Osteonecrosis de los maxilares asociada a drogas antirresortivas en pacientes osteoporóticos: presentación de un caso clínico / Antiresorptive drugs-related jaw osteonecrosis in osteoporotic patients: report of a clinical case

La osteoporosis se caracteriza por una masa ósea baja con deterioro de la microarquitectura del tejido que conduce a la fragilidad, lo que aumenta el riesgo de fracturas. Después de la menopausia, la deficiencia de estrógenos aumenta la exposición del tejido al ligan- do RANK, lo que resulta en un aumento de la reabsorción y pérdida ósea, que pueden provocar osteoporosis. (1) Los bifosfonatos y el denosumab son utilizados para el tratamiento de la osteoporosis debido a su capacidad anticatabólica, que reducen la remodelación previniendo la pérdida de masa ósea, disminuyendo la probabilidad de fracturas y aumentando la densidad mineral del tejido. (2) La osteonecrosis de los maxilares asociadas a drogas antirresortivas es una situación que se presenta en pacientes que consumen de manera crónica antirresortivos para el tratamiento de enfermedades como: osteoporosis, osteogénesis imperfecta, enfermedad de Paget, displasia fi- brosa, hipercalcemia maligna asociada a tratamiento oncológico (AU)

Osteoporosis is characterized by low bone mass with deterioration of the tissue microarchitec- ture leading to fragility, which increases the risk of fractures. After menopause, estrogen deficiency increases tissue exposure to the RANK ligand, resulting in increased bone loss and resorption, which can lead to osteoporosis. (1) Bisphosphonates and denosumab are used for the treatment in low concentration, due to their anticatabolic capacity, which reduce remodeling, preventing loss of bone mass and fractures besides, antiresorptives drugs increase the mineral density of the tissue. (2) Osteonecrosis of the jaw associated with antiresorptives drugs occurs in patients whose chro- nically consume these drugs for the treatment of diseases such as: osteoporosis, imperfect osteogenesis, Paget's disease, fibrous dysplasia, malignant hypercalcemia associated with oncological treatment (AU)

Molecular insights into the interplay between adiposity, breast cancer and bone metastasis.

Cancer is a complex disease, with various pre-existing health ailments enhancing its pathology. In cancer, the extracellular environment contains various intrinsic physiological factors whose levels are altered with aging and pre-existing conditions. In obesity, the tumor microenvironment and metastases are enriched with factors that are both derived locally, and from other physiological compartments. Similarly, in obesity, the cancer cell environment both at the site of origin and at the secondary site i.e., metastatic niche, contains significantly more phenotypically-altered adipocytes than that of un-obese cancer patients. Indeed, obesity has been linked with cancer progression, metastasis, and therapy resistance. Adipocytes not only interact with tumor cells, but also with adjacent stromal cells at primary and metastatic sites. This review emphasizes the importance of bidirectional interactions between adipocytes and breast tumor cells in breast cancer progression and its bone metastases. This paper not only chronicles the role of various adipocyte-derived factors in tumor growth, but also describes the significance of adipocyte-derived bone metastatic factors in the development of bone metastasis of breast cancer. It provides a molecular view of the interplay between the adipocytes and tumor cells involved in breast cancer bone metastasis. However, more research is needed to determine if targeting cancer-associated adipocytes holds promise as a potential therapeutic approach for breast cancer bone metastasis treatment. Interplay between adipocytes and breast cancer cells at primary cancer site and metastatic bone microenvironment. AMSC Adipose-derived mesenchymal stem cell, CAA Cancer associated adipocytes, CAF Cancer associated fibroblast, BMSC Bone marrow derived mesenchymal stem cell, BMA Bone marrow adipocyte.

Bone anti-resorptive effects of coumarins on RANKL downstream cellular signaling: a systematic review of the literature.

BACKGROUND: Members of the botanical families Apiaceae/Umbelliferae, Asteraceae, Fabaceae/Leguminosae, and Thymelaeaceae are rich in coumarins and have traditionally been used as ethnomedicines in many regions including Europe, Asia, and South America. Coumarins are a class of secondary metabolites that are widely present in plants, fungi, and bacteria and exhibit several pharmacological, biochemical, and therapeutic effects. Recently, many plants rich in coumarins and their derivatives were found to affect bone metabolism. OBJECTIVE: To review scientific literature describing the mechanisms of action of coumarins in osteoclastogenesis and bone resorption. MATERIALS AND METHODS: For this systematic review, the PubMed, Scopus, and Periodical Capes databases and portals were searched. We included in vitro research articles published between 2010 and 2020 that evaluated coumarins using osteoclastogenic markers. RESULTS: Coumarins have been reported to downregulate RANKL-RANK signaling and various downstream signaling pathways required for osteoclast development, such as NF-κB, MAPK, Akt, and Ca2+ signaling, as well as pathways downstream of the nuclear factor of activated T-cells (NFATc1), including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinase 9 (MMP-9). CONCLUSIONS: Coumarins primarily inhibit osteoclast differentiation and activation by modulating different intracellular signaling pathways; therefore, they could serve as potential candidates for controlled randomized clinical trials aimed at improving human bone health.

Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss.

Dynamin-related protein 1 (DRP1) is a mitochondrial membrane GTPase and regulates mitochondrial fission. In this study, we found that the cytokine RANKL increased the expression of DRP1 and its receptor proteins, Fis1, Mid49, and Mid 51, during osteoclast formation in mouse bone marrow-derived macrophages. Inactivation of the kinase GSK3ß appeared to induce DRP1 expression. DRP1 knockdown or the DRP1 inhibitor Mdivi1 suppressed osteoclast differentiation via downregulation of c-Fos and NFATc1, the key transcription factor for osteoclast formation. Finally, the DRP1 inhibitor suppressed lipopolysaccharide-induced osteoclast formation in a calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that DRP1 positively contributes to RANKL-induced osteoclast differentiation by regulating the c-Fos-NFATc1 axis, suggesting the importance of mitochondrial DRP1 in osteoclastogenesis.

RANKL as a key figure in bridging between the bone and immune system: Its physiological functions and potential as a pharmacological target.

RANKL is a key molecule that bridges the bone and immune systems. RANKL stimulation activates a signaling pathway downstream of RANK, thereby determining the extent of bone resorption by inducing osteoclast maturation. The signaling pathway also regulates the development of different lymphoid organs, including the thymus, lymph nodes, and Peyer's patches, and plays an essential role in the establishment of immune tolerance. Such characteristics have continued to attract the attention of many researchers, even though it is now more than 20 years since RANKL was identified as a novel member of the TNF superfamily. Recently, we found that RANKL can function not only as a signal input molecule but also as a signal receptor to activate the RANKL reverse signaling pathway, which mediates the coupling between bone resorption and formation. This new finding may provide an important basis for elucidating the complex physiological roles played by RANKL.

Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence.

In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these 2 compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas control mice lost cortical bone between 8 and 24 months of age, mice lacking RANKL in osteocytes gained cortical bone during this period. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice but not in RANKL conditional knockout mice. Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Overexpression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Finally, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone.

Plasma proteomic profiling of young and old mice reveals cadherin-13 prevents age-related bone loss.

The blood exhibits a dynamic flux of proteins that are secreted by the tissues and cells of the body. To identify novel aging-related circulating proteins, we compared the plasma proteomic profiles of young and old mice using tandem mass spectrometry. The expression of 134 proteins differed between young and old mice. We selected seven proteins that were expressed at higher levels in young mice, and confirmed their plasma expression in immunoassays. The plasma levels of anthrax toxin receptor 2 (ANTXR2), cadherin-13 (CDH-13), scavenger receptor cysteine-rich type 1 protein M130 (CD163), cartilage oligomeric matrix protein (COMP), Dickkopf-related protein 3 (DKK3), periostin, and secretogranin-1 were all confirmed to decrease with age. We then investigated whether any of the secreted proteins influenced bone metabolism and found that CDH-13 inhibited osteoclast differentiation. CDH 13 treatment suppressed the receptor activator of NF-κB ligand (RANKL) signaling pathway in bone marrow-derived macrophages, and intraperitoneal administration of CDH-13 delayed age-related bone loss in the femurs of aged mice. These findings suggest that low plasma CDH-13 expression in aged mice promotes aging-associated osteopenia by facilitating excessive osteoclast formation. Thus, CDH-13 could have therapeutic potential as a protein drug for the prevention of osteopenia.

Roles of Olfactomedin 1 in Muscle and Bone Alterations Induced by Gravity Change in Mice.

Microgravity causes both muscle and bone loss. Although we previously revealed that gravity change influences muscle and bone through the vestibular system in mice, its detailed mechanism has not been elucidated. In this study, we investigated the roles of olfactomedin 1 (OLFM1), whose expression was upregulated during hypergravity in the soleus muscle, in mouse bone cells. Vestibular lesion significantly blunted OLFM1 expression in the soleus muscle and serum OLFM1 levels enhanced by hypergravity in mice. Moreover, a phosphatidylinositol 3-kinase inhibitor antagonized shear stress-enhanced OLFM1 expression in C2C12 myotubes. As for the effects of OLFM1 on bone cells, OLFM1 inhibited osteoclast formation from mouse bone marrow cells and mouse preosteoclastic RAW264.7 cells. Moreover, OLFM1 suppressed RANKL expression and nuclear factor-κB signaling in mouse osteoblasts. Serum OLFM1 levels were positively related to OLFM1 mRNA levels in the soleus muscle and trabecular bone mineral density of mice. In conclusion, we first showed that OLFM1 suppresses osteoclast formation and RANKL expression in mouse cells.

F2r negatively regulates osteoclastogenesis through inhibiting the Akt and NFκB signaling pathways.

G-protein-coupled receptors (GPCRs) are pivotal drug targets for many diseases. Coagulation Factor II Thrombin Receptor (F2R) is an important member of GPCR family that is highly expressed in osteoclasts. However, the role of F2r in osteoclasts is still unclear. Here, to examine the functions of F2r on osteoclast formation, differentiation, activation, survival, and acidification, we employed loss-of-function and gain-of-function approaches to study F2r using F2r-targeted short hairpin RNA (sh-F2r) lentivirus and overexpression plasmid pLX304-F2r lentivirus respectively, in mouse bone marrow cells (MBMs) induced osteoclasts. We used three shRNAs targeting F2r which had the ability to efficiently and consistently knock down the expression of F2r at different levels. Notably, F2r knockdown trigged a significant increase in osteoclast activity, number, and size, as well as promoted bone resorption and F-actin ring formation with increased osteoclast marker gene expression. Moreover, F2r overexpression blocked osteoclast formation, maturation, and acidification, indicating that F2r negatively regulates osteoclast formation and function. Furthermore, we investigated the mechanism(s) underlying the role of F2r in osteoclasts. We detected RANKL-induced signaling pathways related protein changes F2r knockdown cells and found significantly increased pAkt levels in sh-F2r infected cells, as well as significantly enhanced phosphorylation of p65 and IKBα in early stages of RANKL stimulation. These data demonstrated that F2r responds to RANKL stimulation to attenuate osteoclastogenesis through inhibiting the both F2r-Akt and F2r-NFκB signaling pathways, which lead a reduction in the expression of osteoclast genes. Our study suggests that targeting F2r may be a novel therapeutic approach for bone diseases, such as osteoporosis.

microRNA-143-3p regulates odontogenic differentiation of human dental pulp stem cells through regulation of the osteoprotegerin-RANK ligand pathway by targeting RANK.

NEW FINDINGS: What is the central question of this study? What is the role of miR-143-3p during human dental pulp stem cell (hDPSC) differentiation. What is the main finding and its importance? miR-143-3p negatively regulates receptor activator of nuclear factor-κB (RANK). RANK ligand (RANKL) binds to RANK and stimulates the development of osteoclasts. Osteoprotegerin (OPG) inhibits the interaction between RANK and RANKL. The OPG-RANKL signalling pathway regulates odontogenic differentiation of hDPSCs. ABSTRACT: Human dental pulp stem cells (hDPSCs) are capable of differentiating into odontoblast-like cells, which secrete reparative dentin after injury, in which the role of microRNA-143-3p (miR-143-3p) has been identified. Therefore, we investigated the mechanism by which miR-143-3p influences odontoblastic differentiation of hDPSCs. The relationship between miR-143-3p and receptor activator of nuclear factor-κB (RANK) was initially identified by bioinformatics prediction and further verified by dual luciferase reporter gene assay. Gain- and loss-of-function analysis with miR-143-3p mimic and miR-143-3p inhibitor was subsequently conducted. Dentin sialophosphoprotein (DSPP), bone sialoprotein (BSP), alkaline phosphatase (ALP), osteocalcin (OCN) and osteopontin (OPN) mRNA levels were then evaluated by RT-qPCR. Osteoprotegerin (OPG), RANK ligand (RANKL), nuclear factor-κB (NF-κB) p65 protein levels and the extent of NF-κB p65 phosphorylation were examined by western blot analysis. Alizarin red staining was performed to assess the mineralization of hDPSCs. Cell apoptosis and cell cycle distribution were determined using flow cytometry. During odontoblastic differentiation of hDPSC, miR-143-3p had high expression, but RANK expression was low. miR-143-3p was found to target RANK, and its inhibition enhanced mineralization and hDPSC apoptosis, while blocking cell cycle entry. At the same time, miR-143-3p inhibition elevated the extent of NF-κB p65 phosphorylation, as well as the expression of RANK, RANKL, DSPP, BSP, ALP, OCN and OPN, while decreasing the OPG level. Silencing RANK had opposite effects on these markers. miR-143-3p regulates odontoblastic differentiation of hDPSCs via the OPG-RANKL pathway that targets RANK. The elucidation of the mechanisms of odontogenic differentiation of hDPSCs may contribute to the development of effective dental pulp repair therapies for the clinical setting.

Negative Regulation of Osteoclast Commitment by Intracellular Protein Phosphatase Magnesium-Dependent 1A.

OBJECTIVE: Increased protein phosphatase magnesium-dependent 1A (PPM1A) levels in patients with ankylosing spondylitis regulate osteoblast differentiation in bony ankylosis; however, the potential mechanisms that regulate osteoclast differentiation in relation to abnormal bone formation remain unclear. This study was undertaken to investigate the relationship of PPM1A to osteoclast differentiation by generating conditional gene-knockout (PPM1Afl/fl ;LysM-Cre) mice and evaluating their bone phenotype. METHODS: The bone phenotypes of LysM-Cre mice (n = 6) and PPM1Afl/fl ;LysM-Cre mice (n = 6) were assessed by micro-computed tomography. Osteoclast differentiation was induced by culturing bone marrow-derived macrophages in the presence of RANKL and macrophage colony-stimulating factor (M-CSF), and was evaluated by counting tartrate-resistant acid phosphatase-positive multinucleated cells. Levels of messenger RNA for PPM1A, RANK, and osteoclast-specific genes were examined by real-time quantitative polymerase chain reaction, and protein levels were determined by Western blotting. Surface RANK expression was analyzed by fluorescence flow cytometry. RESULTS: The PPM1Afl/fl ;LysM-Cre mice displayed reduced bone mass (P < 0.001) and increased osteoclast differentiation (P < 0.001) and osteoclast-specific gene expression (P < 0.05) compared with their LysM-Cre littermates. Mechanistically, reduced PPM1A function in osteoclast precursors in PPM1Afl/fl ;LysM-Cre mice induced osteoclast lineage commitment by up-regulating RANK expression (P < 0.01) via p38 MAPK activation in response to M-CSF. PPM1A expression in macrophages was decreased by Toll-like receptor 4 activation (P < 0.05). The Ankylosing Spondylitis Disease Activity Score was negatively correlated with the expression of PPM1A in peripheral blood mononuclear cells from patients with axial spondyloarthritis (SpA) (γ = -0.7072, P < 0.0001). CONCLUSION: The loss of PPM1A function in osteoclast precursors driven by inflammatory signals contributes to osteoclast lineage commitment and differentiation by elevating RANK expression, reflecting a potential role of PPM1A in dynamic bone metabolism in axial SpA.

Effects of RANKL on the proliferation and apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis through regulating the NF-κB signaling pathway.

OBJECTIVE: The aim of this study is to investigate the regulatory effects of receptor activator of nuclear factor-kappa B ligand (RANKL) on the proliferation and apoptosis of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), and to explore its regulatory mechanism. MATERIALS AND METHODS: Synoviocytes were primarily cultured in rats of recognized collagen-induced arthritis (CIA) model. Meanwhile, they were induced into FLS models by lipopolysaccharides (LPS). All cells were divided into three groups, including blank group, model group and RANKL inhibitor group. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) in the cells were detected by enzyme-linked immunosorbent assay (ELISA). The proliferation and apoptosis of FLS were detected via 3-(4,5)-dimethylthiazol (-z-y1)-3,5-diphenytetrazoliumromide (MTT) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted to measure the messenger ribonucleic acid (mRNA) expression levels of nuclear factor-kappa B ligand (NF-κB) and Caspase-3 in FLS. Furthermore, Western blotting was adopted to detect the protein expression levels of NF-κB and Caspase-3 in FLS. RESULTS: Compared with the blank group, the expression levels of TNF-α and IL-1ß in the cells of the model group increased significantly. Cell proliferation rate increased significantly, whereas the cell apoptosis rate decreased remarkably in the model group. Meanwhile, the mRNA and protein levels of NF-κB and Caspase-3 in FLS were significantly up-regulated. Compared with the model group, the levels of TNF-α and IL-1ß in cells of RANKL inhibitor group notably declined. Similarly, cell proliferation rate was significantly reduced, whereas the cell apoptosis rate increased significantly. Furthermore, the mRNA and protein levels of NF-κB and Caspase-3 in FLS were evidently down-regulated. CONCLUSIONS: RANKL inhibitors can inhibit the proliferation and promote the apoptosis of FLS in RA. In addition, its mechanism may be related to the inhibition of NF-κB signaling pathway.

CCL28-induced RARß expression inhibits oral squamous cell carcinoma bone invasion.

Oral squamous cell carcinoma (OSCC) frequently invades the maxillary or mandibular bone, and this bone invasion is closely associated with poor prognosis and survival. Here, we show that CCL28 functions as a negative regulator of OSCC bone invasion. CCL28 inhibited invasion and epithelial-mesenchymal transition (EMT), and its inhibition of EMT was characterized by induced E-cadherin expression and reduced nuclear localization of ß-catenin in OSCC cells with detectable RUNX3 expression levels. CCL28 signaling via CCR10 increased retinoic acid receptor-ß (RARß) expression by reducing the interaction between RARα and HDAC1. In addition, CCL28 reduced RANKL production in OSCC and osteoblastic cells and blocked RANKL-induced osteoclastogenesis in osteoclast precursors. Intraperitoneally administered CCL28 inhibited tumor growth and osteolysis in mouse calvaria and tibia inoculated with OSCC cells. RARß expression was also increased in tumor tissues. In patients with OSCC, low CCL28, CCR10, and RARß expression levels were highly correlated with bone invasion. Patients with OSCC who had higher expression of CCL28, CCR10, or RARß had significantly better overall survival. These findings suggest that CCL28, CCR10, and RARß are useful markers for the prediction and treatment of OSCC bone invasion. Furthermore, CCL28 upregulation in OSCC cells or CCL28 treatment can be a therapeutic strategy for OSCC bone invasion.

Taurine Chloramine Inhibits Osteoclastic Differentiation and Osteoclast Marker Expression in RAW 264.7 Cells.

Taurine is an abundant sulfur-containing amino acid in myeloid cells. It undergoes halogenation in activated phagocytes and is converted to taurine chloramine (TauCl) and taurine bromamine. Bone homeostasis is mediated by the balance between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoclasts are bone-resorbing multinucleated cells differentiated from monocyte/macrophage precursor cells in response to receptor activator of NF-κB ligand (RANKL). In this study, we investigated the effect of TauCl on RANKL-induced osteoclastogenesis from RAW 264.7 macrophages. TauCl inhibited the formation of multi-nucleated osteoclast and the activity of tartrate-resistant acid phosphatase (TRAP). TauCl decreased the mRNA expression of osteoclast markers, such as TRAP, cathepsin K, and calcitonin receptor. TauCl also inhibited expression of the transcription factors, c-Fos and nuclear factor of activated T cells, which are important for osteoclast differentiation. These results suggest that TauCl might be used as a therapeutic agent to treat bone diseases associated with excessive bone resorption.

Osteoclasts Modulate Bone Erosion in Cholesteatoma via RANKL Signaling.

Cholesteatoma starts as a retraction of the tympanic membrane and expands into the middle ear, eroding the surrounding bone and causing hearing loss and other serious complications such as brain abscess and meningitis. Currently, the only effective treatment is complete surgical removal, but the recurrence rate is relatively high. In rheumatoid arthritis (RA), osteoclasts are known to be responsible for bone erosion and undergo differentiation and activation by receptor activator of NF-κB ligand (RANKL), which is secreted by synovial fibroblasts, T cells, and B cells. On the other hand, the mechanism of bone erosion in cholesteatoma is still controversial. In this study, we found that a significantly larger number of osteoclasts were observed on the eroded bone adjacent to cholesteatomas than in unaffected areas, and that fibroblasts in the cholesteatoma perimatrix expressed RANKL. We also investigated upstream transcription factors of RANKL using RNA sequencing results obtained via Ingenuity Pathways Analysis, a tool that identifies relevant targets in molecular biology systems. The concentrations of four candidate factors, namely interleukin-1ß, interleukin-6, tumor necrosis factor α, and prostaglandin E2, were increased in cholesteatomas compared with normal skin. Furthermore, interleukin-1ß was expressed in infiltrating inflammatory cells in the cholesteatoma perimatrix. This is the first report demonstrating that a larger-than-normal number of osteoclasts are present in cholesteatoma, and that the disease involves upregulation of factors related to osteoclast activation. Our study elucidates the molecular basis underlying bone erosion in cholesteatoma.

Bee venom attenuates Porphyromonas gingivalis and RANKL-induced bone resorption with osteoclastogenic differentiation.

Porphyromonas gingivalis (P. gingivalis) is one of the major periodontal pathogens leading to inflammation and alveolar bone resorption. Bone resorption is induced by osteoclasts, which are multinucleated giant cells. Osteoclastic bone resorption is mediated by enhanced receptor activator of nuclear factor-kappa B ligand (RANKL) signaling. Therefore, the down-regulation of RANKL downstream signals is regarded as an effective therapeutic target in the treatment of bone loss-associated disorders. The aim of this study was to evaluate whether purified bee venom (BV) could attenuate P. gingivalis-induced inflammatory periodontitis and RANKL-induced osteoclast differentiation. Inflammatory periodontitis induced by P. gingivalis increased alveolar bone resorption and increased expression of TNF-α and IL-1ß, while BV treatment resulted in decreased bone loss and pro-inflammatory cytokines. Similarly, RANKL-induced multinucleated osteoclast differentiation and osteoclast-specific gene expression, such as nuclear factor of activated T cells 1 (NFATc1), cathepsin K, tartrate-resistant acid phosphatase (TRAP), and integrin αvß3 were significantly suppressed by treatment with BV. We show that BV reduces P. gingivalis-induced inflammatory bone loss-related periodontitis in vivo and RANKL-induced osteoclast differentiation, activation, and function in vitro. These results suggest that BV exerts positive effects on inflammatory periodontitis associated osteoclastogenesis.

Vav1 inhibits RANKL-induced osteoclast differentiation and bone resorption.

Vav1 is a Rho/Rac guanine nucleotide exchange factor primarily expressed in hematopoietic cells. In this study, we investigated the potential role of Vav1 in osteoclast (OC) differentiation by comparing the ability of bone marrow mononuclear cells (BMMCs) obtained from Vav1-deficient (Vav1-/-) and wild-type (WT) mice to differentiate into mature OCs upon stimulation with macrophage colony stimulating factor and receptor activator of nuclear kappa B ligand in vitro. Our results suggested that Vav1 deficiency promoted the differentiation of BMMCs into OCs, as indicated by the increased expression of tartrate-resistant acid phosphatase, cathepsin K, and calcitonin receptor. Therefore, Vav1 may play a negative role in OC differentiation. This hypothesis was supported by the observation of more OCs in the femurs of Vav1-/- mice than in WT mice. Furthermore, the bone status of Vav1-/- mice was analyzed in situ and the femurs of Vav1-/- mice appeared abnormal, with poor bone density and fewer number of trabeculae. In addition, Vav1-deficient OCs showed stronger adhesion to vitronectin, an αvß3 integrin ligand important in bone resorption. Thus, Vav1 may inhibit OC differentiation and protect against bone resorption. [BMB Reports 2019; 52(11): 659-664].

[Progress of research on the relationship between calcitonin gene-related peptide and RANK/RANKL/OPG system in the bone reconstruction].

OBJECTIVE: To summarize the research progress on the calcitonin gene-related peptide (CGRP) and receptor activator of nuclear factor κB (RANK)/receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) system during bone reconstruction to provide theoretical basis for further research on the prevention and treatment of bone-related diseases. METHODS: The relevant research results at home and abroad in recent years were analyzed and summarized. RESULTS: CGRP and RANK/RANKL/OPG system play important regulatory roles in the bone reconstruction. CONCLUSION: At present, the research on the mechanism of CGRP and RANK/RANKL/OPG system in bone reconstruction is insufficient. Therefore, it is necessary to study further on the process and interrelation of CGRP and RANK/RANKL/OPG system in bone reconstruction to confirm their mechanism, which will bring new ideas and methods for the treatment of bone related diseases in clinic.

Notch Signaling Pathway in Apical Periodontitis: Correlation with Bone Resorption Regulators and Proinflammatory Cytokines.

INTRODUCTION: The exact mechanisms of periapical bone resorption have not been fully elucidated. This study aimed to analyze the expression of Notch signaling molecules (Notch2, Jagged1, and Hey1) and proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1ß, and IL-6) in human apical periodontitis lesions with different receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratios and determine their potential correlation. METHODS: The study group consisted of 50 periapical lesions collected in conjunction with apicoectomy. The relative gene expression of the investigated molecules (Notch2, Jagged1, Hey1, RANKL, OPG, TNF-α, IL-1ß, and IL-6) in all tissue samples was analyzed using reverse transcriptase real-time polymerase chain reaction. The Student t test, Mann-Whitney U test, and Spearman correlation were used for statistical analysis. RESULTS: Based on the RANKL/OPG ratio, periapical lesions were either RANKL predominant (RANKL > OPG, n = 33) or OPG predominant (RANKL < OPG, n = 17). Symptomatic lesions occurred more frequently in RANKL-predominant compared with OPG-predominant lesions (24 vs 7, P = .029). Notch2, Jagged1, Hey1, and TNF-α were significantly overexpressed in lesions with predominant RANKL compared with lesions with predominant OPG (P = .001, P = .001, P = .027, and P = .016, respectively). Significant correlations were observed between the investigated genes in periapical lesions. CONCLUSIONS: Notch signaling appeared to be activated in periapical inflammation. An increase in Notch2, Jagged1, Hey1, and TNF-α expression in RANKL-predominant periapical lesions corroborates their joined involvement in extensive periapical bone resorption.

Dynamics of Bone Cell Interactions and Differential Responses to PTH and Antibody-Based Therapies.

We propose a mathematical model describing the dynamics of osteoblasts and osteoclasts in bone remodeling. The goal of this work is to develop an integrated modeling framework for bone remodeling and bone cell signaling dynamics that could be used to explore qualitatively combination treatments for osteoporosis in humans. The model has been calibrated using 57 checks from the literature. Specific global optimization methods based on qualitative objectives have been developed to perform the model calibration. We also added pharmacokinetics representations of three drugs to the model, which are teriparatide (PTH(1-34)), denosumab (a RANKL antibody) and romosozumab (a sclerostin antibody), achieving excellent goodness-of-fit of human clinical data. The model reproduces the paradoxical effects of PTH on the bone mass, where continuous administration of PTH results in bone loss but intermittent administration of PTH leads to bone gain, thus proposing an explanation of this phenomenon. We used the model to simulate different categories of osteoporosis. The main attributes of each disease are qualitatively well captured by the model, for example changes in bone turnover in the disease states. We explored dosing regimens for each disease based on the combination of denosumab and romosozumab, identifying adequate ratios and doses of both drugs for subpopulations of patients in function of categories of osteoporosis and the degree of severity of the disease.