Transcriptomics‐based analysis of the mechanism by which Wang-Bi capsule alleviates joint destruction in rats with collagen‐induced arthritis

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied with joint destruction that often leads to disability. Wang-Bi capsule (WB), a traditional Chinese medicine-based herbs formula, has exhibited inhibition effect on joint destruction of collagen-induced arthritis (CIA) animal model in our previous study. But its molecular mechanisms are still obscure. Methods CIA rats were treated intragastrical with WB for eight weeks, and the effect of joints protection were evaluated by hematoxylin and eosin (H&E) staining, safranin O fast green staining, tartrate-resistant acid phosphatase (TRAP) staining and micro‑CT scanning analysis. The transcriptomic of tarsal joints were used to investigate how WB alleviated joint destruction. Results The histological examination of ankle joints showed WB alleviated both cartilage damage and bone destruction of CIA rats. This protective effect on joints were further evidenced by micro-CT analysis. The transcriptomic analysis showed that WB prominently changed 12 KEGG signaling pathways (“calcium signaling pathway”, “cAMP signaling pathway”, “cell adhesion molecules”, “chemokine signaling pathway”, “complement and coagulation cascades”, “MAPK signaling pathway”, “NF-kappa B signaling pathway”, “osteoclast differentiation”, “PI3K-Akt signaling pathway”, “focal adhesion”, “Gap junction” and “Rap1 signaling pathway”) associated with bone or cartilage. Several genes (including Il6, Tnfsf11, Ffar2, Plg, Tnfrsf11b, Fgf4, Fpr1, Siglec1, Vegfd, Cldn1, Cxcl13, Chad, Arrb2, Fgf9, Egfr) regulating bone resorption, bone formation and cartilage development were identified by further analysis. Meanwhile, these differentially expressed genes were validated by real-time quantitative PCR. Conclusions Overall, the protective effect of WB treatment on joint were confirmed in CIA rats, and its basic molecular mechanisms may be associated with regulating some genes (including Il6, Tnfsf11, Ffar2 and Plg etc.) involved in bone resorption, bone formation and cartilage development.

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Treatment withRhizoma DioscoreaeExtract Has Protective Effect on Osteopenia in Ovariectomized Rats

The Scientific World JOURNAL ◽

10.1155/2014/645975 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Zhiguo Zhang ◽

Lihua Xiang ◽

Dong Bai ◽

Xiaowei Fu ◽

Wenlai Wang ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Protective Effect ◽

Signaling Pathway ◽

Pathway Analysis ◽

Ovariectomized Rats ◽

Inhibitory Effects ◽

Ovx Rats ◽

Rank Signaling

The aims of this study were to evaluate the osteoprotective effect of aqueous extract fromRhizoma Dioscoreae(RDE) on rats with ovariectomy- (OVX-) induced osteopenia. Our results show that RDE could inhibit bone loss of OVX rats after a 12-week treatment. The microarray analysis showed that 68 genes were upregulated and that 100 genes were downregulated in femurs of the RDE group rats compared to those in the OVX group. The Ingenuity Pathway Analysis (IPA) showed that several downregulated genes had the potential to code for proteins that were involved in the Wnt/β-catenin signaling pathway (Sost, Lrp6, Tcf7l2, and Alpl) and the RANKL/RANK signaling pathway (Map2k6 and Nfatc4). These results revealed that the mechanism for an antiosteopenic effect of RDE might lie in the synchronous inhibitory effects on both the bone formation and the bone resorption, which is associated with modulating the Wnt/β-catenin signaling and the RANKL/RANK signaling.

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Network Pharmacology-Based Strategy for the Investigation of the Anti-Osteoporosis Effects and Underlying Mechanism of Zhuangguguanjie Formulation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.727808 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wang Gong ◽

Xingren Chen ◽

Tianshu Shi ◽

Xiaoyan Shao ◽

Xueying An ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Bone Mass ◽

Signaling Pathway ◽

Osteoclast Differentiation ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Network Pharmacology ◽

Biological Processes

As the society is aging, the increasing prevalence of osteoporosis has generated huge social and economic impact, while the drug therapy for osteoporosis is limited due to multiple targets involved in this disease. Zhuangguguanjie formulation (ZG) is extensively used in the clinical treatment of bone and joint diseases, but the underlying mechanism has not been fully described. This study aimed to examine the therapeutic effect and potential mechanism of ZG on postmenopausal osteoporosis. The ovariectomized (OVX) mice were treated with normal saline or ZG for 4 weeks after ovariectomy following a series of analyses. The bone mass density (BMD) and trabecular parameters were examined by micro-CT. Bone remodeling was evaluated by the bone histomorphometry analysis and ELISA assay of bone turnover biomarkers in serum. The possible drug–disease common targets were analyzed by network pharmacology. To predict the potential biological processes and related pathways, GO/KEGG enrichment analysis was performed. The effects of ZG on the differentiation phenotype of osteoclasts and osteoblasts and the predicted pathway were verified in vitro. The results showed that ZG significantly improved the bone mass and micro-trabecular architecture in OVX mice compared with untreated OVX mice. ZG could promote bone formation and inhibit bone resorption to ameliorate ovariectomy-induced osteoporosis as evidenced by increased number of osteoblast (N.Ob/Tb.Pm) and decreased number of osteoclast (N.Oc/Tb.Pm) in treated group compared with untreated OVX mice. After identifying potential drug–disease common targets by network pharmacology, GO enrichment analysis predicted that ZG might affect various biological processes including osteoblastic differentiation and osteoclast differentiation. The KEGG enrichment analysis suggested that PI3K/Akt and mTOR signaling pathways could be the possible pathways. Furthermore, the experiments in vitro validated our findings. ZG significantly down-regulated the expression of osteoclast differentiation markers, reduced osteoclastic resorption, and inhibited the phosphorylation of PI3K/Akt, while ZG obviously up-regulated the expression of osteogenic biomarkers, promoted the formation of calcium nodules, and hampered the phosphorylation of 70S6K1/mTOR, which can be reversed by the corresponding pathway activator. Thus, our study suggested that ZG could inhibit the PI3K/Akt signaling pathway to reduce osteoclastic bone resorption as well as hamper the mTORC1/S6K1 signaling pathway to promote osteoblastic bone formation.

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Nox4 Mediates RANKL-induced ER-Phagy and Osteoclastogenesis via Activating ROS/PERK/eIF-2α/ATF4 Pathway

10.21203/rs.3.rs-34288/v1 ◽

2020 ◽

Author(s):

Jing Sun ◽

wugui chen ◽

Songtao Li ◽

Sizhen Yang ◽

Ying Zhang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Bone Resorption ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Nuclear Factor Κb ◽

Protein Levels ◽

Unfolded Protein ◽

Regulatory Effects ◽

Protein Response

Abstract Background: Receptor activator of nuclear factor-κB ligand (RANKL) has been found to induce osteoclastogenesis and bone resorption. However, the underlying molecular mechanisms remain unclear. Methods: Osteoclastogenesis was evaluated by number of TRAP-positive multinuclear (≥3) osteoclasts, bone resorption pits and expression levels of related genes. Autophagy activity were evaluated by LC3-II/LC3-I ratio, number of autophagic vacuoles and adenovirus-mRFP-GFP-tagged LC3 reporting system; Inhibitor chloroquine (CQ) was used to verified the role of autophagy in RANKL-induced osteoclastogenesis; Via downregulating Nox4 with inhibitor (DPI) and retrovirus-conveyed shRNA, we further explored the importance of Nox4 in RANKL-induced autophagy and osteoclastogenesis, as well as the regulatory effects of Nox4 on nonmitochondrial reactive oxygen species (ROS) and PERK/eIF-2α/ATF4 pathway. Intracellular ROS scavenger (NAC), mitochondrial-targeted antioxidant (MitoTEMPO) and inhibitor of PERK (GSK2606414) were also employed to investigate the role of ROS and PERK/eIF-2α/ATF4 pathway in RANKL-induced autophagy and osteoclastogenesis. Results: RANKL markedly increased autophagy, while CQ treatment caused reduction of RANKL-induced autophagy and osteoclastogenesis. Consistent with the increased autophagy, the protein levels of Nox4 were significantly increased, and Nox4 was selectively localized within the endoplasmic reticulum (ER) after RANKL stimulation. DPI and shRNA efficiently decreased the protein level and (or) activity of Nox4 in the ER and inhibited RANKL-induced autophagy and osteoclastogenesis. Mechanistically, we found that Nox4 regulates RANKL-induced autophagy activation and osteoclastogenesis by stimulating the production of nonmitochondrial ROS. Additionally, Nox4-derived nonmitochondrial ROS dramatically activate PERK/eIF-2α/ATF4, which is a critical unfolded protein response (UPR)-related signaling pathway during ER stress. Blocking the activation of the PERK/eIF-2α/ATF4 signaling pathway either by Nox4 shRNA, ROS antioxidant or PERK inhibitor (GSK2606414) treatment significantly inhibited endoplasmic reticulum autophagy (ER-phagy) during RANKL-induced osteoclastogenesis. Conclusions: Our findings provide new insights into the processes of RANKL-induced osteoclastogenesis and will help the development of new therapeutic strategies for osteoclastogenesis-related diseases.

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Osteoporosis: From Molecular Mechanisms to Therapies 2.0

International Journal of Molecular Sciences ◽

10.3390/ijms21218005 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8005

Author(s):

Chih-Hsin Tang

Keyword(s):

Side Effects ◽

Bone Resorption ◽

Bone Formation ◽

Molecular Mechanisms ◽

Current Understanding ◽

Special Issue ◽

Trabecular Microarchitecture ◽

Anabolic Agent ◽

Skeletal Disorder

Osteoporosis is a common skeletal disorder, occurring as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis. Teriparatide, an anabolic agent, stimulates bone formation and corrects the characteristic changes in the trabecular microarchitecture. However, these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. This editorial summarizes and discusses the themes of the ten articles published in our Special Issue “Osteoporosis: From Molecular Mechanisms to Therapies 2.0”, a continuation of our 2019 Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies" (https://www.mdpi.com/journal/ijms/special_issues/osteoporosis_ijms). These Special Issues detail important global scientific findings that contribute to our current understanding of osteoporosis.

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Betulinic Acid Ameliorates the T-2 Toxin-Triggered Intestinal Impairment in Mice by Inhibiting Inflammation and Mucosal Barrier Dysfunction through the NF-κB Signaling Pathway

Toxins ◽

10.3390/toxins12120794 ◽

2020 ◽

Vol 12 (12) ◽

pp. 794

Author(s):

Chenxi Luo ◽

Chenglong Huang ◽

Lijuan Zhu ◽

Li Kong ◽

Zhihang Yuan ◽

...

Keyword(s):

Protective Effect ◽

Antioxidant Capacity ◽

Signaling Pathway ◽

Inflammatory Cytokines ◽

Betulinic Acid ◽

Molecular Mechanisms ◽

Mucosal Barrier ◽

Intestinal Damage ◽

Trichothecene Mycotoxin ◽

Anti Inflammatory

T-2 toxin, a trichothecene mycotoxin produced by Fusarium, is widely distributed in crops and animal feed and frequently induces intestinal damage. Betulinic acid (BA), a plant-derived pentacyclic lupane-type triterpene, possesses potential immunomodulatory, antioxidant and anti-inflammatory biological properties. The current study aimed to explore the protective effect and molecular mechanisms of BA on intestinal mucosal impairment provoked by acute exposure to T-2 toxin. Mice were intragastrically administered BA (0.25, 0.5, or 1 mg/kg) daily for 2 weeks and then injected intraperitoneally with T-2 toxin (4 mg/kg) once to induce an intestinal impairment. BA pretreatment inhibited the loss of antioxidant capacity in the intestine of T-2 toxin-treated mice by elevating the levels of CAT, GSH-PX and GSH and reducing the accumulation of MDA. In addition, BA pretreatment alleviated the T-2 toxin-triggered intestinal immune barrier dysregulation by increasing the SIgA level in the intestine at dosages of 0.5 and 1 mg/kg, increasing IgG and IgM levels in serum at dosages of 0.5 and 1 mg/kg and restoring the intestinal C3 and C4 levels at a dosage of 1 mg/kg. BA administration at a dosage of 1 mg/kg also improved the intestinal chemical barrier by decreasing the serum level of DAO. Moreover, BA pretreatment improved the intestinal physical barrier via boosting the expression of ZO-1 and Occludin mRNAs and restoring the morphology of intestinal villi that was altered by T-2 toxin. Furthermore, treatment with 1 mg/kg BA downregulated the expression of p-NF-κB and p-IκB-α proteins in the intestine, while all doses of BA suppressed the pro-inflammatory cytokines expression of IL-1β, IL-6 and TNF-α mRNAs and increased the anti-inflammatory cytokine expression of IL-10 mRNA in the intestine of T-2 toxin-exposed mice. BA was proposed to exert a protective effect on intestinal mucosal disruption in T-2 toxin-stimulated mice by enhancing the intestinal antioxidant capacity, inhibiting the secretion of inflammatory cytokines and repairing intestinal mucosal barrier functions, which may be associated with BA-mediated inhibition of the NF-κB signaling pathway activation.

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Hsp70/Bmi1-FoxO1-SOD Signaling Pathway Contributes to the Protective Effect of Sound Conditioning against Acute Acoustic Trauma in a Rat Model

Neural Plasticity ◽

10.1155/2020/8823785 ◽

2020 ◽

Vol 2020 ◽

pp. 1-22

Author(s):

Guoxia Zhu ◽

Yongxiang Wu ◽

Yang Qiu ◽

Keyong Tian ◽

Wenjuan Mi ◽

...

Keyword(s):

Protective Effect ◽

Signaling Pathway ◽

Rat Model ◽

Molecular Mechanisms ◽

Outer Hair Cell ◽

Acoustic Trauma ◽

Auditory Brainstem Responses ◽

Ultrastructural Changes ◽

Ganglion Neurons ◽

Acute Acoustic Trauma

Sound conditioning (SC) is defined as “toughening” to lower levels of sound over time, which reduces a subsequent noise-induced threshold shift. Although the protective effect of SC in mammals is generally understood, the exact mechanisms involved have not yet been elucidated. To confirm the protective effect of SC against noise exposure (NE) and the stress-related signaling pathway of its rescue, we observed target molecule changes caused by SC of low frequency prior to NE as well as histology analysis in vivo and verified the suggested mechanisms in SGNs in vitro. Further, we investigated the potential role of Hsp70 and Bmi1 in SC by targeting SOD1 and SOD2 which are regulated by the FoxO1 signaling pathway based on mitochondrial function and reactive oxygen species (ROS) levels. Finally, we sought to identify the possible molecular mechanisms associated with the beneficial effects of SC against noise-induced trauma. Data from the rat model were evaluated by western blot, immunofluorescence, and RT-PCR. The results revealed that SC upregulated Hsp70, Bmi1, FoxO1, SOD1, and SOD2 expression in spiral ganglion neurons (SGNs). Moreover, the auditory brainstem responses (ABRs) and electron microscopy revealed that SC could protect against acute acoustic trauma (AAT) based on a significant reduction of hearing impairment and visible reduction in outer hair cell loss as well as ultrastructural changes in OHCs and SGNs. Collectively, these results suggested that the contribution of Bmi1 toward decreased sensitivity to noise-induced trauma following SC was triggered by Hsp70 induction and associated with enhancement of the antioxidant system and decreased mitochondrial superoxide accumulation. This contribution of Bmi1 was achieved by direct targeting of SOD1 and SOD2, which was regulated by FoxO1. Therefore, the Hsp70/Bmi1-FoxO1-SOD signaling pathway might contribute to the protective effect of SC against AAT in a rat model.

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OSTEOPOROSIS: CELLULAR AND MOLECULAR MECHANISMS OF DEVELOPMENT AND TARGET MOLECULES IN SEARCH FOR NEW TREATMENTS OF THE DISEASE

Osteoporosis and Bone Diseases ◽

10.14341/osteo2012115-22 ◽

2012 ◽

Vol 15 (1) ◽

pp. 15-22

Author(s):

S Sagalovski

Keyword(s):

Bone Formation ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Development Process ◽

Molecular Mechanisms ◽

New Drugs ◽

Review Of The Literature ◽

Target Molecules ◽

Mechanisms Of Development ◽

New Treatments

In a review of the literature reflects the modern understanding of the cellular-molecular mechanism development of osteoporosis. Reflects the importance of cytokine RANKL-RANK-OPG sistem and Wnt/β-catenin signaling pathway in the development process of osteoblasto- and osteoclastogenesis. Noting the key role in the process of bone formation a number of molecules of cell signaling pathway and their antagonists are of interest as a target molecule to search for new drugs treatment for osteoporosis.

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The regulatory role of the RANKL/RANK/OPG signaling pathway in the mechanisms of tooth eruption in patients with impacted teeth

10.21203/rs.2.19720/v5 ◽

2020 ◽

Author(s):

Ludmila Brodetska ◽

Larysa Natrus ◽

Olha Lisakovska ◽

Olexandr Kaniura ◽

Liudmyla Iakovenko ◽

...

Keyword(s):

Bone Resorption ◽

Bone Tissue ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Active Form ◽

Tooth Eruption ◽

Control Group ◽

Impacted Teeth ◽

Tooth Impaction

Abstract Background: Tooth impaction is a common problem in orthodontic practice and in some cases accompanied by pain and pathological changes of surrounding teeth. Understanding the cellular and molecular mechanisms underlying tooth impaction allows finding the most effective orthodontic treatment for patients with impacted teeth (IT). RANK (receptor activator of NF-κB) / RANKL (RANK ligand) / OPG (osteoprotegerin) signaling pathway controls bone resorption and may be involved in the regulation of tooth eruption. The study aimed to evaluate bone remodeling based on the assessment of the RANKL/RANK/OPG status in patients with IT. Methods: Bone samples from 18 patients (mean age 25.27±3.34) were divided into 3 groups: 1 – bone tissue of healthy persons (control group); 2 – bone tissue, that was taken near the healthy tooth in patients with tooth impaction; 3 – bone tissue, that was collected near the IT. Levels of RANKL, RANK, OPG, osteocalcin (OC), NF-κB p65 subunit, NFATc1, and caspase-3 were determined by western blotting. The difference between groups was assessed using ANOVA followed by Tukey’s post-hoc test. P-value ≤ 0.05 was considered statistically significant.Results: We established a 1.73-fold elevation of RANK level in the IT area vs. control, indicating the recruitment of preosteoclasts. An increase in RANKL, OPG, and OC content was demonstrated (1.46-, 1.48-, and 1.42-fold respectively), reflecting the high activity of osteoblasts near the IT. Despite the activation of the RANKL/RANK/OPG system in the impaction area, NF-κB and NFATc1 levels did not change compared vs. control, indicating a blocked/delayed process of osteoclastogenesis. We found a decrease in the content of procaspase-3 (1.28-fold), while the level of its active form p17 increased by 2.26 folds near the healthy tooth in patients with IT compared with control. In the area of IT, we observed an increase in procaspase-3 and p17 levels (1.32 and 1.78 folds). This reflects impairments of caspase-3 activation and accumulation of its inactive form in the IT area that may contribute to the tooth eruption failure.Conclusions: Tooth impaction may be associated with the disturbances in the caspase-3 cascade activation and the imbalance in the RANKL/RANK/OPG system, and as a result, blocked bone resorption.

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Enhancing Activity of Pleurotus sajor-caju (Fr.) Sing β-1,3-Glucanoligosaccharide (Ps-GOS) on Proliferation, Differentiation, and Mineralization of MC3T3-E1 Cells through the Involvement of BMP-2/Runx2/MAPK/Wnt/β-Catenin Signaling Pathway

Biomolecules ◽

10.3390/biom10020190 ◽

2020 ◽

Vol 10 (2) ◽

pp. 190

Author(s):

Thanintorn Yodthong ◽

Ureporn Kedjarune-Leggat ◽

Carl Smythe ◽

Pannawich Sukprasirt ◽

Aratee Aroonkesorn ◽

...

Keyword(s):

Bone Formation ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Integration Site ◽

Biological Activities ◽

Mitogen Activated Protein Kinase ◽

Bone Morphogenetic Protein 2 ◽

World Health ◽

Wide Range ◽

Pleurotus Sajor Caju

Osteoporosis is a leading world health problem that results from an imbalance between bone formation and bone resorption. β-glucans has been extensively reported to exhibit a wide range of biological activities, including antiosteoporosis both in vitro and in vivo. However, the molecular mechanisms responsible for β-glucan-mediated bone formation in osteoblasts have not yet been investigated. The oyster mushroom Pleurotus sajor-caju produces abundant amounts of an insoluble β-glucan, which is rendered soluble by enzymatic degradation using Hevea glucanase to generate low-molecular-weight glucanoligosaccharide (Ps-GOS). This study aimed to investigate the osteogenic enhancing activity and underlining molecular mechanism of Ps-GOS on osteoblastogenesis of pre-osteoblastic MC3T3-E1 cells. In this study, it was demonstrated for the first time that low concentrations of Ps-GOS could promote cell proliferation and division after 48 h of treatment. In addition, Ps-GOS upregulated the mRNA and protein expression level of bone morphogenetic protein-2 (BMP-2) and runt-related transcription factor-2 (Runx2), which are both involved in BMP signaling pathway, accompanied by increased alkaline phosphatase (ALP) activity and mineralization. Ps-GOS also upregulated the expression of osteogenesis related genes including ALP, collagen type 1 (COL1), and osteocalcin (OCN). Moreover, our novel findings suggest that Ps-GOS may exert its effects through the mitogen-activated protein kinase (MAPK) and wingless-type MMTV integration site (Wnt)/β-catenin signaling pathways.

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The regulatory role of the RANKL/RANK/OPG signaling pathway in the mechanisms of tooth eruption in patients with impacted teeth

BMC Oral Health ◽

10.1186/s12903-020-01251-y ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ludmila Brodetska ◽

Larysa Natrus ◽

Olha Lisakovska ◽

Olexandr Kaniura ◽

Liudmyla Iakovenko ◽

...

Keyword(s):

Bone Resorption ◽

Bone Tissue ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Caspase 3 ◽

Active Form ◽

Tooth Eruption ◽

Control Group ◽

Impacted Teeth ◽

Tooth Impaction

Abstract Background Tooth impaction is a common problem in orthodontic practice and in some cases accompanied by pain and pathological changes of surrounding teeth. Understanding the cellular and molecular mechanisms underlying tooth impaction allows finding the most effective orthodontic treatment for patients with impacted teeth (IT). RANK (receptor activator of NF-κB) / RANKL (RANK ligand) / OPG (osteoprotegerin) signaling pathway controls bone resorption and may be involved in the regulation of tooth eruption. The study aimed to evaluate bone remodeling based on the assessment of the RANKL/RANK/OPG status in patients with IT. Methods Bone samples from 18 patients (mean age 25.27 ± 3.34) were divided into 3 groups: 1 – bone tissue of healthy persons (control group); 2 – bone tissue, that was taken near the healthy tooth in patients with tooth impaction; 3 – bone tissue, that was collected near the IT. Levels of RANKL, RANK, OPG, osteocalcin (OC), NF-κB p65 subunit, NFATc1, and caspase-3 were determined by western blotting. The difference between groups was assessed using ANOVA followed by Tukey’s post-hoc test. P-value ≤0.05 was considered statistically significant. Results We established a 1.73-fold elevation of RANK level in the IT area vs. control, indicating the recruitment of preosteoclasts. An increase in RANKL, OPG, and OC content was demonstrated (1.46-, 1.48-, and 1.42-fold respectively), reflecting the high activity of osteoblasts near the IT. Despite the activation of the RANKL/RANK/OPG system in the impaction area, NF-κB and NFATc1 levels did not change compared vs. control, indicating a blocked/delayed process of osteoclastogenesis. We found a decrease in the content of procaspase-3 (1.28-fold), while the level of its active form p17 increased by 2.26 folds near the healthy tooth in patients with IT compared with control. In the area of IT, we observed an increase in procaspase-3 and p17 levels (1.32 and 1.78 folds). This reflects impairments of caspase-3 activation and accumulation of its inactive form in the IT area that may contribute to the tooth eruption failure. Conclusions Tooth impaction may be associated with the disturbances in the caspase-3 cascade activation and the imbalance in the RANKL/RANK/OPG system, and as a result, blocked bone resorption.

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