Receptor Activator Of The Nuclear Factor Kappa B Ligand Research Articles

Osteoprotegerin and receptor activator of the nuclear factor kappa B ligand (RANKL) in healthy pubertal girls - relationships with physical growth and classical bone turnover markers.

Osteoprotegerin (OPG) is a trap receptor for the receptor activator of the nuclear factor kappa B ligand (RANKL). We aimed to determine the OPG and free soluble RANKL (sRANKL) concentrations in girls during puberty and their relationships with pubertal stage, growth rate and serum concentrations of estradiol, as well as classical bone formation (N-terminal propeptide of type I collagen (PINP), bone-specific alkaline phosphatase (BALP), osteocalcin (OC)) and bone resorption (C-terminal telopeptide of type I collagen (CTX)) markers. The semi-longitudinal study involved 88 healthy girls, aged 11.8-13.2 years. Their weight and height were measured twice at one-year intervals. Pubertal stages were assessed using the Tanner (T) scale. Blood samples were taken at the first examination. Serum concentrations of OPG, sRANKL, CTX and BALP were determined by enzyme-linked immunosorbent assay, estradiol and PINP by radioimmunoassay and osteocalcin by immunoradiometric assay. The one-year increase in height and weight of girls in the T2 and T3 pubertal stages was greater than that of girls in the T4 stage (p=0.000, p<0.03). OPG concentrations (T2: 4.04±0.62; T3: 4.31±0.79; T4: 4.46±0.84 pmol/L) sRANKL concentrations (T2: 0.22 (IQR 0.09-0.54); T3: 0.42 (IQR 0.22-0.79); T4: 0.35 (IQR 0.16-1.04) pmol/L) and sRANKL/OPG ratios (T2: 0.05 (IQR 0.03-0.13); T3: 0.11 (IQR 0.05-0.19); T4: 0.09 (IQR 0.05-0.19) did not differ significantly between pubertal stages. Concentrations of PINP, CTX, BALP and OC were higher in girls at T3 stage than at the T4 stage (p=0.000, p=0.001, p=0.046, p=0.038; respectively). Concentrations of sRANKL and OPG did not correlate with body weight, height, growth rate, or concentrations of estradiol, PINP, CTX, BALP and OC. There were correlations between the increase in height over one year and the concentrations of PINP (r=0.499, p=0.000), CTX (r=0.311, p=0.003) and BALP (r=0.224, p=0.036), as well as of estradiol (r=-0.473, p=0.000). Unlike PINP, OC, BALP, CTX or estradiol concentrations, sRANKL and OPG concentrations do not change in girls during puberty. Neither OPG nor sRANKL concentrations correlate with somatic characteristics and classical bone turnover markers concentrations.

ER Stress, the Unfolded Protein Response and Osteoclastogenesis: A Review.

Endoplasmic reticulum (ER) stress and its adaptive mechanism, the unfolded protein response (UPR), are triggered by the accumulation of unfolded and misfolded proteins. During osteoclastogenesis, a large number of active proteins are synthesized. When an imbalance in the protein folding process occurs, it causes osteoclasts to trigger the UPR. This close association has led to the role of the UPR in osteoclastogenesis being increasingly explored. In recent years, several studies have reported the role of ER stress and UPR in osteoclastogenesis and bone resorption. Here, we reviewed the relevant literature and discussed the UPR signaling cascade response, osteoclastogenesis-related signaling pathways, and the role of UPR in osteoclastogenesis and bone resorption in detail. It was found that the UPR signal (PERK, CHOP, and IRE1-XBP1) promoted the expression of the receptor activator of the nuclear factor-kappa B ligand (RANKL) in osteoblasts and indirectly enhanced osteoclastogenesis. IRE1 promoted osteoclastogenesis via promoting NF-κB, MAPK signaling, or the release of pro-inflammatory factors (IL-6, IL-1β, and TNFα). CREBH promoted osteoclast differentiation by promoting NFATc1 expression. The PERK signaling pathway also promoted osteoclastogenesis through NF-κB and MAPK signaling pathways, autophagy, and RANKL secretion from osteoblasts. However, salubrinal (an inhibitor of eIF2α dephosphorylation that upregulated p-eIF2α expression) directly inhibited osteoclastogenesis by suppressing NFATc1 expression and indirectly promoted osteoclastogenesis by promoting RANKL secretion from osteoblasts. Therefore, the specific effects and mechanisms of p-PERK and its downstream signaling on osteoclastogenesis still need further experiments to confirm. In addition, the exact role of ATF6 and BiP in osteoclastogenesis also required further exploration. In conclusion, our detailed and systematic review provides some references for the next step to fully elucidate the relationship between UPR and osteoclastogenesis, intending to provide new insights for the treatment of diseases caused by osteoclast over-differentiation, such as osteoporosis.

Calotropis procera latex protein reduces inflammation and bone loss in ligature-induced period ontitis in male rats

ObjectiveCalotropis procera latex protein (CpLP) is a popular anti-inflammatory and therefore we aimed to study its effects on inflammatory bone loss. DesignMale Wistar rats were subjected to a ligature of molars. Groups of rats received intraperitoneally CpLP (0.3 mg/kg, 1 mg/kg, or 3 mg/kg) or saline (0.9% NaCl) one hour before ligature and then daily up to 11 days, compared to naïve. Gingiva was evaluated by myeloperoxidase activity and interleukin-1 beta (IL-1β) expression by ELISA. Bone resorption was evaluated in the region between the cement-enamel junction and the alveolar bone crest. The histology considered alveolar bone resorption and cementum integrity, leukocyte infiltration, and attachment level, followed by immunohistochemistry bone markers between 1st and 2nd molars. Systemically, the weight of the body and organs, and a leukogram were performed. ResultsThe periodontitis significantly increased myeloperoxidase activity and the IL-1β level. The increased bone resorption was histologically corroborated by periodontal destruction, leukocyte influx, and attachment loss, as well as the increasing receptor activator of the nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio, and Tartrate-resistant acid phosphatase (TRAP)+ cells when compared to naïve. CpLP significantly reduced myeloperoxidase activity, level of IL-1β, alveolar bone resorption, periodontal destruction, leukocyte influx, and attachment loss. The CpLp also reduced the RANKL/OPG ratio and TRAP+ cells, when compared with the saline group, and did not affect the systemic parameters. ConclusionsCpLP exhibited a periodontal protective effect by reducing inflammation and restricting osteoclastic alveolar bone resorption in this rat model.

Prognostic Value and Quantitative CT Analysis in RANKL Expression of Spinal GCTB in the Denosumab Era: A Machine Learning Approach.

The receptor activator of the nuclear factor kappa B ligand (RANKL) is the therapeutic target of denosumab. In this study, we evaluated whether radiomics signature and machine learning analysis can predict RANKL status in spinal giant cell tumors of bone (GCTB). This retrospective study consisted of 107 patients, including a training set (n = 82) and a validation set (n = 25). Kaplan-Meier survival analysis was used to validate the prognostic value of RANKL status. Radiomic feature extraction of three heterogeneous regions (VOIentire, VOIedge, and VOIcore) from pretreatment CT were performed. Followed by feature selection using Selected K Best and least absolute shrinkage and selection operator (LASSO) analysis, three classifiers (random forest (RF), support vector machine, and logistic regression) were used to build models. The area under the curve (AUC), accuracy, F1 score, recall, precision, sensitivity, and specificity were used to evaluate the models' performance. Classification of 75 patients with eligible follow-up based on RANKL status resulted in a significant difference in progression-free survival (p = 0.035). VOIcore-based RF classifier performs best. Using this model, the AUCs for the training and validation cohorts were 0.880 and 0.766, respectively. In conclusion, a machine learning approach based on CT radiomic features could discriminate prognostically significant RANKL status in spinal GCTB, which may ultimately aid clinical decision-making.

Therapeutic effects of caffeic acid phenethyl ester on alveolar bone loss in rats with endotoxin-induced periodontitis

Background/purposeCaffeic acid phenethyl ester (CAPE) is an antioxidant which is decreases the bone resorption and enhances the bone healing. The aim of this study was to investigate the effects of administering systemic CAPE on alveolar bone loss in rats with experimental periodontitis. Materials and methodsThirty male Sprague Dawley rats were divided into three groups: control, endotoxin-induced periodontitis (EP), and EP treated with CAPE (EP-CAPE). Endotoxin was injected into the gingiva of test rats on days 1, 3, and 5, whereas saline was injected into the control rats. The EP-CAPE group received 10 mmol/kg/day CAPE intraperitoneally for 28 consecutive days. Saline was given in the control and EP groups in the same manner. At the end of the study, intracardiac blood samples were obtained, and the rats were sacrificed. Alveolar bone loss was analyzed with histometric measurements. The oxidative stress index (OSI) was used to evaluate the oxidative stress. The receptor activator of the nuclear factor kappa B ligand (RANKL) level was analyzed stereologically. ResultsCAPE administration significantly decreased the serum OSI and interleukin-1β levels. Alveolar bone loss was statistically higher in the EP group compared with the EP-CAPE group (P < 0.05). Immunohistochemical analyses of the RANKL were significantly lower in the EP-CAPE group than in the EP group (P < 0.05). ConclusionThis experimental study revealed that CAPE administration significantly prevented alveolar bone loss and stimulated periodontal tissue healing.

Mechanical Stress Modulates the RANKL/OPG System of Periodontal Ligament Stem Cells via α7 nAChR in Human Deciduous Teeth: An In Vitro Study.

The aim of this study was to investigate the mechanism by which periodontal ligament stem cells (PDLSCs) modulate root resorption of human deciduous teeth under mechanical stress. In this investigation, the PDLSCs were derived from deciduous and permanent teeth at different stages of root resorption. A cyclic hydraulic pressure was applied on the PDLSCs to mimic chewing forces in the oral environment. The cultured cells were characterized using osteogenic and adipogenic differentiation assays, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting analysis. The PDLSCs exhibited the ability to induce osteoclast differentiation under certain mechanical stresses. As the expressions of RUNX2, alkaline phosphatase (ALP), and osteoprotegerin (OPG) were significantly reduced, the receptor activator of the nuclear factor kappa-B ligand (RANKL) was upregulated increasing the RANKL/OPG ratio. Under hydrodynamic pressure at 0-135 kPa, the expressions of alpha 7 nicotinic acetylcholine receptors (α7 nAChR), p-GSK-3β, and active-β-catenin were markedly upregulated in PDLSCs from unresorbed deciduous teeth. Treatment with the α7 nAChR inhibitor alpha-bungarotoxin (α-BTX) and the Wnt pathway inhibitor DKK1 may reverse the mechanical stress inducing upregulation of RANKL and reduction of RUNX2, ALP, and OPG. Alizarin red staining confirmed these results. The mechanical stress applied on the deciduous tooth PDLSCs can induce osteoclastic effects through upregulation of α7 nAChR and activation of the canonical Wnt pathway. It can be suggested that chewing forces may play a major role at the beginning of the physiological root resorption of deciduous teeth.

Immunoporosis: A New Role for Invariant Natural Killer T (NKT) Cells Through Overexpression of Nuclear Factor-κB Ligand (RANKL).

BackgroundOsteoporosis affects millions of postmenopausal women worldwide. Invariant natural killer T cells (iNKT) are important cells for bone homeostasis. The sim of this study was to investigate the contribution of invariant natural killer T cells (iNKT) in the increased receptor activator of the nuclear factor-κB ligand (RANKL) pool and bone resorption, a characteristic of patients with osteoporosis.Material/MethodsWhole blood was collected from 79 female patients. The dual energy x-absorptiometry scan was performed in all patients, and the T-score was calculated in order to classify our patients according to the World Human Organization (WHO) criteria for diagnosis and classification of osteoporosis. Eleven patients had a T-score <−1.0 and were encompassed in our normal donors (ND) group, 46 patients had a T-score between −1 and −2.5 and were included in the osteopenia group, while 22 patients had a T-score > −2.5 and were included in the osteoporosis group. We performed a-galactosylceramide activation of iNKT cells in vitro. Surface RANKL expression was detected by multicolor flow cytometry in naive and activated lymphocytes. Beta-Crosslaps (β-CTx) levels were measured in whole blood plasma by ELISA (enzyme-linked immunosorbent assay).ResultsAlthough iNKT cells were not clonally expanded in patients with osteoporosis, iNKT cells from osteoporotic patients overexpressed RANKL compared to ND and osteopenic patients. This is a distinctive feature of iNKT cells and is not seen in conventional T-lymphocytes. RANKL expression in iNKT cells was not related to β-CTx levels in the blood. Finally, iNKT cell activation by the prototypal glycolipid ligand α-galactosylceramide increased by 8 times their RANKL expression.ConclusionsIn patients with osteoporosis, iNKT cells specifically overexpress RANKL, a cytokine that regulates osteoclast activity. It seems that iNKT cells have a long-standing effect of on the bone physiology, which plays an important role in the bone loss of patients with osteoporosis.

Evaluation of Caffeic Acid Phenethyl Ester Administration in Chronically Stressed Rats with Experimental Periodontitis.

Objectives: The aim of the present study was to investigate the therapeutic effects of systemic caffeic acid phenethyl ester treatment on oxidative stress and alveolar bone destruction in lipopolysaccharide (LPS)-induced periodontitis in chronically stressed rats.Materials and Methods: Fourty male Sprague Dawley rats were divided into four groups: 1) control group, 2) experimental periodontitis (EP), 3) EP and chronic stress (CS) group (EP-CS), and 4) EP-CS treated with CAPE (EP-CS-CAPE). To induce periodontitis, LPS was administered into the buccal gingiva of the test groups, and pure saline was administered for the control group. Two test groups were exposed to restraint stress and one group of these groups was treated with only a single dose of CAPE (10 mmol/kg). Likewise, saline was administered in the control, EP, and EP-CS groups. After 14 days, serum samples were collected from the heart, and all rats were sacrificed for analyses. Oxidative stress and interleukin (IL)-1β were investigated. The receptor activator of the nuclear factor kappa B ligand (RANKL) and alveolar bone loss were determined by immunohistochemical analysisResults: The oxidative stress, alveolar bone loss, IL-1β and RANKL levels were found significantly higher in the EP-CS group compared with control and EP groups (p&amp;lt;0.05). However, the administration of CAPE significantly reduced oxidative stress and IL-1β in the EP-CS-CAPE group compared with the EP-CS group (p&amp;lt;0.05). Also, CAPE treatment significantly reduced RANKL and alveolar bone loss in the EP-CS-CAPE group compared with the EP-CS group (p&amp;lt;0.05)Conclusions: The present results indicated that CAPE may inhibit alveolar bone loss by modulating the immune response and inflammatory process.

Effect of Bushen Huoxue decoction on inhibiting osteogenic differentiation of vascular smooth cells by regulating OPG/RANK/RANKL system in vascular calcification.

To investigate the effects of Bushen Huoxue Decoction (BSHXD) and its underlying molecular mechanisms on inhibiting osteogenic differentiation of vascular smooth muscle cells (VSMCs) in vascular calcification via regulating the mRNA expression of osteoprotegerin (OPG) and the receptor activator of the nuclear factor-kappa B ligand (RANKL). VSMCs from the aortas of rats were cultured in vitro. Osteogenic differentiation of VSMCs was induced by high levels of an inorganic phosphate medium (2.4 mM). BSHXD-containing serum was prepared using the serum-pharmacological method. VSMCs were plated using 6-well plates at an approximate density of 4.0×104 cells/mL and cultured for 10 days. This was followed by the application of different concentrations of BSHXD-containing serum. The percentage of concentrations of BSHXD-containing serum in high, middle and low dosage group was 20%, 10% and 5%, respectively. Calcium nodules were evaluated by alizarin red S staining, and alkaline phosphatase (ALP) activity and calcium deposition were both examined as per the instruction of the test kits on the 3rd, 6th, and 10th days. Protein expression level of ALP and α-smooth muscle actin (α-SMA) were detected by Western blot on the 3rd, 6th, and 10th days. The mRNA expression of the OPG and RANKL were also detected by real-time PCR on the 3rd, 6th, and 10th days. Compared with the control group, BSHXD significantly attenuated the calcium nodules that were examined by alizarin red-S staining. Protein expression levels of α-SMA were up-regulated and ALP were down-regulated on the BSHXD group (P<0.05). BSHXD also attenuated the ALP activity and calcium deposition of the VSMCs (P<0.05). These changes were associated with the effect of BSHXD on up-regulating the expression of OPG mRNA and down-regulating the expression of RANKL mRNA in the process of osteogenic differentiation of VSMCs. BSHXD has a beneficial effect on inhibiting osteogenic differentiation of VSMCs induced by high levels of phosphate. The underlying mechanism appears to be related to the modulation of expressions of OPG mRNA and RANKL mRNA in the VSMCs, thereby preventing the phenotypic changes of VSMCs to an osteogenic phenotype.

Can denosumab be a substitute, competitor, or complement to bisphosphonates?

Osteoblasts, originating from mesenchymal cells, make the receptor activator of the nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in order to control differentiation of activated osteoclasts, originating from hematopoietic stem cells. When the RANKL binds to the RANK of the pre-osteoclasts or mature osteoclasts, bone resorption increases. On the contrary, when OPG binds to the RANK, bone resorption decreases. Denosumab (AMG 162), like OPG (a decoy receptor), binds to the RANKL, and reduces binding between the RANK and the RANKL resulting in inhibition of osteoclastogenesis and reduction of bone resorption. Bisphosphonates (BPs), which bind to the bone mineral and occupy the site of resorption performed by activated osteoclasts, are still the drugs of choice to prevent and treat osteoporosis. The merits of denosumab are reversibility targeting the RANKL, lack of adverse gastrointestinal events, improved adherence due to convenient biannual subcutaneous administration, and potential use with impaired renal function. The known adverse reactions are musculoskeletal pain, increased infections with adverse dermatologic reactions, osteonecrosis of the jaw, hypersensitivity reaction, and hypocalcemia. Treatment with 60 mg of denosumab reduces the bone resorption marker, serum type 1 C-telopeptide, by 3 days, with maximum reduction occurring by 1 month. The mean time to maximum denosumab concentration is 10 days with a mean half-life of 25.4 days. In conclusion, the convenient biannual subcutaneous administration of 60 mg of denosumab can be considered as a first-line treatment for osteoporosis in cases of low compliance with BPs due to gastrointestinal trouble and impaired renal function.

RANKL/RANK/OPG Polymorphisms and Heel Quantitative Ultrasound in Young Adults.

The receptor activator of the nuclear factor-kappa B ligand (RANKL), the receptor activator of nuclear factor-kappa B (RANK), and the osteoprotegerin (OPG) signaling pathway play an important role in the regulation of bone remodeling and osteoclast differentiation. Quantitative ultrasound (QUS) is a relatively recent and noninvasive method providing structural information on microstructure, bone elasticity, and connectivity. However, in contrast to bone mineral density measurements, the possible association of the RANKL/RANK/OPG pathway with heel QUS has not been analyzed. The aim of this study was to assess, for the first time, the contribution of the RANKL/RANK/OPG pathway genes in the genetic background of heel QUS parameters. Ten single-nucleotide polymorphisms (SNPs) of RANKL (rs9594759, rs12585014, rs7988338, rs2148073), RANK (rs1805034, rs12458117, rs3018362), and OPG (rs4355801, rs3102735, rs2073618) were selected as genetic markers and genotyped using Open Array technology in 575 self-reported Caucasian individuals aged 18-25. Bone mass in the right calcaneus was estimated with QUS to obtain the broadband ultrasound attenuation (BUA) measurement (dB/MHz). Linear regression analyses were performed to test the possible association between the SNPs and BUA. Linear regression analysis of all the tested SNPs revealed no significant association with the BUA parameter after adjusting for age, gender, weight, height, physical activity, and calcium intake. The lowest p-value was observed for the rs9594759 RANKL polymorphism and heel QUS (p = .06; b* = -.075, 95% CI [-0.960, 0.028]). Our results suggest that the polymorphism of the RANKL, RANK, and OPG genes does not make a significant genetic contribution to heel ultrasound measurements in a population of young Caucasian adults. Further studies replicating the results in independent populations are needed to support these initial findings.

Relationship Between RANK and RANKL Gene Polymorphisms with Osteoporosis in Rheumatoid Arthritis Patients.

Bone disease in rheumatoid arthritis (RA) is a complex phenomenon where genetic risk factors have been partially evaluated. In the present study, we aimed to evaluate the relationship between polymorphisms of the receptor activator of the nuclear factor kappa B (RANK) gene; the receptor activator of the nuclear factor kappa B ligand (RANKL) gene; and RANKL levels with osteoporosis in postmenopausal RA patients. One hundred seventy-two postmenopausal female patients and 176 age- and sex-matched controls were enrolled in the study. All subjects were genotyped for the presence of RANK C575T (rs1805034) and RANKL C290T (rs9525641) gene polymorphisms. RANKL levels, bone mineral density (BMD), and biochemical markers were also obtained. Women with the RANK CC genotype were significantly (2X) more likely to develop osteoporosis than those with the TT genotype (p = 0.024). A significant association was also observed between the RANKL 290TT genotype and both BMD and RANKL levels. In addition, individuals with the -290TT genotype were twice as likely to develop osteoporosis as those with the CC genotype (p < 0.001). Postmenopausal women with RA, carrying either the RANKL-290T allele or possessing the RANK 575CC genotype were more likely to develop osteoporosis. Moreover, our results suggested that the polymorphism 290C>T could be considered a risk factor for genetic susceptibility to osteoporosis and low BMD.

Impact of type 2 diabetes on the gene expression of bone-related factors at sites receiving dental implants

This study evaluated the influence of type 2 diabetes mellitus (T2DM) on the gene expression of bone-related factors in alveolar bone tissue from sites designated to receive dental implants. Bone biopsies were harvested from sites of planned implants for 19 systemically healthy patients and 35 patients with T2DM (17 with better-controlled T2DM (glycated haemoglobin (HbA1c) levels ≤8%) and 18 with poorly controlled T2DM (HbA1c levels >8%)). The mRNA levels of tumour necrosis factor alpha, transforming growth factor beta, receptor activator of the nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), runt-related transcription factor 2, alkaline phosphatase, bone sialoprotein (BSP), type I collagen (COL-I), and osteocalcin were evaluated by quantitative real-time polymerase chain reaction. T2DM up-regulates RANKL levels and the ratio of RANKL/OPG, whereas it down-regulates COL-I and BSP expression (P<0.05). Higher mRNA levels of RANKL/OPG were observed in the poorly controlled T2DM patients compared to those with better-controlled T2DM and systemically healthy patients (P<0.05). A lower amount of COL-I and BSP was detected in the biopsies from individuals with poorly controlled T2DM compared to systemically healthy patients (P<0.05). In conclusion, RANKL, RANKL/OPG, COL-I, and BSP are negatively affected in diabetics. Additionally, the patient's glycaemic status appears to modulate bone-related genes in a different manner.

Zoledronate inhibits receptor activator of nuclear factor kappa-B ligand-induced osteoclast differentiation via suppression of expression of nuclear factor of activated T-cell c1 and carbonic anhydrase 2

Bisphosphonates (BPs) are widely used in the prevention of skeletal-related events (SRE), including osteoporosis, skeletal metastases of malignant tumours, and multiple myeloma. Osteonecrosis of the jaw (ONJ) is frequently reported as a major adverse effect induced by BP treatment. The receptor activator of the nuclear factor kappa-B ligand (RANKL) inhibitor, denosumab, has recently been used to prevent SRE, but the frequency of ONJ induced by denosumab is similar to that by BPs. This finding suggests that the inhibition of RANKL-mediated osteoclastogenesis may have a close relationship with the occurrence of ONJ. We therefore investigated the expression status of RANKL-inducible genes in zoledronate-treated mouse osteoclast precursor cells. The molecular targets of zoledronate in the RANKL signal pathway and additional factors associated with osteoclastogenesis were analysed by genome-wide screening. Microarray analysis identified that among 31 genes on 44 entities of RANKL-inducible genes, the mRNA expression level of two genes, i.e., nuclear factor of activated T-cells c1 (NFATc1) and carbonic anhydrase 2 (CAII), was decreased in zoledronate-treated cells. Subsequent analyses verified that these two genes were significantly silenced by zoledronate treatment and that their expression was restored following inhibition of zoledronate action by geranylgeraniol. Zoledronate inhibited RANKL-induced osteoclast differentiation by suppression of NFATc1 and CAII gene expression. Our results suggest that these genes might be common targets for zoledronate and denosumab in the mechanism underlying RANKL-induced osteoclast differentiation. A clear understanding of the common molecular mechanisms of bone-remodelling agents is thus essential for prevention of ONJ.

Mechanical Stress-Related Calvaria Bone Augmentation by Onlayed Octacalcium Phosphate–Collagen Implant

Previous studies have suggested that the biodegradability of octacalcium phosphate-collagen (OCP/Col) composite by osteoclasts is accelerated in association with mechanical stress suffered by the host tissue around the implant. The present study was designed to investigate whether alleviation of mechanical stress restores the bone regenerative properties of OCP/Col, as previously shown in nonload-bearing sites. OCP/Col discs supported with a polytetrafluoroethylene (PTFE) ring, which has a higher modulus than OCP/Col, were implanted in a rat subperiosteal pocket for up to 12 weeks. The structural features of the implant and biological responses were analyzed by X-ray diffraction, Fourier transform infrared spectroscopy, histomorphometry, histochemistry, and tissue mRNA expression around the implants. The effect of compression was analyzed using mouse stromal ST-2 cells by deforming the cell-seeded OCP/Col discs in vitro with or without a PTFE ring. The results clearly indicated the restoration of bone formation by the alleviation of mechanical stress and the upregulation of osteoblast-related genes, such as osterix on the other hand, the implantation of OCP/Col on calvaria or in an in vitro test without PTFE support resulted in the upregulation of osteoclast-related genes, such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K, in the tissues or receptor activator of the nuclear factor-kappaB ligand (RANKL) in ST-2 cells. The results confirmed that calvaria augmentation is enhanced by implanting OCP/Col if suitable conditions regarding mechanical stress are provided.

Emerging treatments for postmenopausal osteoporosis &amp;ndash; focus on denosumab

The pathway of the receptor activator of the nuclear factor kappaB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget's disease of bone, rheumatoid arthritis [RA], metastatic bone disease). Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in increase in bone mineral density (BMD) in post-menopausal women with low BMD, and has the potential to prevent progression of erosions in RA and of skeletal-related events in metastatic bone disease. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study. In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed.

Factors other than glucocorticoids are involved in the osteoblast activity decrease caused by tissue injury

Serum osteocalcin is a marker of bone formation. The concentration of osteocalcin is decreased with tissue injury. As glucocorticoids are known both to be increased in this situation and to diminish serum osteocalcin, we have hypothesized that they could be involved in this decrease. We compared osteocalcin levels in two groups of patients undergoing abdominal surgery, one receiving thiopental, and the other etomidate, a glucocorticoid synthesis blocker. For comparative reasons, another protein decreased by glucocorticoids (osteoprotegerin) was measured in patients anaesthetized with thiopental. Serum osteocalcin, cortisol and albumin were determined before and over the 24 h following surgery. Serum concentration of osteoprotegerin (OPG) and receptor activator of the nuclear factor kappaB ligand (RANKL) were also determined before and 24 h after surgery in a third group of nine patients who received thiopental for anaesthetic induction. Cortisol levels were increased in the thiopental group, whereas, as expected, were decreased in etomidate patients. However, serum osteocalcin concentration decreased in a similar way in both groups. Serum OPG and RANKL levels were within the normal range at baseline and did not significantly change after surgery. The decrease in serum osteocalcin induced by tissue injury is independent of the increase in cortisol secretion triggered by the latter. In addition, another pharmacologically proven effect of cortisol on bone metabolism, OPG inhibition, could not be demonstrated in the first 24 h following surgery, in spite of the physiological increase in endogenous cortisol secretion taking place in this period.

The Receptor Activator of Nuclear Factor-κB Ligand-mediated Osteoclastogenic Pathway Is Elevated in Amelogenin-null Mice

Amelogenins, major components of developing enamel, are predominantly involved in the formation of tooth enamel. Although amelogenins are also implicated in cementogenesis, their precise spatial expression pattern and molecular role are not clearly understood. Here, we report for the first time the expression of two alternate splice forms of amelogenins, M180 and the leucine-rich amelogenin peptide (LRAP), in the periodontal region of mouse tooth roots. Lack of M180 and LRAP mRNA expression correlated with cementum defects observed in the amelogenin-null mice. The cementum defects were characterized by an increased presence of multinucleated cells, osteoclasts, and cementicles. These defects were associated with an increased expression of the receptor activator of the nuclear factor-kappa B ligand (RANKL), a critical regulator of osteoclastogenesis. These findings indicate that the amelogenin splice variants, M180 and LRAP, are critical in preventing abnormal resorption of cementum.