The Skeletal-Protecting Action and Mechanisms of Action for Mood-Stabilizing Drug Lithium Chloride: Current Evidence and Future Potential Research Areas

Wong, Sok Kuan; Chin, Kok‐Yong

doi:10.3389/fphar.2020.00430

Cited by 30 publications

(25 citation statements)

References 95 publications

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“…Consistent with observations in ovariectomized rats, LiCl significantly reduced orthodontic tooth movement in rats [9] and attenuated force-induced root resorption [10]. The molecular mechanism remains unclear but may be attributed to a positive balance of bone turnover that also helped to compensate for bone loss and stimulates osseointegration in ovariectomized rats [11] involving the Wnt/β-catenin and other signaling pathways [12]. Importantly, biomechanical activation of the Wnt/β-catenin pathway in osteocytes involves nitric oxide production [13] and in OTM, these are the osteocytes that become the major promotors to mediate osteoclastogenesis and to regulate bone formation.…”

Section: Introductionsupporting

confidence: 73%

Effects of Lithium Chloride and Nitric Oxide Inhibitor on Orthodontic Tooth Movement in the Rat

et al. 2021

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Orthodontic tooth movement in a rodent model is reduced by lithium chloride (LiCl), a mood-stabilizing agent with antithyroid effects. Considering the established inhibitory effect of N(omega)-nitro-L-arginine methyl ester (L-NAME) on orthodontic tooth movement and the possible role of nitric oxide synthase in LiCl mechanism of action, the question arises if these two mechanisms are synergistic. To answer this question, 70 male Sprague Dawley rats were randomly divided into seven groups: untreated group without any interventions (i), and the orthodontic tooth movement groups receiving daily saline injection (ii), 300 (iii), and 600 mg/kg (iv) of LiCl per os, 10 mg/kg of L-NAME (v) and the combinations of 300 (vi) and 600 mg/kg LiCl (vii) with L-NAME. The first molar was moved towards the incisor with 60 g of mesial tipping force applied by an activated fixed coil spring for two weeks. The resulted distance between the first and the second molar was measured using a feeler gauge. The serum parameters were also determined. We report here that both concentrations of LiCl significantly decreased tooth movement. Even though L-NAME was capable of reducing orthodontic tooth movement, no synergistic effects with LiCl were observed. Moreover, L-NAME had no impact on the robust and significant increase of thyroid-stimulating hormone (TSH) and decrease of triiodothyronine (T3) and thyroxine (T4) in the LiCl treated rats. These findings suggest LiCl significantly decreases the orthodontic tooth movement in rats; however, this ability seems not to be principally mediated through nitric oxide synthase.

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Section: Introductionsupporting

confidence: 73%

Effects of Lithium Chloride and Nitric Oxide Inhibitor on Orthodontic Tooth Movement in the Rat

et al. 2021

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“…However, small molecules intervening in different compounds may overcome this problem and offer therapeutic potential [ 3 ]. One of these molecules is lithium, which has promising effects on bone healing and inhibits GSK3β, thereby activating Wnt/β-catenin [ 34 , 35 ]. Although the therapeutic effect of lithium in promoting bone healing has been well documented in experimental settings and clinical trials, its major medical limitation is still its clinical underutilization, which is attributable to its unfavorable side effects [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Activation of Focal Adhesion Kinase Restores Simulated Microgravity-Induced Inhibition of Osteoblast Differentiation via Wnt/Β-Catenin Pathway

Fan

Cooper

et al. 2022

IJMS

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Simulated microgravity (SMG) inhibits osteoblast differentiation (OBD) and induces bone loss via the inhibition of the Wnt/β-catenin pathway. However, the mechanism by which SMG alters the Wnt/β-catenin pathway is unknown. We previously demonstrated that SMG altered the focal adhesion kinase (FAK)-regulated mTORC1, AMPK and ERK1/2 pathways, leading to the inhibition of tumor cell proliferation/metastasis and promoting cell apoptosis. To examine whether FAK similarly mediates SMG-dependent changes to Wnt/β-catenin in osteoblasts, we characterized mouse MC3T3-E1 cells cultured under clinostat-modeled SMG (µg) conditions. Compared to cells cultured under ground (1 g) conditions, SMG reduces focal adhesions, alters cytoskeleton structures, and down-regulates FAK, Wnt/β-catenin and Wnt/β-catenin-regulated molecules. Consequently, protein-2 (BMP2), type-1 collagen (COL1), alkaline-phosphatase activity and matrix mineralization are all inhibited. In the mouse hindlimb unloading (HU) model, SMG-affected tibial trabecular bone loss is significantly reduced, according to histological and micro-computed tomography analyses. Interestingly, the FAK activator, cytotoxic necrotizing factor-1 (CNF1), significantly suppresses all of the SMG-induced alterations in MC3T3-E1 cells and the HU model. Therefore, our data demonstrate the critical role of FAK in the SMG-induced inhibition of OBD and bone loss via the Wnt/β-catenin pathway, offering FAK signaling as a new therapeutic target not only for astronauts at risk of OBD inhibition and bone loss, but also osteoporotic patients.

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“…Although the stimulatory effects of Wnt/β-catenin signaling on osteoblast differentiation has previously been wellestablished (32), the effects of LiCl on osteogenesis remains controversial. Several studies have shown the positive effects of LiCl on osteogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Lithium Chloride Exerts Differential Effects on Dentinogenesis and Osteogenesis in Primary Pulp Cultures

Vijaykumar¹,

Mina²

2021

Front. Dent. Med

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Wnt/β-catenin signaling is known to play essential roles in odontoblast differentiation and reparative dentin formation. Various Wnt activators including LiCl have been increasingly studied for their effectiveness to induce repair of the dentin-pulp complex. LiCl is a simple salt thought to activate Wnt/β-catenin signaling by inhibiting GSK3β. Previous in vitro and in vivo studies showed that LiCl increased odontoblast differentiation and enhanced reparative dentin formation. However, the underlying molecular and cellular mechanisms by which LiCl regulates odontoblast and osteoblast differentiation during reparative dentinogenesis are not well-understood. Our in vitro studies show that exposure of early dental pulp progenitors to LiCl increased the survival and the pool of αSMA+ progenitors, leading to enhanced odontoblast and osteoblast differentiation. The positive effects of LiCl in the differentiation of osteoblasts and odontoblasts from αSMA+ progenitors are mediated by Wnt/β-catenin signaling. Our results also showed that continuous and late exposure of dental pulp cells to LiCl increased the expression of odontoblast markers through Wnt/β-catenin signaling, and the number of odontoblasts expressing DMP1-Cherry and DSPP-Cerulean transgenes. However, unlike the early treatment, both continuous and late treatments decreased the expression of Bsp and the expression of BSP-GFPtpz transgene. These observations suggest that prolonged treatment with LiCl in more mature cells of the dental pulp has an inhibitory effect on osteoblast differentiation. The inhibitory effects of LiCl on osteogenesis and Bsp were not mediated through Wnt/β-catenin signaling. These observations suggest that the effects of LiCl, and GSK3β antagonists on reparative dentinogenesis involve multiple pathways and are not specific to Wnt/β-catenin signaling.

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The Skeletal-Protecting Action and Mechanisms of Action for Mood-Stabilizing Drug Lithium Chloride: Current Evidence and Future Potential Research Areas

Cited by 30 publications

References 95 publications

Effects of Lithium Chloride and Nitric Oxide Inhibitor on Orthodontic Tooth Movement in the Rat

Effects of Lithium Chloride and Nitric Oxide Inhibitor on Orthodontic Tooth Movement in the Rat

Activation of Focal Adhesion Kinase Restores Simulated Microgravity-Induced Inhibition of Osteoblast Differentiation via Wnt/Β-Catenin Pathway

Lithium Chloride Exerts Differential Effects on Dentinogenesis and Osteogenesis in Primary Pulp Cultures

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