Search

Survival and apoptosis are of major importance in the osteoclast life cycle. As osteoclasts have short lifespan, any alteration that prolongs their viability may cause enhanced osteoclast activity. Hence, the regulation of OC apoptosis has been recognized as a critical factor in bone remodeling. An imbalance in bone remodeling due to increased osteoclast activity leads to most adult bone diseases such as osteoporosis, rheumatoid arthritis and multiple myeloma. Therefore, manipulating osteoclast death would be a viable therapeutic approach in ameliorating bone diseases, with accelerated resorption. Over the last few decades we have witnessed the unraveling of many of the intracellular mechanisms responsible for osteoclast apoptosis. Thus, an understanding of the underlying mechanisms by which osteoclasts undergo programmed cell death and the regulators that modulate that activity will undoubtedly provide an insight into the development of pharmacological agents to treat such pathological bone diseases., Competing Interests: The authors declare that there are no conflicts of interest., (© 2019 Published by Elsevier Inc.)

The aim of the present systematic review and meta-analysis was to address the following Population, Intervention, Comparison, and Outcome question: Is the efficacy of articaine better than lignocaine in adults requiring dental treatment? Four percent articaine was compared with 2% lignocaine for maxillary and mandibular infiltrations and block anesthesia, and with the principal outcome measures of anesthetic success. Using RevMan software, the weighted anesthesia success rates and 95% confidence intervals (CIs) were estimated and compared using a random-effects model. For combined studies, articaine was more likely to achieve successful anesthesia than lignocaine (N = 18, odds ratio [OR]: 1.92, 95% CI: 1.45-2.56, P < 0.00001, I 2  = 32%). Maxillary and mandibular infiltration studies showed obvious superiority of articaine to lignocaine (N = 8, OR: 2.50, 95% CI: 1.51-4.15, P = 0.0004, I 2  = 41%). Maxillary infiltration subgroup analysis showed no significant difference between articaine and lignocaine (N = 5, OR: 1.69, 95% CI: 0.88-3.23, P = 0.11, I 2  = 19%). For combined mandibular anesthesia studies, articaine was superior to lignocaine (N = 14, OR: 1.99, 95% CI: 1.45-2.72, P < 0.0001, I 2  = 32%), with further subgroup analysis showing significant differences in both mandibular block anesthesia (N = 11, OR: 1.55, 95% CI: 1.19-2.03, P = 0.001), I 2  = 0%) and mandibular infiltration (N = 3, OR: 3.87, 95% CI: 2.62-5.72, P < 0.00001, I 2  = 0%), indicating that articaine is more effective than lignocaine in providing anesthetic success in routine dental procedures., (© 2019 John Wiley & Sons Australia, Ltd.)

In the recent past, there has been a burgeoning interest in targeting cytokines such as IL-3 for specific disease conditions of bone such as rheumatoid arthritis and multiple myeloma. Unlike other cytokines, IL-3 is a cytokine with a multilineage potential and broad spectrum of target cells and it plays a vital role in hematopoiesis. Due to its common receptor subunit, the action of IL-3 shows functional redundancy with other cytokines such as the granulocyte-macrophage colony-stimulating factor and IL-5. IL-3 has been successfully used in ameliorating radiation-induced bone marrow aplasia and similar conditions. However, the role of IL-3 in bone cells has not been fully unraveled yet; therefore, the aim of this overview is to present the effects of IL-3 in bone with a special emphasis on osteoclasts and osteoblasts in a concise manner., (© 2018 Wiley Periodicals, Inc.)

Bone resorption is an important cellular function in skeletal development and remodeling of the adult skeleton. Most of the pathological bone disease conditions like osteoporosis reflect increased osteoclast activity; hence, increased bone resorption. Researchers have unraveled most of the intracellular mechanisms responsible for osteoclast bone-resorbing activity in last few decades. Therefore, understanding the fundamentals of osteoclast-induced bone resorption and the cytokines and other substances that modulate the osteoclast activity unequivocally provide insights into the development of drugs to ameliorate pathological bone diseases with enhanced bone resorption. The aim of this review is to examine the literature on osteoclast function and bone-resorbing activity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Osteoclasts are multinucleated cells of hematopoietic origin which are unique in their ability to resorb bone. Osteoclasts are generated from myeloid progenitors through a progression that involves the fusion of mononuclear precursor cells. The identification of RANK-RANKL signaling as the main signal regulating osteoclast differentiation was a major breakthrough in the bone biology field. In addition remarkable discoveries have been made to broaden the knowledge of the molecular mechanisms of osteoclast formation and differentiation. Despite the vital requirement of osteoclasts in bone modeling and remodeling, bone-related conditions like osteoporosis, Paget's disease and rheumatoid arthritis where accelerated bone resorption takes place pose a major socioeconomic burden to the society. Hence, a better understanding of the pathways leading to osteoclast differentiation is vital in successfully managing such diseases. This is an attempt to give a birds-eye-view of the players in osteoclast formation and differentiation in a brief and concise manner.

Background and Objective: Nuclear factor-κB (NF-κB) is activated at sites of inflammation in many diseases, including periodontitis. Nuclear factor-κB induces the transcription of proinflammatory cytokines, resulting in increased osteoclastogenesis and bone resorption. Recently, it has been shown that the NF-κB alternative pathway is important for maintainance of physiological bone homeostasis. Activation of this pathway is by processing of the inhibitor p100 into the active subunit p52 by nuclear factor-κB-inducing kinase (NIK). Defective NIK in aly/aly mice (NIK(aly)) causes mild osteopetrosis and blunted RANKL-stimulated osteoclastogenesis in vivo and in vitro, suggesting that NIK is necessary for basal and stimulated osteoclastogenesis. Nevertheless, the role of NIK in pathological bone resorption is not well investigated. The present study was undertaken to investigate the role of NIK in lipopolysaccharide (LPS)-induced inflammatory bone resorption using aly/aly mice., Material and Methods: Mice were injected with LPS over the calvariae and killed 5 d later. Calvariae were subjected to radiological analysis. Histological sections were stained for tartrate-resistant acid phosphatase, and histomorphometric analysis was performed to quantify the number of osteoclasts and the area of bone resorption., Results: Lipopolysaccharide-induced inflammation was observed in wild-type and aly/+ mice but not in aly/aly mice. Lipopolysaccharide significantly reduced the calvarial bone mineral density in wild-type and aly/+ mice, whereas bone mineral density was comparable in LPS- and vehicle-injected aly/aly mice. In addition, aly/aly mice were resistant to LPS-induced bone resorption and osteoclastogenesis., Conclusion: Taken together, these data show that NIK is important in the bone-destructive components of inflammation and represents a possible therapeutic target., (© 2010 John Wiley & Sons A/S.)

Bone degenerative diseases, including osteoporosis, impair the fine balance between osteoclast bone resorption and osteoblast bone formation. Single-agent therapy for anabolic and anticatabolic effects is attractive as a drug target to ameliorate such conditions. Inhibition of nuclear factor (NF)-κB reduces the osteoclast bone resorption. The role of NF-κB inhibitors on osteoblasts and bone formation, however, is minimal and not well investigated. Using an established NF-κB inhibitor named S1627, we demonstrated that inhibition of NF-κB increases osteoblast differentiation and bone formation in vitro by up-regulating the mRNAs of osteoblast-specific genes like type I collagen, alkaline phosphatase, and osteopontin. In addition, S1627 was able to increase bone formation and repair bone defect in a murine calvarial defect model. To determine the effect of NF-κB on a model of osteoporosis, we injected two doses of inhibitor (25 and 50 mg/kg·d) twice a day in sham-operated or ovariectomized 12-wk-old mice and killed them after 4 wk. The anabolic effect of S1627 on trabecular bone was determined by micro focal computed tomography and histomorphometry. Bone mineral density of inhibitor-treated ovariectomized animals was significantly increased compared with sham-operated mice. Osteoblast-related indices like osteoblast surface, mineral apposition rate, and bone formation rate were increased in S1627-treated animals in a dose-dependent manner. NF-κB inhibition by S1627 increased the trabecular bone volume in ovariectomized mice. Furthermore, S1627 could inhibit the osteoclast number, and osteoclast surface to bone surface. In vitro osteoclastogenesis and bone resorbing activity were dose-dependently reduced by NF-κB inhibitor S1627. Taken collectively, our results suggest that NF-κB inhibitors are effective in treating bone-related diseases due to their dual anabolic and antiresorptive activities.

The alternative NF-kappaB pathway consists predominantly of NF-kappaB-inducing kinase (NIK), IkappaB kinase alpha (IKKalpha), p100/p52, and RelB. The hallmark of the alternative NF-kappaB signaling is the processing of p100 into p52 through NIK, thus allowing the binding of p52 and RelB. The physiologic relevance of alternative NF-kappaB activation in bone biology, however, is not well understood. To elucidate the role of the alternative pathway in bone homeostasis, we first analyzed alymphoplasic (aly/aly) mice, which have a defective NIK and are unable to process p100, resulting in the absence of p52. We observed increased bone mineral density (BMD) and bone volume, indicating an osteopetrotic phenotype. These mice also have a significant defect in RANKL-induced osteoclastogenesis in vitro and in vivo. NF-kappaB DNA-binding assays revealed reduced activity of RelA, RelB, and p50 and no binding activity of p52 in aly/aly osteoclast nuclear extracts after RANKL stimulation. To determine the role of p100 itself without the influence of a concomitant lack of p52, we used p100(-/-) mice, which specifically lack the p100 inhibitor but still express p52. p100(-/-) mice have an osteopenic phenotype owing to the increased osteoclast and decreased osteoblast numbers that was rescued by the deletion of one allele of the relB gene. Deletion of both allele of relB resulted in a significantly increased bone mass owing to decreased osteoclast activity and increased osteoblast numbers compared with wild-type (WT) controls, revealing a hitherto unknown role for RelB in bone formation. Our data suggest a pivotal role of the alternative NF-kappaB pathway, especially of the inhibitory role of p100, in both basal and stimulated osteoclastogenesis and the importance of RelB in both bone formation and resorption., (Copyright 2010 American Society for Bone and Mineral Research.)

TNF-alpha is a major etiologic factor of inflammatory bone diseases such as periodontitis and rheumatoid arthritis. In addition, patients with metabolic diseases such as chronic heart disease and diabetes have significantly increased plasma levels of TNF-alpha. Several lines of evidence show inhibition of osteoblastogenesis by TNF-alpha in vitro. Therefore, bone formation and osteogenesis in these patients might be inhibited because of TNF-alpha. However, little is known about the inhibitory role of TNF-alpha in bone formation/osteogenesis in vivo. The purpose of this study was to investigate the role of TNF-alpha in osteogenesis using a murine tooth extraction model. Lipopolysaccharide (LPS) was injected subcutaneously into the calvariae of either wildtype (WT) or TNF-alpha-deficient (KO) mice. The left incisor was extracted 4 days after LPS injection. The measuring area was established as the tooth socket under the mesial root of the first molar. A significant increase in serum TNF-alpha levels after LPS injection was observed in WT mice. The BMD of the tooth socket was significantly decreased by LPS injection 21 days after extraction in WT but not in KO mice. Histomorphometric analysis showed a significant decrease in the mineral apposition rate after LPS injection, which appeared at an early stage in WT but not in KO mice. Injection of a peptide that blocked the TNF-alpha signaling pathway by preventing transmission of the NF-kappaB signal recovered the inhibition of osteogenesis observed after LPS injection. In conclusion, TNF-alpha might play a major role in LPS-induced inhibition of osteogenesis under inflammatory conditions.

Confocal laser microscopy is a well-recognized research tool in the fields of biological and material science which enables high-resolution images of samples with minimum requirements for specimen preparation. Here we introduce an innovative technique for the 3-D description and measurement of resorption pits using Super Depth Surface Profile Measurement Microscope based on the principle of confocal microscope. We show one example of culturing for 48 h with an established NF-kappaB inhibitor named NBD-peptide after plating mature osteoclasts on dentine slices with osteoblasts. The activity of osteoclasts is measured by determining the volume of resorbed portion of dentine by osteoclasts in vitro. The 3-D surface profile could be obtained by detecting the position at which the reflected laser intensity from the target becomes the maximum on z-axis. The volume and depth of resorption lacunae by stimulated osteoclasts is significantly increased compared to the un-stimulated group without changing of resorption area. The increase in volume and depth are dose-dependently inhibited by the NBD-peptide. Comparing to the classical method by measuring 2-D area of pits, analysis based on this technique could provide reliable quantitative assessment reflecting the osteoclast activity.

We report here a nanogel-mediated peptide drug delivery system. Low stability is a major drawback towards clinical application of peptide drugs. The W9-peptide, a TNF-alpha and RANKL antagonist, was used as a model for testing the feasibility of cholesterol-bearing pullulan (CHP)-nanogel as the drug delivery system. We found CHP-nanogel could form complex with the W9-peptide and prevents its aggregation in vitro. Murine bone resorption model using low dietary calcium was used to investigate the in vivo effect. Two-time-injection of 24 mg/kg W9-peptide per day with or without CHP-nanogel was given for 7 days. Thereafter, radiological, and histological assessments were performed. The injections of the W9-peptide (24 mg/kg) with CHP-nanogel prevented the reduction in bone mineral density whereas the same dose without CHP-nanogel could not show any inhibitory effect. Histomorphometric analysis of tibiae showed significant decrease of osteoclast number and surface in CHP-W9 complex treated group and the levels of urinary deoxypyridinoline reflected these decrease of bone resorption parameters. Taken together these data shows that CHP-nanogel worked as a suitable carrier for the W9-peptide and it prevented aggregation and increased the stability of the W9-peptide. This study reveals the feasibility of CHP-nanogel-mediated peptide delivery in preventing bone resorption in vivo.

NF-kappaB is a pleiotropic transcription factor, which regulates osteoclast formation, function, and survival. The finding that the deletion of both NF-kappaB p50 and p52 subunits resulted in osteopetrosis due to the absence of osteoclasts was followed by the observation that NF-kappaB is essential for RANK-expressing osteoclast precursors to differentiate into TRAP+ osteoclasts in response to RANKL and other osteoclastogenic cytokines. Thus, inhibitors of NF-kappaB should prevent osteoclast formation induced directly or indirectly by RANKL or TNF. In this mini review, we discuss the research findings that revealed essential roles of NF-kappaB signaling in osteoclasts.

The classical NF-kappaB pathway plays an important role in osteoclast formation and differentiation; however, the role of NF-kappaB in osteoclast bone-resorbing activity is not well understood. To elucidate whether NF-kappaB is important for osteoclast bone-resorbing activity, we used a selective peptide inhibitor of the classical NF-kappaB pathway named the NBD peptide. Osteoclasts were generated using bone marrow macrophages in the presence of M-CSF and RANKL. The NBD peptide dose-dependently blocked the bone-resorbing activity of osteoclasts by reducing area, volume (p < 0.001) and depths (p < 0.05) of pits. The reduced resorption by the peptide was due to reduced osteoclast bone-resorbing activity, but not reduced differentiation as the number of osteoclasts was similar in all groups. The peptide inhibited bone resorption by reducing TRAP activity, disrupting actin rings and preventing osteoclast migration. Gene expressions of a panel of bone resorption markers were significantly reduced. The NBD peptide dose-dependently reduced the RANKL-induced c-Src kinase activity, which is important for actin ring formation and osteoclast bone resorption. Therefore, these data suggest that the classical NF-kappaB pathway plays a pivotal role in osteoclast bone-resorbing activity.

Oral candidosis (syn. Oral candidiasis; OC), is a collective term given to a group of oral mucosal disorders caused by the fugal pathogen belonging to the genus Candida. The association of OC with the human immunodeficiency virus (HIV) infection has been known since the advent of the acquired immune deficiency syndrome (AIDS) pandemic. OC is one of the earliest manifestations of HIV disease in high risk individuals not undergoing chemotherapy and is also a strong predictor of the subsequent risk of AIDS-related illness or death. With the advances in HIV therapy, such as highly active anti-retroviral therapy (HAART), the prevalence and presenting features of OC have changed in HIV-infected individuals, especially those in industrialized countries. The presence of OC in "controlled" HIV-positive individuals may be indicative of a patient nonadherence to therapy or possible failure. The factors contributing to the genesis of OC and its progression in these individuals are poorly understood, but may include an interrelationship between HIV and Candida and/or a dysfunction in the local immunity, superimposed on weakened cell-mediated immunity and depletion of CD4 T cells. The dramatic increase in publications on this topic matches the increased importance and awareness of this opportunistic infection in HIV-infected individuals. In this review we first address the epidemiologic and clinical features of OC in HIV-infected persons, followed by the current understanding of the pathogenesis of OC in the context of HIV infection with a concluding section on the current management concepts of OC.

It has been reported that poor glycaemic control predisposes to oral candidal infection in diabetic patients. For instance, the carriage of Candida species and the density of candidal growth in the oral cavity is frequently claimed to be increased in patients with diabetes mellitus. However, the validity of these observations remains controversial. Hence, we review and discuss here the clinical data in the literature on the relationship between diabetes and oral candidal carriage and infection, and possible mechanisms associated with its pathogenicity.

The increased incidence of oral candidiasis in patients with malignancies stems partly from the systemic disease itself and, partly from the therapeutic measures such as cytotoxic and other immunosuppressive drugs and radiotherapy they receive during management of such malignancies. In this review we discuss the clinical and laboratory findings on the relationship between cytotoxics, radiotherapy and oral candidiasis, possible mechanisms of pathogenicity following such therapy, as well as precautions that could be taken to minimize such recalcitrant yeast infections.