Review Article | Open Access
Melatonin: Bone Metabolism in Oral Cavity
Throughout life, bone tissue undergoes a continuous process of resorption and formation. Melatonin, with its antioxidant properties and its ability to detoxify free radicals, as suggested by Conconi et al. (2000) may interfere in the osteoclast function and thereby inhibit bone resorption, as suggested by Schroeder et al. (1981). Inhibition of bone resorption may be enhanced by a reaction of indoleamine in osteoclastogenesis. That it has been observed melatonin, at pharmacological doses, decrease bone mass resorption by suppressing through down regulation of the RANK-L, as suggested by Penarrocha Diago et al. (2005) and Steflik et al. (1994). These data point an osteogenic effect towards that may be of melatonin of clinical importance, as it could be used as a therapeutic agent in situations in which would be advantageous bone formation, such as in the treatment of fractures or osteoporosis or their use as, a bioactive surface on implant as suggested by Lissoni et al. (1991).
The bone tissue is a variety of connective tissues that are essentially a mineralized extracellular matrix and specialized cells: osteoblasts, osteocytes, and osteoclasts.
The organic component, or osteoid matrix produced by osteoblasts, is constituted by 90% of type I collagen fibers, which represents the major structural protein of bone matrix. The remaining 10% is made up of a series of non-collagenous proteins that modulate smaller mineralization and binding of cells to the matrix, and among them (see Table 1).
The inorganic phase consists of small crystals of a mineral alkaline character, hydroxyapatite [Ca10(PO4)6(OH)2]. These crystals are embedded among the collagen fibers to form a fabric that meets the appropriate characteristics of rigidity, flexibility, and endurance [1–3].
Osteoblasts derived embryologically multipotent progenitor cells from bone marrow stroma. These cells originate from osteoblasts, as well as fibroblasts, chondrocytes, adipocytes, and muscle cells, some of which are phenotypic characteristics similar to those of osteoblast. These cells are metabolically active secretory proteins expressed as osteocalcin and osteopontin, osteonectin and other proteoglycans and soluble markers factors (BMPs, TGF-β, IGF I and II, IL-1 and PDGF). The expression of these products by osteoblasts bone occurs during embryogenesis, and during maintenance (remodeling), and repair. The signals that direct osteoid mineralization have not yet been identified. It is likely that the accumulation of proteins in a calcium will be the beginning of the process of mineralization .
Although osteoblasts are polarized towards the bone, the release of the osteoid matrix proteins is not limited to the basal pole, but many of them are being involved in such a matrix, becoming osteocytes included in the gaps that form in it.
Osteoblasts can lead to surface osteocytes, also known as lining cells. Both types of bone cells possess receptors for parathyroid hormone (PTH) and express mRNA Live: β-actin, transcription factors c-fos and c-jun proteins collagen and collagen as well as mRNA-like growth factor insulin I (IGF-I) .
Already formed in the bone, the osteocytes included in the gaps or osteoplasmas in the mineralized matrix, are star-shaped with numerous thin extensions, and are connected by a network of canals or ducts calcoforos, bathed by the so-called bone fluid. Such networks of channels are formed before they mineralize the osteoid matrix.
When there is bone resorption by osteoclasts, osteocytes are out of the lagoons as cladding in repose cells . Bone resorption is a complex process involving the dissolution of the mineral or inorganic phase and subsequent degradation of bone matrix proteins. Osteoclasts adhere to the bone surface via integrins that specifically recognize osteoid matrix proteins. The sealing area delimits a microgap between osteoclasts and bone surface. Demineralization is produced by acidification of the microgap by the action of Hydrogen (H+) ATPaselocated in the brush border membrane. To maintain the physiological pH within it, the osteoclast has a heat exchanger (Cl−/)on the opposite side of the brush border and, on this edge, a channel Chlorine (Cl−) coupledH+-ATPase. As a consequence the osteoblast secretes HCl in the microsubosteoclastic, thus lowering the pH to 4.4 and the dissolution of the mineral. This dissolution precedes the organic matrix degradation, carried out by proteases such as cathepsin K, secreted by osteoclasts, and collagenase by osteoblasts [6, 7].
2. Bone Remodeling
Throughout life, bone tissue undergoes a continuous process of resorption and formation. By continuing, there are areas of bone which are destroyed to be replaced by newly formed bone tissue. This process is called “bone remodeling” and leads to the replacement of about 7–10% of the total volume of the skeleton each year.
The remodeling is done by groups of cells, osteoblasts and osteoclasts that are called “units of remodeling” or “basic multicellular units.” The process begins when osteoclast precursors are attracted to a particular location of the bone, and the action of cytokines (TNF-α, IL-1, IL-6, M-CSF, RANK-L) differentiates osteoclasts in situ. These begin to reabsorb bone, along untill two weeks later a small cavity is lined by mononuclear cells called the investment phase. After osteoblast precursors are recruited to proliferate and differentiate osteoblasts are arranged in a monolayer to synthesize osteoid filling while the gap is opened by the osteoclasts. It is the bone formation phase, which lasts for 2–4 months. The mineralization of sheets of osteoid is being produced as deposited, but with a delay of 2 weeks. At the end of the process, the result is that a small amount of old bone by new bone renovated  (see Table 2).
Numerous studies documented that melatonin is an important mediator in bone formation and stimulation . At micromolar concentrations, melatonin synthesis stimulates the proliferation and collagen fibers of type I in human osteoblasts in vitro .
The effect of pineal gland/melatonin (aMT) upon circadian secretion of hormones, especially those playing a crucial role in the regulation of bone metabolism appears significant [11, 12]. Early experimental studies conditions have shown that long-term light,and pinealectomy also modified the synthesis aMT administration and/or circadian release of growth hormone (GH), insulin-like growth factor-I (IGF-I) as well as calciotropic, thyroid, adrenal cortex hormones and testes. Also enhances synthesis of aMT and noncollagenic proteins of bone matrix . That characteristic suggests that clinical studies of bone mass changes in postmenopausal osteoporosis may be related to aMT . Studies demonstrate that increased obese women aMT secretion in more than 20% overweight have protective significance in loss of bone mass aftermenopause .
Melatonin is not a hormone in the classic sense, but as a cell protective functions and an antioxidant . It is known that the enzymes required for the biosynthesis of melatonin are found in tissues other than the pineal gland, and it is also known that several of these tissues, amongst them the retina, thymus, spleen, B-lymphocytes, ovaries, testicles, and the intestine, all produce melatonin. Extrapineal melatonin is produced by specific organs used locally as paracoid or autocoid and does not enter the circulation . Melatonin does not act upon specific target organ and stock. It reaches all tissues and due to amphiphilicity, it enters to all subcellular compartments [17, 18]. Moreover, several organelles and the nucleus including the mitochondria may accumulate melatonin [18, 19].
Melatonin, with its antioxidant properties and its ability to detoxify free radicals  in this may interference of the osteoclast function and thereby inhibit bone resorption . Inhibition of bone resorption may be enhanced by a reaction of indoleamine in osteoclastogenesis. It has been observed that melatonin, at pharmacological doses, increases bone mass by supressing resorption trough down-regulation of the RANKL-mediated osteoclast formation and activation. These data point an osteogenic effect towards that may be of melatonin of clinical importance, as it could be used as a therapeutic agent in situations in which there would be advantageous bone formation, such as in the treatment of fractures or osteoporosis .
Links between melatonin metabolism and bone have been documented in many studies [10, 21, 22]. Investigations, acted melatonin on the bone as a local growth factor, with paracrine effects on nearby cells [23, 24].
3. Osseointegration in Oral Implantology
Osseointegration requires the formation of new bone around the implant, resulting in the remodeling process within the bone tissue. The process was initiated by osteoclasts, which are the cells responsible for reabsorbing the necrotic area originated by bone drilling during the preparation of the recipient bone. With them, vascular neoformation provide the cells elements, the osteoblasts, which create new bone able to interact with the titanium oxide layer of the implant to integrate biologically to it. Osteoblasts are differentiated osteocytes subsequently included in the mineralized bone matrix. Considering ultrastructurally bone-implant interface must refer to the concept of biointegration, which is the direct biochemical joint between the bone and the implant surface, demonstrable through electronic microscopy, regardless any interunion mechanism. Thus, the space between the mineralized bone tissue and titanium plasma coating of the implant is not more than 10 Angstrom and appears filled with a matrix material, the proteoglycans . A network of collagen is surrounding the osteocytes and inserted into the layer of glycoproteins, which fusions with titanium oxide layer. It is believed that the implant titanium oxide induces the formation of sulfated glycosaminoglycans . The bony trabeculae grow closer to the implant contacting the plasma layer. From them come the vessels supplying nutrition, cellular elements for remodeling and around the implant, fibroblasts, and osteoblasts to increase and approach the implant which is attached to the oxide layer. They are fundamental substances that fills the trabecular spaces and fuse with the titanium oxide layer. Therefore, and contrary to what is believed, the oral tissue-implant interface is a dynamic area under intense remodeling activity by the bone cells and the extracellular matrix .
4. Melatonin and Cancer
Melatonin can kill directly many different types of human tumor cells [28, 29]. It is a naturally produced cytotoxin, which can induce tumor cell death (apoptosis) [30, 31]. In instances where the tumor has already established itself in the body, melatonin has been shown to inhibit the tumor’s growth rate [32, 33]. Melatonin exhibits natural oncostatic activity and inhibits cancer cell growth . In patients in whom cancer already has become a noticeable physical burden which produces overt symptoms, melatonin has been shown to alleviate numerous cancer symptoms  and to inhibit development of new tumor blood vessels (tumor angiogenesis) , which in turn inhibits the cancer from spreading further (metastasis) . Melatonin can retard tumor metabolism and development by lowering the body temperature; it is a natural inducer of hypothermia. Furthermore, as an inducer of antioxidants , and itself a weak preventive antioxidant, melatonin hinders tumor cells from participating in free radical damage to normal cells and consequently limits oxidative damage to DNA, lipids, amino acids, and proteins. Melatonin promotes bone formation  and on the other hand with its antioxidant action on free radicals interferes with the osteoclast and thus inhibits bone resorption [40, 41].
Although today the designs and surface treatment of implants are allowing in some cases reduce load times, generally provides a period of osseointegration in the mandible 3 months and 6 months in the maxilla.Cutando et al.  found that at 2 weeks of melatonin implants significantly increased all parameters of osseointegration of them: percentage of bone contact, total peri-implant bone, bone interscrew, and the percentage of new bone formation. Roth et al looked melatonin stimulated, the expression of bone, sialoprotein genes, alkaline phosphatase and osteocalcin for a period of time from 5 to 9 days, founding a highly significant evidence for this relationship because the genes of many of the bone matrix proteins (BSP, ALP, OC, and SPARC) contain the sequence of bases (RGGTCA) required for nuclear receptor binding of melatoninRZR to its promoter region. However, this increase in bone tissue formation may also be mediated by membrane receptors of the indoleamine, and that treatment with pertussis toxin and luzindole is able to reduce the expression of BSP and ALP .
All these data confirm that an osteogenic effect of melatonin may be clinically important as it could be used as a potential therapeutic agent in situations where it is desirable to increase bone formation and healing of fractures or osteoporosis, or their use as a bioactive surface on implant .
- T. R. Arnett, “Estructura y remodelado de hueso,” in Manual Practico de Osteoporosis y Enfermedades del Metabolismo Mineral, J. A. Riancho Moral and J. Gonzales Macias, Eds., pp. 1–6, Jarpyo Editores, Madrid, Spain, 2004.
- P. Gehron Robey, “Bone matrix proteoglycans and glycoproteins,” in Principles of Bone Biology, J. P. Bilezikian, L. G. Raisz, and G. A. Rodan, Eds., vol. 1, pp. 225–238, Academic Press, San Diego, Calif, USA, 2nd edition, 2002.
- S. Prieto, “Fisiologia del hueso,” in Fisiologia Humana, J. A. F. Tresguerres, Ed., pp. 981–994, McGraw Hill, Madrid, Spain, 3rd edition, 2005.
- T. L. McCarthy, C. Ji, and M. Centrella, “Links among growth factors, hormones and nuclear factors with essential roles in bone formation,” Critical Reviews in Oral Biology and Medicine, vol. 11, no. 4, pp. 409–422, 2000.
- J. M. Lean, A. G. Mackay, J. W. M. Chow, and T. J. Chambers, “Osteocytic expression of mRNA for c-fos and IGF-I: an immediate early gene response to an osteogenic stimulus,” American Journal of Physiology, vol. 270, no. 6, pp. E937–E945, 1996.
- K. Vaananen and H. Zhao, “Osteoclast function: biology and mechanism,” in Principles of Bone Biology, J. P. Bilezikian, L. G. Raisz, and G. A. Rodan, Eds., vol. 1, pp. 127–140, Academic Press, San Diego, Calif, USA, 2nd edition, 2002.
- S. L. Teitelbaum, “Bone resorption by osteoclasts,” Science, vol. 289, no. 5484, pp. 1504–1508, 2000.
- I. Fernandez-Treguerres Hernandez Gil, M. A. Alobera Garcia, M. Del Canto Pingarrón, and L. Blanco Jerez, “Bases fisiológicas de la regeneración osea II. El proceso de remodelado,” Medicina Oral Patologia Oral y Cirugia Bucal, vol. 11, pp. 151–157, 2006.
- P. A. Witt-Enderby, N. M. Radio, J. S. Doctor, and V. L. Davis, “Therapeutic treatments potentially mediated by melatonin receptors: potential clinical uses in the prevention of osteoporosis, cancer and as an adjuvant therapy,” Journal of Pineal Research, vol. 41, no. 4, pp. 297–305, 2006.
- O. Nakade, H. Koyama, H. Ariji, A. Yajima, and T. Kaku, “Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro,” Journal of Pineal Research, vol. 27, no. 2, pp. 106–110, 1999.
- J. Badurski, A. Sawicki, and S. Boczo, Osteoporosis, Osteoprint, Białystok, Poland, 2nd edition, 1994.
- K. Galus, “Bone Metabolism Disease,” Med Tour International, Warszawa, Poland, 1995.
- R. Sandyk, “The pineal gland and the clinical course of multiple sclerosis,” International Journal of Neuroscience, vol. 62, no. 1-2, pp. 65–74, 1992.
- Z. Ostrowska, B. Kos-Kudla, E. Swietochowska, B. Marek, B. Kajdaniuk, and N. Ciesielska-Kopacz, “Influence of pinealectomy and long-term melatonin administration on GH-IGF-I axis function in male rats,” Neuroendocrinol Letters, vol. 22, no. 4, pp. 255–262, 2001.
- D. X. Tan, L. C. Manchester, M. P. Terron, L. J. Flores, and R. J. Reiter, “One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?” Journal of Pineal Research, vol. 42, no. 1, pp. 28–42, 2007.
- R. J. Reiter, “Pineal melatonin: cell biology of its synthesis and of its physiological interactions,” Endocrine Reviews, vol. 12, no. 2, pp. 151–180, 1991.
- D. Acuña-Castroviejo, G. Escames, M. Macías et al., “Cell protective role of melatonin in the brain,” Journal of pineal research, vol. 19, no. 2, pp. 57–63, 1995.
- C. D. Acuña, G. Escames, A. Carazo, J. León, H. Khaldy, and R. J. Reiter, “Melatonin, mitochondrial homeostasis and mitochondrial-related diseases,” Current Topics in Medicinal Chemistry, vol. 2, no. 2, pp. 133–151, 2002.
- D. Acuna-Castroviejo, M. I. Pablos, A. Menendez-Pelaez, and R. J. Reiter, “Melatonin receptors in purified cell nuclei of liver,” Research Communications in Chemical Pathology and Pharmacology, vol. 82, no. 2, pp. 253–256, 1993.
- M. D. Maldonado, F. Murillo-Cabezas, M. P. Terron et al., “The potential of melatonin in reducing morbidity-mortality after craniocerebral trauma,” Journal of Pineal Research, vol. 42, no. 1, pp. 1–11, 2007.
- D. P. Cardinali, M. G. Ladizesky, V. Boggio, R. A. Cutrera, and C. Mautalen, “Melatonin effects on bone: experimental facts and clinical perspectives,” Journal of Pineal Research, vol. 34, no. 2, pp. 81–87, 2003.
- H. Koyama, O. Nakade, Y. Takada, T. Kaku, and K. H. W. Lau, “Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation,” Journal of Bone and Mineral Research, vol. 17, no. 7, pp. 1219–1229, 2002.
- D. X. Tan, L. D. Chen, and B. Poeggeler, “Melatonin: a potent endogenous hydroxyl radical scavenger,” Endocrine Journal, vol. 1, pp. 52–60, 1993.
- S. Conconi, E. Hertens, K. Skwarlo-Sonta, M. Markowska, and G. J. M. Maestroni, “Evidence for melatonin synthesis in mouse and human bone marrow cells,” Journal of Pineal Research, vol. 28, no. 4, pp. 193–202, 2000.
- A. Schroeder, E. Van Der Zypen, H. Stich, and F. Sutter, “The reactions of bone, connective tissue, and epithelium to endosteal implants with titanium-sprayed surfaces,” Journal of Maxillofacial Surgery, vol. 9, no. 1, pp. 15–25, 1981.
- M. Penarrocha Diago, M. J. Oltra Moscardo, and J. M. Sanchis Bielsa, “Conceptos generales de implantologia,” in Implantologia Oral, pp. 3–17, Ars Medica, Barcelona, Spain, 2005.
- D. E. Steflik, G. R. Parr, A. L. Sisk et al., “Osteoblast activity at the dental implant-bone interface: transmission electron microscopic and high voltage electron microscopic observations,” Journal of Periodontology, vol. 65, no. 5, pp. 404–413, 1994.
- D. E. Blask, L. A. Sauer, and R. T. Dauchy, “Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy,” Current Topics in Medicinal Chemistry, vol. 2, no. 2, pp. 113–132, 2002.
- T. P. Riabykh, T. G. Nikolaeva, and N. B. Bodrova, “Effects of biorhythm regulator melatonin on DNA synthesis in short-term cultures of human malignant tumors,” Vestnik Rossiiskoi Akademii Meditsinskikh Nauk, no. 8, pp. 30–33, 2000.
- S. C. Miller, S. R. Pandi-Perumal, A. I. Esquifino, D. P. Cardinali, and G. J. M. Maestroni, “The role of melatonin in immuno-enhancement: potential application in cancer,” International Journal of Experimental Pathology, vol. 87, no. 81, p. 87, 2006.
- R. M. Sainz, J. C. Mayo, C. Rodriguez, D. X. Tan, S. Lopez-Burillo, and R. J. Reiter, “Melatonin and cell death: differential actions on apoptosis in normal and cancer cells,” Cellular and Molecular Life Sciences, vol. 60, no. 7, pp. 1407–1426, 2003.
- P. Lissoni, S. Barni, G. Cattaneo et al., “Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies,” Oncology, vol. 48, no. 6, pp. 448–450, 1991.
- S. Y. W. Shiu, I. C. Law, K. W. Lau, P. C. Tam, A. W. C. Yip, and W. T. Ng, “Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed MT 1 receptor subtype,” Journal of Pineal Research, vol. 35, no. 3, pp. 177–182, 2003.
- S. Cos and E. J. Sánchez-Barceló, “Melatonin, experimental basis for a possible application in breast cancer prevention and treatment,” Histology and Histopathology, vol. 15, no. 2, pp. 637–647, 2000.
- G. Mantovani, A. Macciò, E. Massa, and C. Madeddu, “Managing cancer-related anorexia/cachexia,” Drugs, vol. 61, no. 4, pp. 499–514, 2001.
- P. Lissoni, F. Rovelli, F. Malugani, R. Bucovec, A. Conti, and G. J. M. Maestroni, “Anti-angiogenic activity of melatonin in advanced cancer patients,” Neuroendocrinology Letters, vol. 22, no. 1, pp. 45–47, 2001.
- S. Cos, R. Fernández, A. Güézmes, and E. J. Sánchez-Barcelo, “Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells,” Cancer Research, vol. 58, no. 19, pp. 4383–4390, 1998.
- V. Srinivasan, “Melatonin oxidative stress and neurodegenerative diseases,” Indian Journal of Experimental Biology, vol. 40, no. 6, pp. 668–679, 2002.
- E. Gitto, M. Karbownik, R. J. Reiter et al., “Effects of melatonin treatment in septic newborns,” Pediatric Research, vol. 50, no. 6, pp. 756–760, 2001.
- J. A. Roth, B.-G. Kim, W.-L. Lin, and M.-I. Cho, “Melatonin promotes osteoblast differentiation and bone formation,” Journal of Biological Chemistry, vol. 274, no. 31, pp. 22041–22047, 1999.
- H. Koyama, O. Nakade, Y. Takada, T. Kaku, and K.-H. W. Lau, “Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation,” Journal of Bone and Mineral Research, vol. 17, pp. 1219–1229, 2002.
- A. Cutando, G. Gómez-Moreno, C. Arana, D. Acuña-Castroviejo, and R. J. Reiter, “Melatonin: potential functions in the oral cavity,” Journal of Periodontology, vol. 78, no. 6, pp. 1094–1102, 2007.
- J. A. Roth, B. G. Kim, W. L. Lin, and M. I. Cho, “Melatonin promotes osteoblast differentiation and bone formation,” Journal of Biological Chemistry, vol. 274, no. 31, pp. 22041–22047, 1999.
- B. Kasemo and J. Gold, “Implant surfaces and interface processes,” Advances in Dental Research, vol. 13, pp. 8–20, 1999.
Copyright © 2012 Fanny López-Martínez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.