notably in the control of metabolism and bone development.6Liu J, Huang F, He HW. Melatonin effects on hard tissues: bone and tooth. → Int J Mol Sci. 2013 May;14(5):10063–74. Melatonin is currently used in therapies as a coadjuvant in cancer therapy,7Rapozzi V, Zorzet S, Comelli M, Mavelli I, Perissin L, Giraldi T. Melatonin decreases bone marrow and lymphatic toxicity of adriamycin in mice bearing TLX5 lymphoma. → Life Sci. 1998 Oct;63(19):1701–13. for anti-aging,8Poeggeler B. Melatonin, aging, and age-related diseases: perspectives for prevention, intervention, and therapy. → Endocrine. 2005 Jul;27(2):201–12. as an immunostimulatory agent9Maestroni GJ. MLT and the immunehematopoietic system. In: Olcese J, editor. Melatonin after four decades: an assessment of its potential. → New York: Springer; 1999. p. 395–405. (Advances in Experimental Medicine and Biology; vol. 460). or as a sleep regulator,10Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, Klassen T. Melatonin for treatment of sleep disorders. → Evid Rep Technol Assess (Summ). 2004 Nov;(108):1–7. as well as to increase bone density in menopausal patients11Ostrowska Z, Kos-Kudla B, Marek B, Swietochowska E, Górski J. Assessment of the relationship between circadian variations of salivary melatonin levels and type I collagen metabolism in postmenopausal obese women. → Neuro Endocrinol Lett. 2001 Apr;22(2):121–7. (Fig. 1). It is reported that salivary melatonin is released by the acinar cells of the major salivary glands and the gingival crevicular fluid. It follows a circadian rhythm, with the highest values at night. Moreover, in the oral cavity, melatonin can act both by receptor-mediated and by receptor-independent pathways.12Reiter RJ, Rosales-Corral SA, Liu XY, Acuna-Castroviejo D, Escames G, Tan DX. Melatonin in the oral cavity: physiological and pathological implications. → J Periodontal Res. 2015 Feb;50(1):9–17. Therefore, through complex molecular pathways that have gained special interest for the research community in periodontology, it may play a role in alveolar periodontal and periimplant bone maintenance and regeneration.

Melatonin is an amphiphilic molecule that is able to cross most biological barriers. It can exert its effect by binding to G-protein-coupled membrane receptors (MT1 and MT2) or by penetrating the cell through a specific family of transmembrane channels,13Reppert SM, Weaver DR, Godson C. Melatonin receptors step into the light: cloning and classification of subtypes. → Trends Pharmacol Sci. 1996 Mar;17(3):100–2. subsequently initiating a nuclear or cytoplasmic molecular cascade. When it reaches the nuclei, melatonin binds to a subfamily of nuclear receptors key in regulating bone metabolism, the RZR (retinoid Z receptor)/ROR (retinoid orphan receptor) receptor.14Meyer T, Kneissel M, Mariani J, Fournier B. In vitro and in vivo evidence for orphan nuclear receptor RORα function in bone metabolism. → Proc Natl Acad Sci U S A. 2000 Aug;97(16):9197–202. It then regulates a number of cellular events, such as promotion of mitosis, induction of DNA repair,15Tan D, Reiter RJ, Chen LD, Poeggeler B, Manchester LC, Barlow-Walden LR. Both physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safrole. → Carcinogenesis. 1994 Feb;15(2):215–8. or cell differentiation and proliferation.16Nakade O, Koyama H, Ariji H, Yajima A, Kaku T. Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro. → J Pineal Res. 1999 Sep;27(2):106–10.

Interestingly, it is known that melatonin can be synthesized in the bone marrow, where its concentration is around 100-fold higher than in serum.17Tan DX, Manchester LC, Reiter RJ, Qi WB, Zhang M, Weintraub ST, Cabrera J, Sainz RM, Mayo JC. Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. → Biochim Biophys Acta. 1999 Oct;1472(1-2):206–14. Furthermore, melatonin in the bone marrow protects its cells against cytotoxic agents in vivo.18Anwar MM, Mahfouz HA, Sayed AS. Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs. → Comp Biochem Physiol A Mol Integr Physiol. 1998 Feb;119(2):493–501. However, the specific biochemical mechanisms that regulate this modulation, specifically in alveolar bone in humans, are currently not fully understood.19Ostrowska Z, Kos-Kudla B, Marek B, Swietochowska E, Górski J. Assessment of the relationship between circadian variations of salivary melatonin levels and type I collagen metabolism in postmenopausal obese women. → Neuro Endocrinol Lett. 2001 Apr;22(2):121–7. Hence, it is the purpose of this review to describe the properties of melatonin in regulating bone homeostasis, directly and indirectly, as well as to analyze different therapeutic strategies for the use of melatonin as an agent to promote periodontal and periimplant bone maintenance and regeneration (Fig. 2).

Direct effects on bone

I. Melatonin and bone formation

The major organic component of bone extracellular matrix is Type I collagen, which supports the expression of bone cell phenotypes and enhances mineralization. Melatonin has been shown to regulate the synthesis of Type I collagen as a preliminary step to the expression of other bone-related proteins, such as bone sialoprotein, alkaline phosphatase and osteocalcin, during osteoblastic maturation.20Nakade O, Koyama H, Ariji H, Yajima A, Kaku T. Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro. → J Pineal Res. 1999 Sep;27(2):106–10.

Bone sialoprotein (BSP) is referred to as a marker of the late stage of osteoblastic differentiation. BSP is expressed during osteoblastic cell differentiation in the extracellular matrix, where it is essential for osteoblast attachment and bone mineralization. Within this context, it has been reported that MC3T3 pre-osteoblast cells matured in 12 days in the presence of melatonin compared with 21 days without melatonin. Gene expression of BSP and related proteins of osteoblastic differentiation (e.g., osteocalcin, alkaline phosphatase) is also accelerated and increased in melatonin-treated compared with nontreated cells.21Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA, Mautalen C. Melatonin effects on bone: experimental facts and clinical perspectives. → J Pineal Res. 2003 Mar;34(2):81–7. Furthermore, by inhibiting the interaction of BSP with osteoblastic cell lines, the activity of alkaline phosphatase, osteocalcin synthesis and cellular response to parathyroid hormone (PTH) are also inhibited22Mizuno M, Imai T, Fujisawa R, Tani H, Kuboki Y. Bone sialoprotein (BSP) is a crucial factor for the expression of osteoblastic phenotypes of bone marrow cells cultured on type I collagen matrix. → Calcif Tissue Int. 2000 May;66(5):388–96. and, subsequently, osteoblast differentiation is impaired.23Cooper LF, Yliheikkilä PK, Felton DA, Whitson SW. Spatiotemporal assessment of fetal bovine osteoblast culture differentiation indicates a role for BSP in promoting differentiation. → J Bone Miner Res. 1998 Apr;13(4):620–32. Thus, these findings suggest that melatonin may have an effect in regulating osteoblast proliferation and differentiation. These effects could lead to beneficial effects in the treatment of pathological processes associated with bone resorption or destruction by mediating not only in the expression of BSP but of other bone glycoproteins as well, resulting in enhanced bone apposition.

Fig. 1

Fig. 1 Melatonin properties.

II. Melatonin and bone resorption

Melatonin also exerts an important direct biological action on the osteoclast, another key cell in bone turnover. The biological activity of osteoclasts is bone resorption, initiated by attachment to the surface of the bone tissue and secreting protons and free radicals into the cell compartment formed below their ruffled border. The activity of osteoclasts is essentially regulated by the molecular triad osteoprotegerin/receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa-B ligand (OPG/RANK/RANKL). The balance and expression of this triad in bone tissue decisively influence differentiation and activation of osteoclasts and play an important role in coordinating osteogenesis, odontogenesis and tooth eruption. The proteins of this triad can be synthesized by a large number of cells, including bone marrow cells, dendritic cells, lymphoid cells and endothelial cells. Osteoblasts are the key cell type in the secretion of OPG and RANKL and, therefore, orchestrate the bone turnover. Changes in the expression balance of this triad can be responsible for hereditary bone disorders, such as familiar expansile osteolysis, expansile skeletal hyperphosphatasia and juvenile Paget’s disease; different forms of osteoporosis; and other metabolic bone diseases.

The OPG/RANK/RANKL triad can be modulated by numerous molecules, including melatonin.24Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. → Cytokine Growth Factor Rev. 2004 Dec;15(6):457–75. Melatonin suppresses osteoclastic and osteoblastic activity by interacting with this triad.25Suzuki N, Hattori A. Melatonin suppresses osteoclastic and osteoblastic activities in the scales of goldfish. → J Pineal Res. 2002 Nov;33(4):253–8. It reduces the expression of RANK in osteoblasts26Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. → J Bone Miner Res. 2002 Jul;17(7):1219–29. and RANK receptor in osteoclasts27Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA, Mautalen C. Melatonin effects on bone: experimental facts and clinical perspectives. → J Pineal Res. 2003 Mar;34(2):81–7. while increasing OPG,28Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. → J Bone Miner Res. 2002 Jul;17(7):1219–29. eventually preventing the appearance and activation of osteoclasts.29Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA, Mautalen C. Melatonin effects on bone: experimental facts and clinical perspectives. → J Pineal Res. 2003 Mar;34(2):81–7. This suggests that melatonin in pharmacological doses can inhibit bone resorption and increase bone mass by down-regulating RANK-mediated osteoclast proliferation and activation.30Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. → J Bone Miner Res. 2002 Jul;17(7):1219–29.

Another important aspect of the relationship between osteoclasts and melatonin concerns the production of free radicals by osteoclasts during osteolysis. Osteoclasts generate high levels of superoxide anions during bone resorption that contribute to the degenerative process of the organic bone matrix. One of the most important mechanisms underlying this resorption involves the protective superoxide-scavenging enzyme superoxide dismutase. Melatonin is a significant free-radical scavenger and antioxidant at both physiological and pharmacological concentrations.31Liu J, Huang F, He HW. Melatonin effects on hard tissues: bone and tooth. → Int J Mol Sci. 2013 May;14(5):10063–74. Beside its ability to directly neutralize a number of free radicals and reactive oxygen and nitrogen species, melatonin stimulates several antioxidative enzymes,32Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA, Mautalen C. Melatonin effects on bone: experimental facts and clinical perspectives. → J Pineal Res. 2003 Mar;34(2):81–7.33Ladizesky MG, Boggio V, Albornoz LE, Castrillón PO, Mautalen C, Cardinali DP. Melatonin increases oestradiol-induced bone formation in ovariectomized rats. → J Pineal Res. 2003 Mar;34(2):143–51. limiting the resorptive osteoclast activity.

Fig 2

Fig. 2 Effects of melatonin on bone.
ALP: alkaline phosphatase;
OC: osteocalcin.

Indirect effects on bone

I. Relationship with hormones and genes involved in bone turnover

Melatonin is an important modulator of calcium and phosphorus metabolism.34Ladizesky MG, Cutrera RA, Boggio V, Somoza J, Centrella JM, Mautalen C, Cardinali DP. Effect of melatonin on bone metabolism in ovariectomized rats. → Life Sci. 2001 Dec;70(5):557–65. In addition to its direct actions on cells that modulate bone homeostasis, melatonin may exert its effects indirectly on the bone system by influencing the activity of important regulators of the phosphorus–calcium balance and bone metabolism. Many studies have indicated that melatonin may influence the release of several factors that affect bone, such as calcitonin,35Turgut M, Uslu S, Uysal A, Yurtseven ME, Ustün H. Changes in vascularity of cartilage endplate of degenerated intervertebral discs in response to melatonin administration in rats. → Neurosurg Rev. 2003 May;26(2):133–8. corticosterone,36Hakanson DO, Bergstrom WH. Pineal and adrenal effects on calcium homeostasis in the rat. → Pediatr Res. 1990 Jun;27(6):571–3. growth factors37Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D. Influence of lighting conditions on daily rhythm of bone metabolism in rats and possible involvement of melatonin and other hormones in this process. → Endocr Regul. 2003 Sep;37(3):163–74. and immunological factors.38Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX. Melatonin and its relation to the immune system and inflammation. → Ann N Y Acad Sci. 2000 Jan;917:376–86.

Calcitonin, together with bisphosphonates and estrogens, is an important regulator of the apoptosis of osteoclasts. It is a powerful inhibitor of osteoclastic resorptive activity by promoting the reduction of contact between osteoclasts and the bone surface, altering the morphology of osteoclasts and decreasing their mobility. Melatonin increases secretion of calcitonin in rats, and this may inhibit bone resorption.39Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D, Ciesielska-Kopacz N. The relationship between the daily profile of chosen biochemical markers of bone metabolism and melatonin and other hormone secretion in rats under physiological conditions. → Neuro Endocrinol Lett. 2002 Oct-Dec;23(5-6):417–25. References Effects of Melatonin on Bone Journal of Oral Science & Rehabilitation 15 Volume 2 | Issue 2/2016

  • PTH increases the expression of RANKL and decreases the expression of OPG. Melatonin decreases the levels of PTH, and this may, indirectly, generate an increase in bone mineralization.40Sandyk R, Anastasiadis PG, Anninos PA, Tsagas N. Is postmenopausal osteoporosis related to pineal gland functions? → Int J Neurosci. 1992 Feb;62(3-4):215–25.
  • Cortisol (also known as hydrocortisone) and other glucocorticoids are increased when melatonin is reduced. They are responsible for inhibiting bone formation through direct actions on osteoblasts by blocking their recruitment and differentiation, and subsequently inhibiting the production of Type I collagen. An increase in cortisol is also responsible for an increase in bone resorption via antagonism of the 1,25-dihydroxyvitamin D. Therefore, as melatonin increases, glucocorticoids are reduced and their pro-resorptive effects are limited.
  • Melatonin also stimulates estrogen secretion and, therefore, limits the associated deleterious effects of deficiency.41Okatani Y, Morioka N, Wakatsuki A. Changes in nocturnal melatonin secretion in perimenopausal women: correlation with endogenous estrogen concentrations. → J Pineal Res. 2000 Mar;28(2):111–8.

II. Action in immune system

The role played by melatonin in the immune system is well documented.42Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. → Endocrine. 2005 Jul;27(2):189–200. The effects of melatonin have been most widely studied in the context of depressed immune systems with the aim of improving immunodeficiency situations. Melatonin regulates the apoptosis of B and T cells and has been reported to accelerate the production of leukocytes.43Guerrero JM, Reiter RJ. Melatoninimmune system relationships. → Curr Top Med Chem. 2002 Feb;2(2):167–79.

In addition to the direct effect on cells of the immune system, melatonin reduces the synthesis of prostaglandins, especially PGE-2; prevents the translocation of nuclear factor-kappa B to the nucleus and its binding to DNA, thereby reducing the up-regulation of a variety of pro-inflammatory cytokines;44Mohan N, Sadeghi K, Reiter RJ, Meltz ML. The neurohormone melatonin inhibits cytokine, mitogen and ionizing radiation induced NF-kappa B. → Biochem Mol Biol Int. 1995 Dec;37(6):1063–70. inhibits the production of adhesion molecules that promotes the adhesion of leukocytes to endothelial cells;45Bertuglia S, Marchiafava PL, Colantuoni A. Melatonin prevents ischemia reperfusion injury in hamster cheek pouch microcirculation. → Cardiovasc Res. 1996 Jun;31(6):947–52. and attenuates transendothelial cell migration and edema, which contribute to tissue damage.46Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX. Melatonin and its relation to the immune system and inflammation. → Ann N Y Acad Sci. 2000 Jan;917:376–86. It also stimulates the release of interleukin-2 in Jurkat cells47Guerrero JM, Pozo D, García-Mauriño S, Osuna C, Molinero P, Calvo JR. Involvement of nuclear receptors in the enhanced IL-2 production by melatonin in Jurkat cells. → Ann N Y Acad Sci. 2000 Jan;917:397–403. and interleukin-6 in peripheral blood mononuclear cells,48Garcia-Mauriño S, Gonzalez-Haba MG, Calvo JR, Goberna R, Guerrero JM. Involvement of nuclear binding sites for melatonin in the regulation of IL-2 and IL-6 production by human blood mononuclear cells. → J Neuroimmunol. 1998 Dec;92(1-2):76–84. while it inhibits the inflammatory enzyme cyclooxygenase-2 (COX-2) and binds to the active sites of COX-1 and COX-2.49De la Rocha N, Rotelli A, Aguilar CF, Pelzer L. Structural basis of the anti-inflammatory activity of melatonin. → Arzneimittelforschung. 2007;57(12):782–6. Therefore, melatonin can inhibit acute inflammatory reaction and contribute to generating an immune reaction, minimizing the associated bone loss.50Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX. Melatonin and its relation to the immune system and inflammation. → Ann N Y Acad Sci. 2000 Jan;917:376–86.

III. Action on free radicals

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One of the principal biological actions of melatoninis its wide antioxidant spectrum and powerful endogenous effect as a free-radical scavenger.51Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. → Acta Biochim Pol. 2003 Jan;50(4):1129–46. Thus, it has an indirect reparative effect and prevents intracellular damage, protecting cells from free radicals and chemical substances. Melatonin acts on oxygen- and nitrogen-derived free radicals,including the highly toxic hydroxyl radical,52Stasica P, Ulanski P, Rosiak JM. Melatonin as a hydroxyl radical scavenger. → J Pineal Res. 1998 Aug;25(1):65–6. peroxynitriteanion53Gilad E, Cuzzocrea S, Zingarelli B, Salzman AL, Szabó C. Melatonin is a scavenger of peroxynitrite. → Life Sci. 1997 Jan;60(10):PL169–74. and hypochlorous acid.54Marshall KA, Reiter RJ, Poeggeler B, Aruoma OI, Halliwell B. Evaluation of the antioxidant activity of melatonin in vitro. → Free Radic Biol Med. 1996 Dec;21(3):307–15. In addition to directly neutralizing free radicals and reactive species of nitrogen and oxygen, melatonin stimulates other antioxidant enzymes, such asglutathione.55Chapple IL. Reactive oxygen species and antioxidants in inflammatory diseases. → J Clin Periodontol. 1997 May;24(5):287–96.

At the bone level, these effects are of vital importance because osteoclasts secrete a wide variety of molecular agents for bone degradation. Free radicals are the highly secreted ones. Osteoclastsgenerate superoxide anions during resorption that contribute to the degradative processes of the organic bone matrix. Other celltypes, such as monocytes, macrophages and neutrophils, accumulate on the adjacent surfaces of the bone in chronic inflammatory processes.These cells have the capacity to produce freeradicals and, as previously mentioned, are able to stimulate osteoclastic response by liberating mediators (cytokines, tumor necrosis factors,etc.). Therefore, the use of anti-free-radicalagents might be an adequate alternative therapy for these types of pathologies, by limiting osteoclastic activation or free-radical production.

Melatonin and periodontal disease

Periodontal disease is caused by a bacterial challenge that triggers an inflammatory reaction in a susceptible host. Alterations in the OPG/RANK/ RANKL complex, among other cytokines and local factors, have been linked to an increase in the periodontal destruction, mediated by the increase in RANKL production by inflammatory cells, mainly macrophages, and the decrease of OPG. Additionally, the periodontal tissue is affected by the free radicals that burst from phagocytic cells, such as neutrophils and macrophages, which significantly damage the gingival tissue.

In view of these common factors and targets, it is reasonable to expect an association between periodontal disease and levels of melatonin.56Cengiz Mİ, Cengiz S, Wang HL. Melatonin and oral cavity. → Int J Dent [Internet]. 2012 Jun 25 [cited 2016 May 4];2012:Article 491872 [9 p.]. Available from: downloads.hindawi.com/journals/ijd/2012/491872.pdf doi:10.1155/2012/491872. Several clinical studies have demonstrated it.57Cutando A, Galindo P, Gómez-Moreno G, Arana C, Bolaños J, Acuña-Castroviejo D, Wang HL. Relationship between salivary melatonin and severity of periodontal disease. → J Periodontol. 2006 Sep;77(9):1533–8.58Gómez-Moreno G, Cutando-Soriano A, Arana C, Galindo P, Bolaños J, Acuña-Castroviejo D, Wang HL. Melatonin expression in periodontal disease. → J Periodontal Res. 2007 Dec;42(6):536–40.59Srinath R, Acharya AB, Thakur SL. Salivary and gingival crevicular fluid melatonin in periodontal health and disease. → J Periodontol. 2010 Feb;81(2):277–83. These studies showed that levels of melatonin in serum, saliva, gingival crevicular fluid or all three are inversely associated with the severity of the disease, which indicates that melatonin may have a protective role against periodontal disease.

Moreover, the effects of melatonin on the reduction of osteoclastogenesis, the capture of reactive oxygen species and their metabolites in the inflamed area, the increase in bone mineralization through the increase in proliferation, differentiation and activity of osteoblasts, and collagen and BSP regulation, as already explained, together with its anti-fibrotic and anti-inflammatory effects on gingival tissue by a reduction of the matrix metalloproteinase-1/tissue inhibitor of metalloproteinases-1 ratio, suggest the possibility of using melatonin as a host-modulating agent in the treatment and control of periodontal disease, improving the bone tissue conditions and the soft-tissue stability.60Gómez-Florit M, Ramis JM, Monjo M. Anti-fibrotic and anti-inflammatory properties of melatonin on human gingival fibroblasts in vitro. → Biochem Pharmacol. 2013 Dec;86(12):1784–90. The in vivo administration of local or systemic melatonin could, therefore, be indicated in these patients, although no studies have yet been performed in this sense with validated methods.

Melatonin and dental implants

Dental implants are commonly used in current treatment of tooth loss. However, to avoid potential early complications and implant failures,61Galindo-Moreno P, Padial-Molina M, Avila G, Rios HF, Hernández-Cortés P, Wang HL. Complications associated with implant migration into the maxillary sinus cavity. → Clin Oral Implants Res. 2012 Oct;23(10):1152–60.62Galindo-Moreno P, Padial-Molina M, Sánchez-Fernández E, Hernández-Cortés P, Wang HL, O’Valle F. Dental implant migration in grafted maxillary sinus. → Implant Dent. 2011 Dec;20(6):400–5. bone healing must occur in the proper way. Bone remodeling around dental implants is highly influenced by the implant surface characteristics and evolves as a balance between the activity of osteoblasts and osteoclasts.63Padial-Molina M, Galindo-Moreno P, Fernández-Barbero JE, O’Valle F, Jódar-Reyes AB, Ortega-Vinuesa JL, Ramón-Torregrosa PJ. Role of wettability and nanoroughness on interactions between osteoblast and modified silicon surfaces. → Acta Biomater. 2011 Feb;7(2):771–8.64Padial-Molina M, Galindo-Moreno P, Avila-Ortiz G. Biomimetic ceramics in implant dentistry. → Minerva Biotecnol. 2009 Sep;21(3):173–86. Therefore, the use of melatonin as a topical agent to induce biomimetic properties of the implant surface has emerged as a promising technique.65Gómez-Moreno G, Aguilar-Salvatierra A, Boquete-Castro A, Guardia J, Piattelli A, Perrotti V, Delgado-Ruiz RA, Calvo-Guirado JL. Outcomes of topical applications of melatonin in implant dentistry: a systematic review. → Implant Dent. 2015 Feb;24(1):25–30. Melatonin directly influences the osteoblast’s response to the implant surface and osseointegration. The addition of melatonin improves results for cell adhesion, proliferation and differentiation on different titanium surface modifications at early time points, although longer culturing times seem to reduce those differences.66Solá-Ruiz MF, Pérez-Martínez C, Martín-del-Llano JJ, Carda-Batalla C, Labaig-Rueda C. In vitro preliminary study of osteoblast response to surface roughness of titanium discs and topical application of melatonin. → Med Oral Patol Oral Cir Bucal. 2015 Jan;20(1):e88–93.

These effects have been confirmed in vivo in several studies.67Tresguerres IF, Clemente C, Blanco L, Khraisat A, Tamimi F, Tresguerres JA. Effects of local melatonin application on implant osseointegration. → Clin Implant Dent Relat Res. 2012 Jun;14(3):395–9.68Calvo-Guirado JL, Gómez-Moreno G, Maté-Sánchez JE, López-Marí L, Delgado-Ruiz R, Romanos GE. New bone formation in bone defects after melatonin and porcine bone grafts: experimental study in rabbits. → Clin Oral Implants Res. 2015 Apr;26(4):399–406. The effects around dental implants are similar to those that take place in bone repair. Bone repair consists, biologically, of three different stages: inflammatory, proliferative and remodeling. Melatonin may play a role in these phases owing to its regulatory effects on inflammation, antioxidant properties, regulation of bone cells, and stimulation of collagen synthesis and deposition. Moreover, melatonin has been shown to increase the number of blood vessels, which is a prerequisite for the supply of mineral elements and the migration of angiogenic and osteogenic cells. As a consequence, histological evaluation of the periimplant bone shows more trabecular bone, but less cortical bone and higher bone-to-implant contact in melatonin-treated sockets compared with controls. 69Tresguerres IF, Clemente C, Blanco L, Khraisat A, Tamimi F, Tresguerres JA. Effects of local melatonin application on implant osseointegration. → Clin Implant Dent Relat Res. 2012 Jun;14(3):395–9. Therefore, the use of melatonin for osseointegration might be of interest as a biomimetic agent. Moreover, it has been suggested to induce bone growth when applied in combination with bone grafts.70Calvo-Guirado JL, Gómez-Moreno G, Maté-Sánchez JE, López-Marí L, Delgado-Ruiz R, Romanos GE. New bone formation in bone defects after melatonin and porcine bone grafts: experimental study in rabbits. → Clin Oral Implants Res. 2015 Apr;26(4):399–406. However, its potential use in regenerating post-periimplantitis defects has not been studied yet.

Conclusion

Melatonin positive regulation of bone formation and homeostasis, in combination with the inhibitory effects on bone resorption, highlights the potential use of melatonin as a marker of periodontal and periimplant bone-related diseases. Moreover, in vitro and animal studies are starting to show promising results on its use as a regenerative agent, although no clinical studies have yet been performed. This new strategy may create possibilities for novel therapies in the treatment of periodontal disease or enhancing the outcomes of implant dentistry.

Competing interests

The authors declare that they have no conflict of interests related to this study.

Acknowledgements

The authors would like to thank Mr. Chris Jung for the original images presented in this review. MPM received funding from the Talentia Fellowship Program (Regional Government of Andalusia, Spain). The authors have been partially supported by Research Groups No. CTS-138 and No. CTS-583 (Regional Government of Andalusia) and by the Andalucía Talent Hub Fellowship Program (European Union’s Seventh Framework Programme, Marie Skłodowska-Curie actions, COFUND, grant agreement No. 291780; and Regional Government of Andalusia).

References   [ + ]

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2. Eastell R, Calvo MS, Burritt MF, Offord KP, Russell RG, Riggs BL. Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. → J Clin Endocrinol Metab. 1992 Mar;74(3):487–94.
3, 57. Cutando A, Galindo P, Gómez-Moreno G, Arana C, Bolaños J, Acuña-Castroviejo D, Wang HL. Relationship between salivary melatonin and severity of periodontal disease. → J Periodontol. 2006 Sep;77(9):1533–8.
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