Int. J. Mol. Sci. 201314, 10063-10074; doi:10.3390/ijms140510063 


International Journal of 

Molecular Sciences 

ISSN 1422-0067 


Melatonin Effects on Hard Tissues: Bone and Tooth 

Jie Liu 


, Fang Huang 


* and Hong-Wen He 



  Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University,   

Guangzhou 510055, China; E-Mail: 


  Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510080, China 

*  Authors to whom correspondence should be addressed: E-Mails: (F.H.); (H.-W.H.); Tel.: +86-13660464293 (F.H.); +86-13660222628 (H.-W.H.). 

Received: 22 March 2013; in revised form: 29 April 2013 / Accepted: 2 May 2013 /   
Published: 10 May 2013 

Abstract: Melatonin is an endogenous hormone rhythmically produced in the pineal gland 
under the control of the suprachiasmatic nucleus (SCN) and the light/dark cycle. This indole 
plays an important role in many physiological processes including circadian entrainment, 
blood pressure regulation, seasonal reproduction, ovarian physiology, immune function, etc. 
Recently, the investigation and applications of melatonin in the hard tissues bone and tooth 
have received great attention. Melatonin has been investigated relative to bone remolding, 
osteoporosis, osseointegration of dental implants and dentine formation. In the present 
review, we discuss the large body of published evidence and review data of melatonin 
effects on hard tissues, specifically, bone and tooth. 

Keywords: melatonin; bone remolding; osteoporosis; tooth development; osseointegration 


1. Introduction 

Melatonin is an endogenous hormone rhythmically produced in the pineal gland under the control of 

the suprachiasmatic nucleus (SCN) and the light/dark cycle [1–3]. Beyond that, it is also produced by 
several other tissues, amongst them the retina, thymus, spleen, ovaries, testicles, intestine and bone 
marrow [4,5]. Extrapineal melatonin secreted by specific organs is used locally as an autocoid or 
paracoid and does not enter circulation [4]. Melatonin from pineal gland does not act upon any specific 
target organ; it reaches all tissues and, due to its amphiphilicity, it easily enters all subcellular 
compartments, such as mitochondria and the nucleus [5–7]. 


Int. J. Mol. Sci. 201314 10064 

Melatonin plays an important role in many physiological processes including circadian entrainment, 

blood pressure regulation, seasonal reproduction, ovarian physiology, immune function, etc. [8]. The 
mechanism of melatonin action also is various. In some cases, melatonin actions are mediated by  
the binding of the indoleamine to membrane receptors  (MT


, MT


, MT


)  or nuclear receptors 

(ROR/RZR) [9]. Moreover, because of its lipophilic properties, melatonin passes through cell 
membranes to gain access to subcellular organelles [7]. It also probably binds to some cytosolic proteins 
like kinase C, calmodulin and calreticulin [10–12].   

Recently, the investigation and applications of melatonin in the hard tissues, bone and tooth,  

have received great attention. Melatonin has been investigated relative to bone remolding [13], 
osteoporosis [14,15], osseointegration of dental implants [5,16], and dentine formation [17]. In the 
present review, we discuss the large body of published evidence and review data of melatonin effects on 
hard tissues, namely, bone and teeth. 

2. Bone and Tooth 

Bone and tooth are the hard tissues of mammals. They are very similar in many aspects, such as their 

structure, composition, marker proteins, and mineralization process, etc. 

Structurally, bone is composed by compact bone, spongy bone and bone marrow. Bone marrow, 

inside the spongy bone, provides abundant blood for bone activities. Tooth is composed by enamel, 
dentine, cementum and dental pulp which supply the nutrition for the tooth.   

The main component of bone substance, enamel, dentine and cementum are mineralized extracellular 

matrices consisting of organic and inorganic substances. In all of the components (except enamel),  
the organic component is comprised of 90% (by weight) of type I collagen fibers and 10% of 
non-collagenous proteins. The inorganic phase is constituted by small crystals of a mineral alkaline 
character, hydroxyapatite (HA) [Ca








] [18]. 

Type I collagen is the most abundant and important matrix molecule in bone, dentine and cementum. 

It forms a three-dimensional network into which non-collagenous proteins and the nucleation of 
hydroxyapatite crystals are deposited [19]. 

Although the non-collagenous proteins are minor constituents of the matrix, they have various 

proteins (including of BSP, DSP, DPP, OPN, etc.) and play an important role in regulating the 
mineralization process. Most of them are the mineralization promoters, inhibitors or signaling 
molecules. For example, bone sialoprotein (BSP) and dentin sialoprotein (DSP) are involved in the 
initial formation of HA; DPP enhances the formation and growth of HA, while osteopontin (OPN) 
inhibits the formation and growth of HA [20,21]. 

Bone, dentine, and cementum have many similarities in general, but also some differences. 

Throughout life, bone tissue undergoes a continuous process of bone remolding, which consists of new 
bone formation and already-formed bone resorption, but dentine and cementum are not subject to 
remodeling; on the contrary, they must retain their stability over a long period of time [20], whereas the 
dentine matrix is continuously deposited throughout life. In this context, it is also interesting to study 
differences in dentinogenesis and osteogenesis. Previous studies have revealed that there were not only 
similarities of melatonin effects on bone formation and dentine formation, but also some differences, 
which will be summarized respectively in the following. 

Int. J. Mol. Sci. 201314 10065 
3. Melatonin and Bone 

3.1. Melatonin and Bone Remolding 

Bone is a dynamic tissue undergoing remodeling throughout life, and this remodeling requires a 

balance between deposition of new bone by osteoblasts and resorption of old bone by osteoclasts [13]. 

Bone modeling requires the interaction between multiple bone cells (osteoblasts/osteoclasts/osteocytes) 

to renew, maintain, or adjust bone strength and/or mineral homeostasis in response to changing 
environmental influences [14]. There are four distinct phases to this process: activation, resorption, 
reversal, and formation with resorption and formation taking place via osteoclasts and osteoblasts, 
respectively [14]. Initially, osteoclast precursors are attracted to a particular area of bone surface, then 
differentiation into osteoclast, which is responsible to bone resorption by acidification and proteolytic 
digestion [18]. In the reversal phase, bone resorption transitions into bone formation, and osteoblast 
precursors are recruited to proliferate and differentiate into osteoblasts that invade the resorption area 
and begin to form new bone by secreting osteoid, which is eventually mineralized [14].   

Bone remolding processes are mediated by hormones, cytokines, growth factors and other  

molecules [22]. One of the hormones modulating bone formation and resorption is melatonin. It is 
hypothesized that melatonin, perhaps through three principle actions, modulates bone metabolism. 
Firstly, melatonin directly affects the actions of osteoblast and osteoclast. Numerous studies documented 
that melatonin increases pre-osteoblast/osteoblast/osteoblast-like cell proliferation, promotes the 
expression of type I collagen and bone marker proteins (e.g., alkaline phosphatase, osteopontin, bone 
sialoprotein and osteocalcin), and stimulates the formation of a mineralized matrix in these cells [23–27]. 
Besides, melatonin inhibits the differentiation of osteoclasts via decreases in the expression of RANK 
mRNA and increases in both the mRNA and protein levels of osteo-protegerin  [28,29]. Secondly, 
melatonin indirectly regulates bone metabolism through the interaction with systemic hormones  
(e.g., PTH, calcitonin, and estrogen) or other moleculars. Ladizesky et al. [15] revealed that estradiol 
treatment could prolong the effect of melatonin to augment bone remodeling in ovariectomized rats; it 
indicates that appropriate circulating estradiol levels might be needed for melatonin effects on bone. 
Thirdly, osteoclasts generate high levels of superoxide anions during bone resorption that contribute to 
the degradative process. Melatonin is a significant free-radical scavenger and antioxidant. It can clear up 
the free radicals generated by osteoclast during the bone resorption process and protect bone cells from 
oxidative attacks [18,30,31]. 

3.2. Melatonin and Bone Repair 

Bone fracture and bone defect are the common bone disease which originate from trauma, neoplasm 

invasiveness, surgery, or as a secondary effect from some bone diseases. The repair of bone fracture and 
bone defect is an important process to maintain the integrity and function of the bone. 

Bone repair is a complex and continuous process. Biologically, it takes place in three stages: 

inflammatory, proliferative and remodeling phases [32]. During these stages, a set of complex 
biochemical events take place, including inflammatory cell infiltration, angiogenesis, cell proliferation 
and differentiation, collagen deposition, granulation tissue formation and mineral matrix  
deposition, etc. [32,33]. Previous studies have indicated that melatonin may play an important role in the 

Int. J. Mol. Sci. 201314 10066 
bone-healing process due to its antioxidant properties, regulation of bone cells, and promotion of 
angiogenesis actions [33,34].   

In the early stage of bone fracture/defect healing, the inflammatory phase is characterized by clot 

formation, ischemia and reperfusion injury and inflammatory cells (leukocytes, macrophage and mast 
cells) infiltration [35]. During this period, neutrophils produce free oxygen radicals that initiate a chain 
reaction leading to cell membrane damage via lipid peroxidation [35,36]. It has a negative effect on 
fracture/defect healing. The pineal hormone melatonin is a significant free radical scavenger and 
antioxidant at both physiological and pharmacological concentrations. Halici et al. [33] carried out 
biochemical and histopathologic observation of the outcomes of intraperitoneal applications of melatonin 
(30 mg/kg/day) for accelerating bone fracture healing in a rat model. The authors found that 
malondialdehyde (MDA) levels (indicator of free-radical concentration), superoxide dismutase (SOD) 
activity and myeloperoxidase ((MPO) plays a fundamental role in oxidant production) in the melatonin 
group decreased at the early stage of fracture healing compare to the control group, and SOD activity 
returned to the first-day value after 28 days in the melatonin group . These findings indicate that  
the administration of melatonin maybe beneficial in suppressing the effects of free oxygen radicals  
and regulating antioxidant enzyme (SOD) activity, thereby accelerating bone formation in the 
fracture-healing process [33]. 

In the proliferative phase, angiogenesis, osteoblast and fibroblast differentiation, collagen deposition 

and formation of granulation tissue take place in this phase. As mentioned before in this review, 
melatonin promotes the osteoblast proliferation and differentiation and enhances the type I collagen 
deposition [23,24]. Additionally, a recent study revealed that melatonin promotes angiogenesis during 
repair of bone defect in rabbit [32]. They observed the commencement of neovascularization and a 
significant increase in the number of vessels in the melatonin group in the first two weeks, which were 
also accompanied by an increase in the length of cortical formation. A similar outcome was also found 
by Soybir et al. [37] who reported an increase in the number of blood vessels resulting from melatonin 
applications to wounds in rats. Angiogenesis is an important physiological process in bone wound 
healing. Yamada et al. [38] suggest that angiogenesis precedes osteogenesis. The regeneration of new 
bone was dependent on blood vessels for the supply of mineral elements and the migration of angiogenic 
and osteogenic cells into secluded spaces. 

That melatonin influences the remolding process during the remolding phase has been elaborated 

clearly elsewhere [23–31]. 

3.3. Melatonin and Osteoporosis 

Osteoporosis was defined as “a systemic skeletal disease characterised by low bone mass and 

microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and 
susceptibility to fracture” by the World Health


Organization [39]. It has been a major public health 

problem for healthy adults over the age of 55 years and with a major prevalence in women. About 50% 
of women will go on to develop an osteoporotic fracture, compared to 25% of men [40]. Without an 
intervention strategy, it is likely that the amount of people with osteoporosis will increase threefold over 
the next 25 years because of an increase in the aging population worldwide [41]. Recent therapies 
include targeting bone-resorbing osteoclasts by use of bisphosphonates, estrogen, selective estrogen 

Int. J. Mol. Sci. 201314 10067 
receptor modulators (SERM) and calcitonin to prevent further bone breakdown, and stimulating 
bone-forming osteoblasts by anabolic drugs (e.g., teriparatide) to increase bone mass [42,43]. However, 
these therapies are limited because of their negative side effects or high costs [44,45]. In this sense, 
melatonin as a complementary therapy for the prevention and treatment of osteoporosis should be 
considered, because of its modulating bone metabolism function, lack of side effects, and  
economical advantages. 

Some studies revealed the possible etiologic role of melatonin in osteoporosis. Nocturnal plasma 

melatonin levels decline with age. It has also been reported that melatonin secretion decreases sharply 
during menopause, which is associated with post-menopausal osteoporosis [46,47]. A correlation 
between decreased plasma melatonin levels and an increased incidence of bone deterioration as seen in 
post-menopausal women has been examined [48]. Furthermore, Ostrowska et al. [49] found that  
a pinealectomy in rats promotes the induction of bone metabolism biomarkers. In addition,  
Feskanich et al. [50] reported that twenty or more years of nightshift work significantly increased the 
risk of wrist and hip fractures in post-menopausal women. Nightshift work leads to disturbances of 
melatonin secretion as well as severe circadian rhythm disruption. These observations taken together 
suggest that melatonin may be involved in the pathogenesis of osteoporosis. 

At present, few clinical trials have focused on the possible therapeutic value of melatonin in the 

prevention/treatment of osteoporosis. Most experimental studies were performed in ovariectomized rats, 
as a model for menopause. Uslu et al. [51] described that melatonin treatment increased trabecular 
thickness and the trabecular area of vertebra and femur and cortical thickness of femur, which decreased 
after ovariectomy in rats. Another similar study reported that melatonin significantly reduced the 
number of apoptotic cells in nucleus pulposus and epiphyseal cartilage of the spinal column and the 
expression of inducible nitric oxide synthase (iNOS), which increased after ovariectomy [52]. iNOS 
plays a pivotal role in the pathogenesis of osteoporosis. It generates nitric oxide, a free radical 
contributing to the imbalance between bone resorption and formation caused by estrogen depletion [52]. 

Recently, a randomized, double-blind, placebo-controlled clinical trial was carried out by  

Kotlarczyk et al. [14]. In this study, 18 perimenopausal women (ages 45–54) were randomized to 
receive melatonin (3 mg, per. os. n = 13) or placebo (n = 5) nightly for six months.


The results showed no 

significant change in bone density,


Type-I collagen cross-linked N-telopeptide (NTX), or osteocalcin 

(OC) between groups; however, the ratio of NTX:OC trended downward over time toward a ratio of 1:1 
in the melatonin group, while the trend was not seen in the placebo group. NTX and OC are the bone 
turnover markers: NTX for bone resorption, and OC for bone formation. The ratio of NTX:OC trending 
downward to 1:1 in the melatonin group indicates that melatonin supplementation


may restore 

imbalances in bone remodeling to prevent bone loss in perimenopausal women. 

From these studies, we found that melatonin application markedly influenced the bone 

microenviroment and bone metabolism after ovariectomy or menopausal, suggesting its potential use in 
the prevention/treatment of osteoporosis. 

Int. J. Mol. Sci. 201314 10068 
4. Melatonin and Tooth 

4.1. Possible Involvement of Melatonin in Tooth Development   

Melatonin concentrations change in a specific manner during the lifespan of human [53]. Melatonin 

is a lipophilic hormone that crosses the placenta barrier easily, thus, prenatally, the fetal obtain 
melatonin from mothers [54]. During the first two weeks of life, melatonin could be detected in infant 
blood, but there was no daily rhythm [55,56]. The nocturnal rise of melatonin concentrations appears in 
the sixth to eighth week of life [53,55,57], and its circadian rhythm seems to be well established around 
three months of age [57]. After this period, the melatonin concentration continues to increase. The 
amplitude of the nocturnal peak in melatonin secretion reaches the highest levels in the ages between 
four and seven years [53]. Until the onset of puberty (about 10–12 years old), the melatonin 
concentrations begin to decline [1]. Interestingly, over this time period, teeth undergo a series of pivotal 
activities including


histogenesis, development, eruption, replacement and maturity. The development of 

deciduous teeth and permanent teeth start from the second and fourth month of gestation, respectively. 
Deciduous teeth begin eruption in the sixt month of life, until 2.5–3 years of age all of deciduous teeth 
have erupted. From about six years old, permanent teeth begin to replace the deciduous teeth until  
10–12 years old. Since the time course of melatonin secretion and the progression of tooth development 
run in parallel, the possible role of melatonin in tooth development should be worthy of study. 

The most striking feature of the melatonin is the circadian rhythm which is controlled by the


endogenous circadian clock, suprachiasmatic nucleus (SCN) and environmental ligh


. Many studies also 

reported that tooth development exhibits circadian rhythmicity [58,59]. Periodic growth incremental 
lines are found universally in the dental tissues of animals, especially in the dentine and enamel, which 
reflect circadian rhythms of tooth growth [59,60]. A previous study had also demonstrated that SCN 
plays an important role in generating circadian dentine increments [59]. Complete lesion of the SCN led 
to a failure of the dentine increments’ appearance, and the authors presumed that this was associated 
with changes in hormones under tight circadian


control [59]. Therefore, we presumed that melatonin 

may be involved in the development of circadian dental formation. 

Recently, some experimental studies focused on the possible role of melatonin in tooth development 

have been performed. Kumasaka et al. [61]


revealed that melatonin 1a receptor is expressed in secretory 

ameloblasts, the stratum intermedium and stellate reticulum cells, external dental epithelial cells, 
odontoblasts, and dental sac cells in the tooth germs of the mandibular third molar of human. An   
in vitro
 study showed that HAT-7, a rat dental epithelial cell line, expressed Mel1aR and its expression 
levels increased after the cells reached confluence. Moreover, our previous study [17] demonstrated that 
melatonin (physiological dose range) induced a dose-dependent reduction in rat dental papilla cell 
(rDPCs) proliferation, increased ALP activity, DSP expression, and mineralized matrix formation   
in vitro
In vivo melatonin inhibited dentine formation in rats. We also found that melatonin suppressed, 
in a basal medium, the activities of complex I and IV of mitochondrial respiratory chain, but enhanced 
these activities in an osteogenic medium. Our data strongly suggest a physiological role of melatonin   
in tooth development by regulating cellular processes in odontogenic cells, which may involve the 
modulation of mitochondria function. 

Int. J. Mol. Sci. 201314 10069 
4.2. Melatonin and Osseointegration of Dental Implant   

Dentition defect and dentition missing are the most common dental diseases, especially in 

middle-aged and elderly people. There are various conventional restorative options for edentulous 
patients, such as removable dentures, fixed dentures, overdentures, etc. Unfortunately conventional 
denture wearers experience a number of problems on a daily basis, such as instability of their removable 
dentures, inability to comminute foods, decreased self-confidence, and so on [62]. Nowadays, 
implant-supported denture, a new technology for restoration, has addressed these daily problems.



in the past several decades, implant-supported prosthesis has expanded to become a widely accepted 
treatment for the restoration of fully and partially edentulous patients [62]. 

The premise of the success of dental implant is osseointegration, which refers to the direct contact 

histologically between living bone and the surfaces of commercially pure titanium implants. It is critical 
for providing rigid fixation of a dental implant within the alveolar bone and promoting the long-term 
success of dental implants [63,64]. The most widely investigated topics include enhancing the success 
rate of the dental implant, minimizing the time of osseointegration, modifying


implant surfaces, and 

seeking novel biomaterials to


positively modulate the host/implant tissue response [65,66]. Several 

experimental investigations show that melatonin may be a potent biomimetic agent in the placement of 
endo-osseous dental implants. Cutando et al. [5] revealed that after a two-week treatment period, 
melatonin significantly increased the perimeter of bone that was in direct contact with the treated 
implants, bone density, new bone formation and inter-thread bone in comparison with control implants. 
During this study, they observed the increase in osteoblast proliferation brought about by melatonin in 
the peri-implant zone. The same outcome also was demonstrated by another study; Guardia et al. [67] 
found that after five- and eight-week treatment periods, melatonin significantly increased the 
inter-thread bone and new bone formation in comparison to control implants in both weeks. Moreover, 
in a further study performed by


Calvo-Guirado et al. [68], the result showed that melatonin plus porcine 

bone significantly increased the perimeter of bone that was in direct contact with the treated implants, 
and that bone density and new bone formation increased in comparison with porcine bone alone around 
the implants. These actions of melatonin on osseointegration are of interest as it may be possible to apply 
melatonin to dental implant surgery as a biomimetic agent. 

5. Conclusions   

Melatonin, as an endogenous hormone, participates in many physiological and pharmacological 

processes. The above analyzed data indicate that melatonin may be involved in the development of the 
hard tissues bone and teeth. Decreased melatonin levels may be related to bone disease and abnormality. 
Due to its ability of regulating bone metabolism, enhancing bone formation, promoting osseointegration 
of dental plant and cell and tissue protection, melatonin may used as a novel mode of therapy for 
augmenting bone mass in bone diseases characterized by low bone mass and increased fragility, bone 
defect/fracture repair and dental implant surgery. The investigation of melatonin on tooth still 
insufficient and requires further research. 

Int. J. Mol. Sci. 201314 10070 

This review was supported by the National Natural Science Foundation of China (No. 30472248) and 

the Science Technology Program of Guangdong (No. 2008B030301102). 

Conflict of Interest 

The authors declare no conflict of interest. 


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