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ISSN : 1226-7155(Print)
ISSN : 2287-6618(Online)

International Journal of Oral Biology Vol.49 No.3 pp.53-60
DOI : https://doi.org/10.11620/IJOB.2024.49.3.53

Nicotinamide as a therapeutic agent for bone diseases

Heein Yoon¹, Woo-Jin Kim¹, Young-Dan Cho², Hyun-Mo Ryoo¹*

¹Department of Molecular Genetics and Dental Pharmacology, Dental Multiomics Center, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 08826, Republic of Korea
²Department of Periodontology, Seoul National University Dental Hospital, Dental Research Institute, School of Dentistry, Seoul
National University, Seoul 03080, Republic of Korea

^*Correspondence to: Hyun-Mo Ryoo, E-mail: hmryoo@snu.ac.krhttps://orcid.org/0000-0001-6769-8341

Received August 28, 2024 Review Accepted September 9, 2024

Abstract

Nicotinamide (NAM), a water-soluble derivative of vitamin B3, has emerged as a potential therapeutic agent for bonerelated disorders. In particular, it promotes bone metabolism and alleviates delayed tooth eruptions associated with cleidocranial dysplasia (CCD). NAM serves as a precursor for nicotinamide adenine dinucleotide, a key coenzyme involved in cellular metabolism that plays an essential role in oxidative phosphorylation and mitochondrial function. Recent research has highlighted the capacity of NAM to enhance osteogenic differentiation and regulate the interaction between osteoblasts and osteoclasts, which is critical for maintaining bone homeostasis. Moreover, the effect of NAM in preventing delayed tooth eruptions in CCD models underscores its potential as a noninvasive therapeutic option. Considering its safety profile and therapeutic potential, NAM is a promising candidate for longterm treatment of bone diseases and prevention of age-related bone disorders.

Key Words : Nicotinamide , Tooth eruption , Cleidocranial dysplasia , Mitochondria , Osteoblasts

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Main Text

1. General features of nicotinamide

Nicotinamide (NAM), the water-soluble derivative of vitamin B3, is classified as a food additive rather than as a pharmaceutical [1] and has shown a favorable safety profile in a clinical trial [2]. NAM has demonstrated effectiveness in various areas, including Parkinson’s disease and insulin sensitivity/ diabetes. Additionally, a previous phase 3 clinical trial reported that NAM can safely and effectively reduce the incidence of new nonmelanoma skin cancers (NMSCs) and actinic keratoses. Moreover, it is well-established that nicotinamide adenine dinucleotide (NAD⁺) levels decline due to aging and various forms of nutrient stress [3]. Based on this, recent studies have emphasized the importance of boosting NAD⁺ levels through the use of various NAD⁺ precursors, including NAM.

2. Role of NAM in NAD⁺ biosynthesis and cell metabolism

NAD⁺ is an essential cofactor involved in regulating cellular metabolism and energy homeostasis, playing a key role in processes such as glycolysis in the cytosol, and the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and the oxidation of fatty acids and amino acids within the mitochondria [4]. NAM is one of several precursors of NAD⁺, alongside tryptophan, nicotinic acid (NA), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR). NAD⁺ can be synthesized through both de novo and salvage pathways. In the de novo pathway, the dietary amino acid L-tryptophan is first converted into quinolic acid and then into nicotinic acid mononucleotide (NaMN). This is subsequently transformed into nicotinic acid adenine dinucleotide (NaAD), which is then amidated by NAD synthase to produce NAD⁺ [4]. Conversely, the salvage pathway regenerates NAD⁺ by utilizing its precursors, including NAM, NA, NMN, and NR. Specifically, NAM and NR are converted into NMN by the enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide riboside kinase (NRK), respectively. Subsequently, NMN is transformed into NAD⁺ by the action of nicotinamide mononucleotide acetyltransferase (NMNAT). As a precursor to NAD⁺, NAM can effectively elevate NAD⁺ levels, much like NA, NMN, and NR. Modulating NAD⁺ levels with these precursors has demonstrated significant benefits, not only at the cellular level—such as enhanced mitochondrial efficiency and improved cellular metabolism under oxidative stress—but also at the systemic level, by extending healthspan and lowering the risk of agerelated diseases [5]. Despite NAM being a critical dietary NAD precursor that regulates NAD levels via the salvage pathway, the extent of research on NAM is comparatively less than that on NMN or NR.

3. Role of NAM in sirtuin regulation and bone metabolism

Sirtuins, which belong to class III histone deacetylases (HDACs), were first identified in yeast as the silent information regulator 2 (Sir2) [6]. During the deacetylation reaction, sirtuins release NAM from NAD⁺, and NAM can subsequently react with O-alkyl-amidate intermediate in a process known as NAM exchange, acting as a non-competitive inhibitor [7]. Due to the role of NAM in feedback inhibition of sirtuin activity, it has been utilized as a sirtuin inhibitor. However, when NAM is applied to cells, it is quickly converted to NAD⁺, leading to a reduction in NAM concentration [8]. Additionally, at low concentrations (μM), NAM serves as an NAD⁺ precursor, while at high concentrations (mM), it affects cell survival, differentiation, DNA repair, and deacetylation by inhibiting sirtuin activity [9]. The effects of sirtuins can vary depending on the subcellular localization of sirtuins or the cell type [10]. Given the conflicting findings across various studies, further research is required to fully elucidate the effect of NAM on sirtuins.

In our previous study, we demonstrated that NAM could alleviate delayed tooth eruption, one of the chief complaints of cleidocranial dysplasia (CCD) patients. The findings indicated that NAM enhanced osteoclast (OC) differentiation by inhibiting Sirt2 in osteoblasts (OB) and promoting the RUNX2-colonystimulating factor 1 (CSF1) axis. Furthermore, a subsequent study revealed that NAM could regulate oxidative stress and mitochondrial metabolism in OB by promoting Sirt3 activity within mitochondria. NAM not only enhanced OB function but also showed promise as the therapeutic agent for alleviating delayed tooth eruption and improving bone quality by maintaining the balance between OB and OC (OB-OC). Unlike many HDAC inhibitors, which are often highly toxic and are potent enough to be used as anticancer agents, NAM is a watersoluble vitamin with a well-established safety profile, making it a relatively safe candidate for improving bone metabolism.

4. Medical significance and therapeutic potential of NAM

NAM, an active, water-soluble form of vitamin B3, is abundantly present in animal products such as red meat, chicken and fish [11]. Deficiency in NAM leads to pellagra, which is characterized by photosensitive dermatitis, diarrhea, and dementia and can be effectively treated through NAM supplementation [12]. Topical NAM has demonstrated efficacy in alleviating a range of skin conditions, including acne vulgaris [13], melasma, NMSC [14], and atopic dermatitis [15]. Oral administration of NAM has also been shown to prevent NMSC [2] and manage of diabetes [16]. A notable phase 3 clinical trial reported that administering 500 mg of NAM twice daily for 12 months safely and effectively reduced the incidence of new NMSC and actinic keratoses in high-risk patients [2]. Due to its established safety profile, NAM is considered an affordable over-the-counter, especially in comparison to other pharmacological agents used for NMSC managements.

In our previous research, we explored the potential of NAM to restore delayed tooth eruption in Runx2^+/- mice, a model for CCD [17]. The administration of 1% NAM (w/v) in drinking water to pregnant and nursing mice, equivalent to 1.19 g/kg/day, did not exhibit any notable toxic effects. When this dosage is adjusted to human equivalent dose, it corresponds to approximately 5.76 g dose of NAM for a 60 kg person, which falls within the range of safety profile. Additionally, NAM has been reported as a safety profile even at higher dose, such as 8 g/ day in humans [18]. Considering the importance of safety in long-term treatment for young CCD patients, NAM presents a viable option as a therapeutic agent for prolonged use in treating bone diseases.

NAM Metabolism in Tooth Eruption

1. Genetic factors influencing delayed tooth eruption

Tooth eruption is a complex process that is tightly regulated, involving cells within both the tooth and the surrounding alveolar bone. OC are necessary for the formation of the eruption pathway through their interactions with OB and stromal cells [19]. Key factors such as CSF1, receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegrin (OPG), which are secreted by OB lineage cells, are essential for osteoclastogenesis and play an important role in forming the eruption pathway [20]. Mice lacking Csf1, known as osteopetrotic (op/op) mice, show an arrest in tooth eruption due to a deficiency on OC activity [21]. Similarly, mice deficient in Rankl exhibit defects in tooth eruption due to the absence of OC [22]. Opg functions as a soluble decoy receptor, inhibiting OC differentiation by disrupting the interaction between RANKL and RANK [23]. In an earlier study, the expression patterns of mRNA for cytokines associated with osteoclastogenesis during tooth eruption in the mouse mandible were examined using in situ hybridization [20]. The findings confirmed that Csf1, Rankl, and Opg were expressed in distinct temporal and spatial patterns from postnatal day 1 to 14. As a result, the accurate and timely expression of these molecules is essential for the proper regulation of OC differentiation, which is critical for the successful process of tooth eruption.

Delayed tooth eruption has been associated with several factors [24]. Local factors, such as dentigerous cysts, and ameloblastomas, can obstruct the normal eruption process. Additionally, drug-induced factors, including gingival hypertrophy caused by immunosuppressors and the use of medications such as aspirin and acetaminophen, may also delay eruption [25]. Furthermore, genetic disorders are also significant cause of delayed tooth eruption. Notable genetic disorders characterized by delayed tooth eruption include amelogenesis imperfecta [26], Apert syndrome [27], and CCD [28]. In amelogenesis imperfecta, delayed tooth eruption is linked to incomplete root formation and dentin exposure, resulting from abnormal enamel, which can lead to resorption and ankylosis [29]. The delayed eruption in Apert syndrome, caused by gain-offunction mutations of FGFR2, may be a result of the crowding, stacking, and displacement of teeth within the alveolus, which is spacious enough to accommodate the tooth buds in two rows [30]. CCD, a rare skeletal dysplasia caused by mutation of Runx2, show several clinical characteristics such as hypoplastic clavicles, delayed ossification of sutures and cranial base, and dental anomalies including delayed tooth eruption of permanent teeth [28].

2. NAM rescues delayed tooth eruption in cleidocranial dysplasia

RUNX2 is a key transcription factor crucial for skeletal development [31]. Mutations in the Runx2 gene cause CCD, characterized by premature closure of cranial sutures, hypoplastic clavicles, and dental anomalies [32,33]. A primary concern for CCD patients is the functional and aesthetic challenges associated with delayed or unerupted permanent dentition. Current therapeutic approaches are limited to surgical and orthodontic interventions during the constrained period of permanent tooth eruption, underscoring the necessity of developing pharmacological treatments to manage these symptoms [34]. Patients with CCD experience abnormal skeletal development, with dental anomalies, such as delayed or unerupted permanent teeth, posing significant challenges. Timely surgical and orthodontic interventions are critical for effective dental management in CCD [35]. However, the reliance on conventional, invasive treatments presents a significant unmet clinical need. As a result, there is a pressing need to develop pharmacological treatments to alleviate the symptoms of delayed tooth eruption associated with various syndromes, including CCD.

Previously, it has been reported that the impaired OC differentiation observed in CCD patients is attributed to reduced RANKL expression and a lower RANKL/OPG ratio in boneforming cells resulting from the loss of RUNX2. In Runx2^+/- mice, a well-established model for CCD, it has also been reported that delayed tooth eruption is attributed to decreased OC formation in the alveolar bone surrounding the teeth [36].

We were the first to demonstrate that delayed tooth eruption symptoms in a CCD mouse model could be improved using a pharmacological approach (Fig. 1) [17]. In this study, when pregnant or nursing mice were administered NAM through their drinking water, it successfully rescued the tooth eruption in Runx2^+/- mice. The findings revealed that CSF1 expression was significantly lower in Runx2^+/- OB compared to wild-type, whereas RANKL and OPG levels were not significantly different between the two groups. NAM-induced enhancement of osteoclastogenesis in bone marrow-derived macrophages from Runx2^+/- mice was attributed to increased expression of RUNX2 and CSF1, along with a higher RANKL/OPG ratio. These results suggest that the delay in tooth eruption is due to reduced osteoclastogenesis. Moreover, the study showed that pharmacological intervention with NAM could alleviate delayed or unerupted teeth in CCD patients. Considering that NAM has the potential to promote bone remodeling by stimulating both OB and OC, it may also aid in orthodontic tooth movement by enhancing the remodeling process.

NAM Metabolism in Osteogenesis

1. Problems in osteogenesis and NAM metabolism

NAD is a vital cofactor for enzymes that are integral to the respiratory chain and the TCA cycle, both of which are key components of mitochondrial energy metabolism [37]. Mitochondrial OXPHOS, crucial for adenosine triphosphate (ATP) production, plays a significant role in OB differentiation, with NAD⁺ acting as an essential cofactor in this process [38]. Studies have demonstrated that ATP production through OXPHOS is particularly important during the early stages of osteogenic differentiation [39]. Moreover, the activity of antioxidant enzymes that suppress reactive oxygen species (ROS), which are byproducts of OXPHOS primarily generated in mitochondria, is essential for this process [40]. Thus, maintaining mitochondrial homeostasis, which is the main source of ROS, is essential for the proper OB differentiation.

However, NAD levels decline with age [41], a reduction that is associated with various age-related diseases, such as cancer, arthritis, and cognitive decline. Consequently, restoring NAD levels through dietary precursors has been identified as a key strategy for alleviating these age-related conditions [42]. Moreover, regulating NAD levels using NAD precursors has also been reported to be effective in modulating bone metabolism.

2. Regulation of NAM metabolism linked to osteoblast differentiation

Administration of NMN, a precursor of NAD⁺, to 12-monthold mice for 3 months resulted in increased osteogenesis and decreased adipogenesis [43]. NMN also inhibited aluminuminduced bone loss by preventing inflammasome formation [44] and mitigated glucocorticoid-induced inhibition of osteogenesis by activating SIRT1 and PGC-1α [45]. Similarly, NR administration over 8 months reduced bone loss in 12-monthold mice [46]. Furthermore, bone marrow stromal cells from Nampt-deficient mice, lacking the enzyme that converts NAM to NMN, exhibited reduced osteogenic differentiation due to decreased NAMPT-induced Runx2 expression [47]. Furthermore, NAMPT expression was found to increase during osteogenic differentiation in both multipotent fibroblast (C3H10T1/2) cells and a omnipotent (MC3T3-E1) cells [48]. Additionally, bone marrow-derived macrophages from aged mice treated with NR exhibited enhanced OC differentiation [46] and NAMPT in osteogenic cells was shown to recruit OC, thereby stimulating bone remodeling [49]. In summary, various NAD precursors can promote bone metabolism by modulating both OB differentiation and OC differentiation.

We previously reported that NAM promotes not only mitochondrial metabolism but also osteogenic differentiation by regulating antioxidant enzymes (Fig. 2) [39]. The results of this study indicate that NAM enhances OXPHOS in mitochondria, thereby generating the ATP necessary for osteogenic differentiation. Additionally, NAM stabilized FOXO3a, a key regulator of antioxidant enzyme expression, which in turn alleviated oxidative stress and promoted OB differentiation. Although studies on the effects of NAM in bone metabolism are less extensive compared to other NAD precursors, its mechanism of action has been reported to enhance OB function by promoting the mitochondrial antioxidant defense system, which is critical for bone formation and the prevention of bone aging. Therefore, NAM is considered a promising candidate for treating bone diseases and preventing age-related bone loss by modulating NAD levels.

Conclusion

NAM is a promising treatment candidate since it maintains bone homeostasis and can regulate delayed tooth eruption. Recent studies reveal that NAM is critical in regulating the interaction between OB and OC, which is necessary for bone homeostasis and tooth eruption, in addition to improving OB function, which in turn promotes bone production.

The research discussed in this article highlights NAM’s capacity to promote bone formation while maintaining a balance between bone production and resorption, which is essential for bone health. These results imply that NAM may be used as a therapeutic drug for the prevention and treatment of other bone-related disorders as well as delayed tooth eruption. Its possible application in managing delayed tooth eruption, particularly in patients with CCD, is especially noteworthy.

However, despite these encouraging results, further research is necessary to fully understand the mechanisms by which NAM influences bone metabolism. If these findings are confirmed, NAM could be integrated into treatment strategies not only to maintain bone health and support timely tooth eruption in those with bone-related conditions but also as a preventive measure in the general population.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020R1A4A1019423, RS-2023-00207971, RS-2024- 00340752, RS-2024-00349549). This work also supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) and funded by the Korean government (MSIT) (No. 2022M3A9F3082330).

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Figure

Fig. 1.

Nicotinamide (NAM) promotes CSF1 expression in Runx2 -haploinsufficient osteoblasts by enhancing RUNX2 levels through the inhibition of Sirt2. This process supports osteoclast differentiation, contributing to alveolar bone resorption necessary for tooth eruption.

CSF1, colony-stimulating factor 1; RANKL, receptor activator of nuclear factor-kappa B ligand; OPG, osteoprotegrin.

Reused from the article of Yoon et al. (J Dent Res 2021;100:423-31) [17] with original copyright holder’s permission.

Fig. 2.

Nicotinamide (NAM) improves both osteoblast (OB) differentiation and mitochondrial function. Previously, we showed that NAM promotes mitochondrial biogenesis and the expression of antioxidant enzymes, leading to enhanced OB differentiation. NAM supports osteogenic differentiation under both normal physiological conditions and oxidative stress.

NAD⁺, nicotinamide adenine dinucleotide; ATP, adenosine triphosphate; ROS, reactive oxygen species.

Reused from the article of Yoon et al. (Exp Mol Med 2023;55:1531-43) [39].

Table

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