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ePaper created 2016-06-09, 15:16:05 | version 1.38.0
Journal of Oral Science & Rehabilitation 9 Volume 2 | Issue 2/2016 E f f e c t s o f m e l a t o n i n o n b o n e Introduction Numerous systemic hormonal changes are known to be associated with aging.1 Some con- ditions linked to circadian rhythms and age may alter bone metabolism, resulting in changes in immuneactivityorbone-associatedpathologies,2 suchasperiodontaldisease.Thesedisordersmay be associatedwith alterations in normallevels of melatonin.3, 4 Melatonin (N-acetyl-5-methoxytryptamine), a hormone that is endogenously synthesized, primarily in the pineal gland, is a molecule with intense antioxidant activity5 and a wide range of biological actions, notably in the control of me- tabolism and bone development.6 Melatonin is currently used in therapies as a coadjuvant in cancer therapy,7 for anti-aging,8 as an immuno- stimulatory agent9 or as a sleep regulator,10 as well as to increase bone density in menopausal patients11 (Fig. 1). It is reported that salivary me- latonin is released bythe acinarcells ofthe major salivary glands and the gingival crevicular fluid. It follows a circadian rhythm, with the highest values at night. Moreover, in the oral cavity, me- latonin can act both by receptor-mediated and by receptor-independent pathways.12 Therefore, through complex molecular pathways that have gained special interest for the research commu- nityin periodontology, it mayplaya role in alveo- larperiodontaland periimplant bone maintenan- ce and regeneration. Melatonin is an amphiphilic molecule that is ableto cross most biologicalbarriers. It can exert its effect by binding to G-protein-coupled mem- brane receptors (MT1 and MT2) or by penetrating the cell through a specific family of transmem- brane channels,13 subsequently initiating a nu- clearorcytoplasmic molecularcascade.When it reachesthenuclei,melatoninbindstoasubfamily of nuclear receptors key in regulating bone me- tabolism, the RZR (retinoid Z receptor)/ROR (re- tinoid orphan receptor) receptor.14 It then regu- lates a number of cellular events, such as promotion of mitosis, induction of DNA repair,15 or cell differentiation and proliferation.16 Interestingly, it is known that melatonin can be synthesized in the bone marrow, where its concentration is around 100-fold higher than in serum.17 Furthermore,melatonininthebonemar- row protects its cells against cytotoxic agents in vivo.18 However, the specific biochemical mechanisms that regulate this modulation, spe- cifically in alveolar bone in humans, are current- ly not fully understood.11 Hence, it is the purpose of this review to describe the properties of me- latonin in regulating bone homeostasis, directly and indirectly, aswellasto analyze differentthe- rapeutic strategiesforthe use ofmelatonin as an agent to promote periodontal and periimplant bone maintenance and regeneration (Fig. 2). Direct effects on bone I . M e l a t o n i n a n d b o n e f o r m a t i o n The major organic component of bone extracel- lularmatrixisTypeIcollagen,whichsupportsthe expression of bone cell phenotypes and en- hances mineralization. Melatonin has been showntoregulatethesynthesisofTypeIcollagen as a preliminary step to the expression of other bone-related proteins, such as bone sialoprotein, alkaline phosphatase and osteocalcin, during osteoblastic maturation.16 Bone sialoprotein (BSP) is referred to as a marker ofthe late stage of osteoblastic differen- tiation. BSP is expressed during osteoblastic cell differentiation in the extracellular matrix, where itisessentialforosteoblastattachmentandbone mineralization. Within this context, it has been reported that MC3T3 pre-osteoblast cells ma- tured in 12 days in the presence of melatonin comparedwith 21 dayswithout melatonin. Gene expression of BSP and related proteins of osteo- blastic differentiation (e.g., osteocalcin, alkaline phosphatase) is also accelerated and increased in melatonin-treated compared with nontreated cells.19 Furthermore, byinhibitingthe interaction of BSPwith osteoblastic cell lines, the activity of alkaline phosphatase, osteocalcin synthesis and cellular response to parathyroid hormone (PTH) arealsoinhibited20 and,subsequently,osteoblast differentiation is impaired.21 Thus,thesefindings suggest that melatonin may have an effect in regulating osteoblast proliferation and differen- tiation. These effects could lead to beneficial effectsinthetreatmentofpathologicalprocesses associated with bone resorption or destruction by mediating not only in the expression of BSP but ofotherbone glycoproteins aswell, resulting in enhanced bone apposition. I I . M e l a t o n i n a n d b o n e r e s o r p t i o n Melatoninalsoexertsanimportantdirectbiolog- ical action on the osteoclast, another key cell in