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OPG
Kinds of OPG Terms modified by OPG Selected AbstractsAssociation between plasma osteoprotegerin concentrations and urinary albumin excretion in Type 2 diabetesDIABETIC MEDICINE, Issue 4 2009G. D. Xiang Abstract Aims Osteoprotegerin (OPG) is a recently identified inhibitor of bone resorption. Recent studies indicate that OPG is also associated with endothelial dysfunction in Type 2 diabetes. The aim was to investigate the relationship between plasma OPG levels and urinary albumin excretion (UAE) in Type 2 diabetic patients. Methods This study included 154 newly diagnosed Type 2 diabetic patients and 46 healthy subjects. Plasma OPG and 24-h UAE were measured. High-resolution ultrasound was used to measure flow-mediated (endothelium-dependent arterial) dilation (FMD). Results Compared with the normoalbuminuric subgroup, OPG levels in the microalbuminuric subgroup were significantly higher, and OPG levels in macroalbuminuria subgroup were significantly higher than those in the normoalbuminuria and albuminuria subgroups. Multiple regression analysis showed that only FMD (r = ,0.26), C-reactive protein (r = 0.23), fasting blood glucose (r = 0.25), 2-h blood glucose (r = 0.21), HbA1c (r = 0.28), UAE (r = 0.27) and retinopathy (r = 0.27) were significant factors associated with OPG. Pearson's correlation analyses showed a positive correlation between OPG and logUAE (r = 0.440) and negative correlations between OPG and FMD (r = ,0.284), and between FMD and logUAE (r = ,0.602). Conclusions Plasma OPG levels are significantly associated with UAE in Type 2 diabetic patients. [source] Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathwayEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 4 2008B. G. Choi ABSTRACT Background, Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor-,, ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis. Materials and methods, Age-matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post-procedure, atherosclerosis was induced by 15 months 0·2%-cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (µCT) and molecular analysis of the vascular tissue. Results, Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8·4 ± 2·8 vs. 1·9 ± 0·6 mg cm,3, P = 0·042, and 94 ± 26 vs. 33 ± 7 particles cm,3, P = 0·046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 ± 7° vs. SHAM 33 ± 5°, P = 0·99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0·029, primarily by decreasing RANKL (P = 0·019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study. Conclusions, In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ-specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post-menopausal women. [source] Bumetanide, the Specific Inhibitor of Na+ -K+ -2Cl, Cotransport, Inhibits 1,,25-Dihydroxyvitamin D3 -Induced Osteoclastogenesis in a Mouse co-culture SystemEXPERIMENTAL PHYSIOLOGY, Issue 5 2003Hyun-A Lee The Na+ -K+ -2Cl, cotransporter (NKCC1) is responsible for ion transport across the secretory and absorptive epithelia, the regulation of cell volume, and possibly the modulation of cell growth and development. It has been reported that a variety of cells, including osteoblasts, contain this cotransporter. In this study, the physiological role of NKCC1 in osteoclastogenesis was exploited in a co-culture system. Bumetanide, a specific inhibitor of NKCC1, reduced the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. In order to investigate the mechanism by which bumetanide inhibits osteoclastogenesis, the mRNA expressions of the receptor activator of nuclear factor (NF)-,B ligand (RANKL) and osteoprotegerin (OPG) were analysed by RT-PCR. Exposure of osteoblastic cells to a medium containing 1 µM bumetanide reduced RANKL mRNA expression induced by 10 nM 1,,25-dihydroxyvitamin D3 (1,,25(OH)2D3, in a dose-dependent manner. In addition, RANKL expression was also analysed with enzyme-linked immunosorbant assay (ELISA) using anti-RANKL antibody. The expression of RANKL was decreased with the increase of bumetanide concentration. In contrast, the expression of OPG mRNA, a novel tumour necrosis factor (TNF) receptor family member was increased in the presence of bumetanide. These results imply that bumetanide inhibits osteoclast differentiation by reducing the RANKL/OPG ratio in osteoblastic cells. However, no significant difference in M-CSF mRNA expression was observed when bumetanide was added. Also, we found that the phosphorylation of c-Jun NH2 -terminal kinase (JNK), which regulates the activity of various transcriptional factors, was reduced by bumetanide treatment. Conclusively, these findings suggest that NKCC1 in osteoblasts has a pivotal role in 1,,25(OH)2D3 -induced osteoclastogenesis partly via the phosphorylation of JNK. [source] Osteoprotegerin and bone turnover markers in heavily pretreated HIV-infected patientsHIV MEDICINE, Issue 3 2005E Seminari Objectives To characterize osteoprotegerin (OPG) levels, bone remodelling and bone mineral density (BMD) in heavily pretreated HIV-infected patients on antiretroviral therapy, and to evaluate the clinical factors associated with bone density decline. Methods Heavily pretreated (>5 years) HIV-positive patients were enrolled in this cross-sectional, observational study, which was based on a total body bone densitometry examination and a comprehensive evaluation of bone and mineral parameters. Results Sixty-eight patients (55 male and 13 female) with a median age of 41 years (range 25,60 years) were included in the study. Their antiretroviral treatment lasted for 82 months. On the basis of the World Health Organization criteria, nine patients (13.2%) were osteoporotic [T-score<,2.5 standard deviation (SD)] and 19 patients (27.9%) were osteopenic (T-score between,1 and,2.5). The principal outcomes associated with the presence of a low BMD were high OPG and lysylpyridinoline/creatinine ratio (Dpd) values. Most of the patients (39 of 48; 81.25%) showed vitamin D insufficiency [Vitamin D (25(OH)D)<18 ng/mL] with secondary hyperparathyroidism (13 of 50 patients: 26%), which proved to be correlated to osteocalcin (BGP) levels [parathyroid hormone (PTH) vs. BGP: r=0.34; P<0.01]. There was an inverse correlation between T-scores and serum osteocalcin and alkaline phosphatase (AP) levels, on one hand, and Dpd, on the other. High AP and Dpd values were associated with relative risks of 4.1 [95% confidence interval (CI)=1.01,17.6] and 7.2 (95% CI=1.67,31.03), respectively, of a pathological T-score. Multivariate analysis revealed that the factors associated with the presence of osteopenia or osteoporosis were older age and lower body mass index. Conclusions About 40% of our heavily pretreated subjects with advanced HIV infection had a low BMD, and 56% (24 of 44 patients) showed a high bone turnover rate with marked osteoclast activation. High OPG levels may protect against bone resorption. [source] Multiple myeloma biology: lessons from the 5TMM modelsIMMUNOLOGICAL REVIEWS, Issue 1 2003Karin Vanderkerken Summary:, Multiple myeloma (MM) is a B cell neoplasm characterized by the monoclonal proliferation of plasma cells in the bone marrow, the development of osteolytic lesions and the induction of angiogenesis. These different processes require three-dimensional interactions, with both humoral and cellular contacts. The 5TMM models are suitable models to study these interactions. These murine models originate from spontaneously developed myeloma in elderly mice, which are propagated by in vivo transfer of the myeloma cells into young syngeneic mice. In this review we report on studies performed in the 5TMM models with special emphasis on the homing of the myeloma cells, the characterization of the migrating and proliferating clone and the identification of the isotype switch variants. The bone marrow microenvironment was further targeted with osteoprotegerin (OPG) to block the RANK/RANKL/OPG system and with potent bisphosphonates. Both treatments resulted in a significant protection against myeloma-associated bone disease, and they decreased myeloma disease, as evidenced by a lower tumor load and an increased survival of the mice. These different studies demonstrate the strength of these models, not only in unraveling basic biological processes but also in the testing of potentially new therapeutic targets. [source] Serum osteoprotegerin is increased in Crohn's disease: A population-based case control studyINFLAMMATORY BOWEL DISEASES, Issue 4 2005Charles N Bernstein MD Abstract Background: There is a potential interface between osteoporosis and the chronic inflammation of inflammatory bowel disease (IBD), and the osteoprotegerin (OPG)/receptor for activated nuclear factor-,B (RANK)/RANK ligand (RANKL) signaling pathway may be an important mediator, although data are limited. Methods: We conducted a population-based case-control seroassay study to look for alterations in serum OPG and soluble RANKL (sRANKL). The study population included IBD patients who were 18 to 50 years old with Crohn's disease (CD; n = 287) or ulcerative colitis (UC; n = 166), age-matched healthy controls (n = 368), and nonaffected siblings of IBD patients (n = 146). Serum OPG and sRANKL were measured by enzyme-linked immunoassay. Sex-specific reference ranges were derived from the healthy controls. Results: Analysis of variance (ANOVA) confirmed significant group differences in women for mean serum OPG (P = 0.018). CD women had higher values of OPG than UC women (P = 0.028) or healthy controls (P = 0.045), whereas the other groups were similar. OPG levels were above the reference range in 13/173 (8%) of CD women, exceeding the expected proportion (P = 0.032). In contrast, no differences in OPG were seen in men between controls, CD, or UC. Estrogen use in women (P = 0.000002) and corticosteroid use in men (P = 0.026) were associated with higher OPG levels. In multivariate analysis, CD diagnosis (P = 0.031) and estrogen use (P = 0.000002) were independently associated with higher OPG levels. No group differences were seen in mean serum sRANKL measurements. Conclusions: An OPG:sRANKL imbalance with OPG exceeding sRANKL should inhibit osteoclastogenesis and promote bone formation. CD is associated with increased fracture risk, and possibly, the paradoxically higher OPG is a counterregulatory response to factors such as inflammatory cytokines, promoting high bone turnover. Alternatively, elevated OPG in CD may reflect T-cell activation. [source] Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: Implication for breast cancer osteolytic bone metastasesINTERNATIONAL JOURNAL OF CANCER, Issue 5 2008Guojun Bu Abstract Most breast cancer metastases in bone form osteolytic lesions, but the mechanisms of tumor-induced bone resorption and destruction are not fully understood. Although it is well recognized that Wnt/,-catenin signaling is important for breast cancer tumorigenesis, the role of this pathway in breast cancer bone metastasis is unclear. Dickkopf1 (Dkk1) is a secreted Wnt/,-catenin antagonist. In the present study, we demonstrated that activation of Wnt/,-catenin signaling enhanced Dkk1 expression in breast cancer cells and that Dkk1 overexpression is a frequent event in breast cancer. We also found that human breast cancer cell lines that preferentially form osteolytic bone metastases exhibited increased levels of Wnt/,-catenin signaling and Dkk1 expression. Moreover, we showed that breast cancer cell-produced Dkk1 blocked Wnt3A-induced osteoblastic differentiation and osteoprotegerin (OPG) expression of osteoblast precursor C2C12 cells and that these effects could be neutralized by a specific anti-Dkk1 antibody. In addition, we found that breast cancer cell conditioned media were able to block Wnt3A-induced NF-kappaB ligand reduction in C2C12 cells. Finally, we demonstrated that conditioned media from breast cancer cells in which Dkk1 expression had been silenced via RNAi were unable to block Wnt3A-induced C2C12 osteoblastic differentiation and OPG expression. Taken together, these results suggest that breast cancer-produced Dkk1 may be an important mechanistic link between primary breast tumors and secondary osteolytic bone metastases. © 2008 Wiley-Liss, Inc. [source] Osteoprotegerin (OPG),a potential new role in the regulation of endothelialcell phenotype and tumour angiogenesis?INTERNATIONAL JOURNAL OF CANCER, Issue 8 2006Simon S. Cross Abstract The progression of cancer depends on the establishment of a tumour blood supply, and therefore tumour angiogenesis has been identified as a major target for new anticancer agents. Recent reports have suggested that osteoprotegerin (OPG) is involved in the control of endothelial cell survival through the inhibition of the activity of tumour necrosis factor- (TNF) related apoptosis-inducing ligand (TRAIL). The role of OPG in human tumour development and angiogenesis is currently unknown. In the present study we demonstrate the ability of OPG to support endothelial cell survival, as well as the formation of cord-like structures in vitro using a matrigel tubule formation assay. Investigation of various human cancers demonstrated endothelial OPG expression in 59% of malignant tumours (n = 512), but in contrast, OPG was absent in endothelial cells associated with benign tumours and normal tissues (n = 178). In a series of 400 breast tumours, endothelial OPG expression was associated with high tumour grade and certain histological types. Our data show a clear separation in endothelial OPG expression between malignant tumours and nonmalignant tissues, supporting a potential biological role for this molecule in the development and/or maintenance of the tumour vasculature. This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours. © 2005 Wiley-Liss, Inc. [source] A new role for OPG: Putting RANKL in its placeJOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2010Michael C Ostrowski No abstract is available for this article. [source] Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in menJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2010Delnaz Roshandel Abstract The aim of this study was to determine if single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r2,,,0.8) were selected for RANKL, RANK, and OPG and their 10-kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (PINP) and C-terminal cross-linked telopeptide of type I collagen (CTX-I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total-hip areal BMD (BMDa) was measured by dual-energy X-ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP (,,=,1.83, p,=,.004) and CTX-I (,,=,17.59, p,=,4.74,×,10,4), and lower lumbar spine BMDa (,,=,,0.02, p,=,.026). The minor allele of rs9594759 (C) was associated with lower PINP (,,=,,1.84, p,=,.003) and CTX-I (,,=,,27.02, p,=,6.06,×,10,8) and higher ultrasound BMD at the calcaneus (,,=,0.01, p,=,.037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men. © 2010 American Society for Bone and Mineral Research [source] Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2010Hsiao-Chi Yu Abstract Mechanical loading is known to be important for maintaining the formation and resorption rates of bone. To study the mechanisms by which mechanical loading regulates osteogenesis, we investigated the role of the Wnt pathway in C2C12 cells committed to osteogenic differentiation in response to cyclic mechanical stretching. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL to inhibit osteoclastogenesis and resorption of bone. Our results demonstrate that stretching leads to a sustained increase in OPG expression in C2C12 cells. The expression of osteogenic marker genes, such as osteocalcin and alkaline phosphatase, was transiently decreased by stretching at 24 hours and returned to control levels at 48 hours. The addition of inhibitors of the canonical Wnt/,-catenin pathways, such as the secreted FZD-related peptide sRFP2, as well as siRNA-mediated knockdown, did not inhibit the effect of stretching on OPG expression. In contrast, treatment with inhibitors of noncanonical Wnt signaling, including KN93, and siRNA for Nemo-like kinase (NLK) blocked most of the mechanical inductive effect on OPG. Furthermore, stretching-induced OPG production in the culture medium was able to inhibit the osteoclast formation of bone marrow macrophages. These results suggest that mechanical stretching may play an important role in bone remodeling through the upregulation of OPG and that the mechanical signaling leading to OPG induction involves the noncanonical Wnt pathway. © 2010 American Society for Bone and Mineral Research [source] Inhibition of Lamin A/C Attenuates Osteoblast Differentiation and Enhances RANKL-Dependent Osteoclastogenesis,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2009Martina Rauner Abstract Age-related osteoporosis is characterized by low bone mass, poor bone quality, and impaired osteoblastogenesis. Recently, the Hutchinson-Gilford progeria syndrome (HGPS), a disease of accelerated aging and premature osteoporosis, has been linked to mutations in the gene encoding for the nuclear lamina protein lamin A/C. Here, we tested the hypothesis that inhibition of lamin A/C in osteoblastic lineage cells impairs osteoblastogenesis and accelerates osteoclastogenesis. Lamin A/C was knocked-down with small interfering (si)RNA molecules in human bone marrow stromal cells (BMSCs) differentiating toward osteoblasts. Lamin A/C knockdown led to an inhibition of osteoblast proliferation by 26% and impaired osteoblast differentiation by 48% based on the formation of mineralized matrix. In mature osteoblasts, expression levels of runx2 and osteocalcin mRNA were decreased by lamin A/C knockdown by 44% and 78%, respectively. Furthermore, protein analysis showed that osteoblasts with diminished levels of lamin A/C also secreted less osteocalcin and expressed a lower alkaline phosphatase activity (,50%). Lamin A/C inhibition increased RANKL mRNA and protein levels, whereas osteoprotegerin (OPG) expression was decreased, resulting in an increased RANKL/OPG ratio and an enhanced ability to support osteoclastogenesis, as reflected by a 34% increase of TRACP+ multinucleated cells. Our data indicate that lamin A/C is essential for proper osteoblastogenesis. Moreover, lack of lamin A/C favors an osteoclastogenic milieu and contributes to enhanced osteoclastogenesis. [source] RANKL Inhibition with Osteoprotegerin Increases Bone Strength by Improving Cortical and Trabecular bone Architecture in Ovariectomized Rats,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2008Michael S Ominsky Abstract Introduction: Ovariectomy (OVX) results in bone loss caused by increased bone resorption. RANKL is an essential mediator of bone resorption. We examined whether the RANKL inhibitor osteoprotegerin (OPG) would preserve bone volume, density, and strength in OVX rats. Materials and Methods: Rats were OVX or sham-operated at 3 mo of age. Sham controls were treated for 6 wk with vehicle (Veh, PBS). OVX rats were treated with Veh or human OPG-Fc (10 mg/kg, 2/wk). Serum RANKL and TRACP5b was measured by ELISA. BMD of lumbar vertebrae (L1,L5) and distal femur was measured by DXA. Right distal femurs were processed for bone histomorphometry. Left femurs and the fifth lumbar vertebra (L5) were analyzed by ,CT and biomechanical testing, and L6 was analyzed for ash weight. Results: OVX was associated with significantly greater serum RANKL and osteoclast surface and with reduced areal and volumetric BMD. OPG markedly reduced osteoclast surface and serum TRACP5b while completely preventing OVX-associated bone loss in the lumbar vertebrae, distal femur, and femur neck. Vertebrae from OPG-treated rats had increased dry and ash weight, with no significant differences in tissue mineralization versus OVX controls. ,CT showed that trabecular compartments in OVX-OPG rats had significantly greater bone volume fraction, vBMD, bone area, trabecular thickness, and number, whereas their cortical compartments had significantly greater bone area (p < 0.05 versus OVX-Veh). OPG improved cortical area in L5 and the femur neck to levels that were significantly greater than OVX or sham controls (p < 0.05). Biomechanical testing of L5 and femur necks showed significantly greater maximum load values in the OVX-OPG group (p < 0.05 versus OVX-Veh). Bone strength at both sites was linearly correlated with total bone area (r2 = 0.54,0.74, p < 0.0001), which was also significantly increased by OPG (p < 0.05 versus OVX). Conclusions: OPG treatment prevented bone loss, preserved trabecular architecture, and increased cortical area and bone strength in OVX rats. [source] Differential Effects of Vitamin D Analogs on Vascular Calcification,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2007Anna Cardús Abstract We tested the effects of calcitriol and its analog paricalcitol on VSMC calcification in vitro and in vivo. For that reason, cells and animals with five-sixths nephrectomy were treated with both compounds. Calcitriol, but not paricalcitol, increased VSMC calcification in vitro and in vivo independently of calcium and phosphate levels. This increase in calcification was parallel to an increase in the RANKL/OPG ratio. Introduction: Vascular calcification is a common finding in patients with endstage renal disease. Furthermore, those patients often present secondary hyperparathyroidism, partly because of a decrease of calcitriol synthesis on the kidney. Thus, one of the main therapeutic options is to treat those patients with calcitriol or analogs. However, this treatment presents unwanted side effects, such as increases in vascular calcification. Materials and Methods: We tested the effect on vascular smooth muscle cell (VSMC) calcification of calcitriol and one of its analogs, paricalcitol, in vitro and in vivo in animals with endstage renal disease. Results: Calcitriol increased calcification of VSMCs cultured in calcification media. This effect was not present when cells were incubated with paricalcitol. Furthermore, only cells incubated with calcitriol showed an increased RANKL/ osteoprotegerin (OPG) expression. Animals with renal failure treated with hypercalcemic doses of calcitriol and paricalcitol showed an increase in systolic blood pressure. However, diastolic blood pressure only raised significantly in those animals treated with paricalcitol. This effect led to a significant increase in pulse pressure in animals treated with calcitriol. The increase in pulse pressure was likely caused by the extensive calcification observed in arteries of animals treated with calcitriol. This increase in calcification was not seen in arteries of animals treated with paricalcitol, despite having similar levels of serum calcium and phosphorus as animals treated with calcitriol. Furthermore, the decreases in serum PTH levels were similar in both treatments. Conclusions: We conclude that paricalcitol has a different effect than calcitriol in VSMC calcification and that this could explain part of the differences observed in the clinical settings. [source] Juvenile Paget's Disease: The Second Reported, Oldest Patient Is Homozygous for the TNFRSF11B "Balkan" Mutation (966_969delTGACinsCTT), Which Elevates Circulating Immunoreactive Osteoprotegerin Levels,,§¶JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2007Michael P Whyte MD Abstract The oldest person (60 yr) with juvenile Paget's disease is homozygous for the TNFRSF11B mutation 966_969delTGACinsCTT. Elevated circulating levels of immunoreactive OPG and soluble RANKL accompany this genetic defect that truncates the OPG monomer, preventing formation of OPG homodimers. Introduction: Juvenile Paget's disease (JPD), a rare autosomal recessive disorder, features skeletal pain, fracture, and deformity from extremely rapid bone turnover. Deafness and sometimes retinopathy also occur. Most patients have diminished osteoprotegerin (OPG) inhibition of osteoclastogenesis caused by homozygous loss-of-function defects in TNFRSF11B, the gene that encodes OPG. Circulating immunoreactive OPG (iOPG) is undetectable with complete deletion of TNFRSF11B but normal with a 3-bp in-frame deletion. Materials and Methods: We summarize the clinical course of a 60-yr-old Greek man who is the second reported, oldest JPD patient, including his response to two decades of bisphosphonate therapy. Mutation analysis involved sequencing all exons and adjacent mRNA splice sites of TNFRSF11B. Over the past 4 yr, we used ELISAs to quantitate his serum iOPG and soluble RANKL (sRANKL) levels. Results: Our patient suffered progressive deafness and became legally blind, although elevated markers of bone turnover have been normal for 6 yr. He carries the same homozygous mutation in TNFRSF11B (966_969delTGACinsCTT) reported in a seemingly unrelated Greek boy and Croatian man who also have relatively mild JPD. This frame-shift deletes 79 carboxyterminal amino acids from the OPG monomer, including a cysteine residue necessary for homodimerization. Nevertheless, serum iOPG and sRANKL levels are persistently elevated. Conclusions: Homozygosity for the TNFRSF11B "Balkan" mutation (966_969delTGACinsCTT) causes JPD in the second reported, oldest patient. Elevated circulating iOPG and sRANKL levels complement evidence that this deletion/insertion omits a cysteine residue at the carboxyterminus needed for OPG homodimerization. [source] Remodeling and Vascular Spaces in BoneJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2007Erik Fink Eriksen Abstract In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed. [source] Loss of Chaotic Trabecular Structure in OPG-Deficient Juvenile Paget's Disease Patients Indicates a Chaogenic Role for OPG in Nonlinear Pattern Formation of Trabecular BoneJOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2004Phil Salmon PhD Abstract The RANK-RANKL-OPG system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's disease patients deficient in functional OPG shows parallel, anisotropic structure instead of normal chaotic structure. Evidence from experimental systems suggests that RANK-RANKL-OPG controls key nonlinear "chaogenic" parameters, such as friction, forcing frequency, feedback, and boundary forcing. The RANK-RANKL-osteoprotegerin (OPG) system of osteoclast regulation may play a key role in determining chaotic structure in trabecular bone. Iliac trabecular bone from juvenile Paget's disease (JPD) patients deficient in functional OPG shows parallel, anisotropic structure instead of normal chaotic structure. Evidence from experimental systems suggests that RANK-RANKL-OPG controls key nonlinear "chaogenic" parameters, such as friction, forcing frequency, feedback, and boundary forcing. The Belousov-Zhabotinsky reaction-diffusion system, the catalytic oxidation of CO on platinum surfaces, and thermal diffusion in liquid helium allow visualization of nonlinear emergent patterns such as labyrinthine structures, turbulence, and cellular structures, all of which bear some resemblance to trabecular bone. In JPD, the gene for OPG (TNFRSF11B) is subject to an inactivating mutation, leading to increased resorption and accelerated remodeling. Histomorphometric images of iliac crest trabecular bone from teenagers suffering from JPD show a highly unusual array of parallel, regular trabecular plates, instead of the typical chaotic, fractal patterns of normal trabecular bone. Loss of OPG function is associated with a change from chaotic to regular structure, suggesting that the RANK-RANKL-OPG system is controlling key nonlinear "chaogenic" parameters. Looking at trabecular bone from the perspective of nonlinear pattern formation may help understand other phenomena, such as the marked dependence of trabecular bone's architectural and mechanical quality on remodeling rate independent of the trabecular bone mass. [source] Selective Blockade of Voltage-Gated Potassium Channels Reduces Inflammatory Bone Resorption in Experimental Periodontal Disease,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2004Paloma Valverde Abstract The effects of the potassium channel (Kv1.3) blocker kaliotoxin on T-cell-mediated periodontal bone resorption were examined in rats. Systemic administration of kaliotoxin abrogated the bone resorption in conjunction with decreased RANKL mRNA expression by T-cells in gingival tissue. This study suggests a plausible therapeutic approach for inflammatory bone resorption by targeting Kv1.3. Introduction: Kv1.3 is a critical potassium channel to counterbalance calcium influx at T-cell receptor activation. It is not known if Kv1.3 also regulates RANKL expression by antigen-activated T-cells, and consequently affects in vivo bone resorption mediated by activated T-cells. Materials and Methods:Actinobacillus actinomycetemcomitans 29-kDa outer membrane protein-specific Th1-clone cells were used to evaluate the expression of Kv1.3 (using reverse transcriptase-polymerase chain reaction [RT-PCR] and Western blot analyses) and the effects of the potassium channel blocker kaliotoxin (0,100 nM) on T-cell activation parameters ([3H]thymidine incorporation assays and ELISA) and expression of RANKL and osteoprotegerin (OPG; flow cytometry, Western blot, and RT-PCR analyses). A rat periodontal disease model based on the adoptive transfer of activated 29-kDa outer membrane protein-specific Th1 clone cells was used to analyze the effects of kaliotoxin in T-cell-mediated alveolar bone resorption and RANKL and OPG mRNA expression by gingival T-cells. Stimulated 29-kDa outer membrane protein-specific Th1 clone cells were transferred intravenously on day 0 to all animals used in the study (n = 7 animals per group). Ten micrograms of kaliotoxin were injected subcutaneously twice per day on days 0, 1, 2, and 3, after adoptive transfer of the T-cells. The control group of rats was injected with saline as placebo on the same days as injections for the kaliotoxin-treated group. The MOCP-5 osteoclast precursor cell line was used in co-culture studies with fixed 29-kDa outer membrane protein-specific Th1-clone cells to measure T-cell-derived RANKL-mediated effects on osteoclastogenesis and resorption pit formation assays in vitro. Statistical significance was evaluated by Student's t -test. Results: Kaliotoxin decreased T-cell activation parameters of 29-kDa outer membrane protein-specific Th1 clone cells in vitro and in vivo. Most importantly, kaliotoxin administration resulted in an 84% decrease of the bone resorption induced in the saline-treated control group. T-cells recovered from the gingival tissue of kaliotoxin-treated rats displayed lower ratios of RANKL and OPG mRNA expression than those recovered from the control group. The ratio of RANKL and osteoprotegerin protein expression and induction of RANKL-dependent osteoclastogenesis by the activated T-cells were also markedly decreased after kaliotoxin treatments in vitro. Conclusion: The use of kaliotoxin or other means to block Kv1.3 may constitute a potential intervention therapy to prevent alveolar bone loss in periodontal disease. [source] Idiopathic Hyperphosphatasia and TNFRSF11B Mutations: Relationships Between Phenotype and Genotype,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2003Belinda Chong Abstract Homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin, were found in affected members from six of nine families with idiopathic hyperphosphatasia. The severity of the phenotype was related to the predicted effects of the mutations on osteoprotegerin function. Introduction: Idiopathic hyperphosphatasia (IH) is a rare high bone turnover congenital bone disease in which affected children are normal at birth but develop progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and deafness. There is, however, considerable phenotypic variation from presentation in infancy with severe progressive deformity through to presentation in late childhood with minimal deformity. Two recent reports have linked idiopathic hyperphosphatasia with deletion of, or mutation in, the TNFRSF11B gene that encodes osteoprotegerin (OPG), an important paracrine modulator of RANKL-mediated bone resorption. Materials and Methods: We studied subjects with a clinical diagnosis of IH and unaffected family members from nine unrelated families. Clinical, biochemical, and radiographic data were collected, and genomic DNA examined for mutations in TNFRSF11B. The relationship between the mutations, their predicted effects on OPG function, and the phenotype were then examined. Results: Of the nine families studied, affected subjects from six were homozygous for novel mutations in TNFRSF11B. Their parents were heterozygous, consistent with autosomal recessive inheritance. Four of the six mutations occurred in the cysteine-rich ligand-binding domain and are predicted to disrupt binding of OPG to RANKL. Missense mutations in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype (deformity developing before 18 months age and severe disability), as was a large deletion mutation. Non-cysteine missense mutations in the ligand-binding domain were associated with an intermediate phenotype (deformity recognized around the age of 5 years and an increased rate of long bone fracture). An insertion/deletion mutation at the C-terminal end of the protein was associated with the mildest phenotype. Conclusion: Mutations in TNFRSF11B account for the majority of, but not all, cases of IH, and there are distinct genotype-phenotype relationships. [source] MLO-Y4 Osteocyte-Like Cells Support Osteoclast Formation and Activation,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2002S. Zhao Abstract Osteocytes are terminally differentiated cells of the osteoblast lineage that have become embedded in mineralized matrix and may send signals that regulate bone modeling and remodeling. The hypothesis to be tested in this study is that osteocytes can stimulate and support osteoclast formation and activation. To test this hypothesis, an osteocyte-like cell line called MLO-Y4 and primary murine osteocytes were used in coculture with spleen or marrow cells. MLO-Y4 cells support osteoclast formation in the absence of 1,25-dihydroxyvitamin D3 [1,25(OD)2D3] or any other exogenous osteotropic factor. These cells alone stimulate osteoclast formation to the same extent or greater than adding 1,25(OH)2D3. Coaddition of 1,25(OH)2D3 with MLO-Y4 cells synergistically increased osteoclast formation. Optimal osteoclast formation and pit formation on dentine was observed with 200,1000 MLO-Y4 cells per 0.75-cm2 well. No osteoclast formation was observed with 2T3, OCT-1, or MC3T3-E1 osteoblast cells (1000 cells/well). Conditioned media from the MLO-Y4 cells had no effect on osteoclast formation, indicating that cell contact is necessary. Serial digestions of 2-week-old mouse calvaria yielded populations of cells that support osteoclast formation when cocultured with 1,25(OH)2D3 and marrow, but the population that remained in the bone particles supported the greatest number of osteoclasts with or without 1,25(OH)2D3. To examine the mechanism whereby these cells support osteoclast formation, the MLO-Y4 cells were compared with a series of osteoblast and stromal cells for expression of macrophage colony-stimulating factor (M-CSF), RANKL, and osteoprotegerin (OPG). MLO-Y4 cells express and secrete large amounts of M-CSF. MLO-Y4 cells express RANKL on their surface and their dendritic processes. The ratio of RANKL to OPG mRNA is greatest in the MLO-Y4 cells compared with the other cell types. RANK-Fc and OPG-Fc blocked the formation of osteoclasts by MLO-Y4 cells. These studies suggest that both RANKL and OPG may play a role in osteocyte signaling, OPG and M-CSF as soluble factors and RANKL as a surface molecule that is functional in osteocytes or along their exposed dendritic processes. [source] Is Leptin the Link Between Fat and Bone Mass?,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2002Thierry Thomas Ph.D. Abstract Recently, leptin has emerged as a potential candidate responsible for protective effects of fat on bone tissue. However, it remains difficult to draw a clear picture of leptin effects on bone metabolism because published data are sometimes conflicting or apparently contradictory. Beyond differences in models or experimental procedures, it is tempting to hypothesize that leptin exerts dual effects depending on bone tissue, skeletal maturity, and/or signaling pathway. Early in life, leptin could stimulate bone growth and bone size through direct angiogenic and osteogenic effects on stromal precursor cells. Later, it may decrease bone remodeling in the mature skeleton, when trabecular bone turnover is high, by stimulating osteoprotegerin (OPG) expression. Leptin negative effects on bone formation effected through central nervous system pathway could counterbalance these peripheral and positive effects, the latter being predominant when the blood-brain barrier permeability decreases or the serum leptin level rises above a certain threshold. Thus, the sex-dependent specificity of the relationship between leptin and bone mineral density (BMD) in human studies could be, at least in part, caused by serum leptin levels that are two- to threefold higher in women than in men, independent of adiposity. Although these hypotheses remain highly speculative and require further investigations, existing studies consistently support the role of leptin as a link between fat and bone. [source] Proposed Standard Nomenclature for New Tumor Necrosis Factor Family Members Involved in the Regulation of Bone Resorption ,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2000Article first published online: 1 DEC 2000 Abstract Recently, three new family members of the tumor necrosis factor (TNF) ligand and receptor signaling system that play a critical role in the regulation of bone resorption have been identified and cloned. These also have been shown to play an important role in regulating the immune system. A proliferation of synonyms for these molecules has led to miscommunication and redundancy. To resolve this, the President of the American Society for Bone and Mineral Research (ASBMR) appointed a special committee to recommend a standard nomenclature. After considerable deliberation and after vetting by workers in the field, the Committee recommends the names of receptor activator of NF-,B (RANK) for the membrane receptor, RANK ligand (RANKL) for the ligand, and osteoprotegerin (OPG) for the decoy receptor. [source] The Roles of Osteoprotegerin and Osteoprotegerin Ligand in the Paracrine Regulation of Bone ResorptionJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2000Lorenz C. Hofbauer Abstract Although multiple hormones and cytokines regulate various aspects of osteoclast formation, the final two effectors are osteoprotegerin ligand (OPG-L)/osteoclast differentiation factor (ODF), a recently cloned member of the tumor necrosis factor superfamily, and macrophage colony,stimulating factor. OPG-L/ODF is produced by osteoblast lineage cells and exerts its biological effects through binding to its receptor, osteoclast differentiation and activation receptor (ODAR)/receptor activator of NF-,B (RANK), on osteoclast lineage cells, in either a soluble or a membrane-bound form, the latter of which requires cell-to-cell contact. Binding results in rapid differentiation of osteoclast precursors in bone marrow to mature osteoclasts and, at higher concentrations, in increased functional activity and reduced apoptosis of mature osteoclasts. The biological activity of OPG-L/ODF is neutralized by binding to osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF), a member of the TNF-receptor superfamily that also is secreted by osteoblast lineage cells. The biological importance of this system is underscored by the induction in mice of severe osteoporosis by targeted ablation of OPG/OCIF and by the induction of osteopetrosis by targeted ablation of OPG-L/ODF or overexpression of OPG/OCIF. Thus, osteoclast formation may be determined principally by the relative ratio of OPG-L/ODF to OPG/OCIF in the bone marrow microenvironment, and alterations in this ratio may be a major cause of bone loss in many metabolic disorders, including estrogen deficiency and glucocorticoid excess. That changes in but two downstream cytokines mediate the effects of large numbers of upstream hormones and cytokines suggests a regulatory mechanism for osteoclastogenesis of great efficiency and elegance. [source] 2-methoxyestradiol-mediated anti-tumor effect increases osteoprotegrin expression in osteosarcoma cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2010Michaela B. Benedikt Abstract Osteosarcoma is a bone tumor that frequently develops during adolescence. 2-Methoxyestradiol (2-ME), a naturally occurring metabolite of 17,-estradiol, induces cell cycle arrest and cell death in human osteosarcoma cells. To investigate whether the osteoprotegrin (OPG) protein plays a role in 2-ME actions, we studied the effect of 2-ME treatment on OPG gene expression in human osteosarcoma cells. 2-ME treatment induced OPG gene promoter activity and mRNA levels. Also, Western blot analysis showed that 2-ME treatment increased OPG protein levels in MG63, KHOS, 143B and LM7 osteosarcoma cells by 3-, 1.9-, 2.8-, and 2.5-fold, respectively, but did not affect OPG expression in normal bone cells. In addition, increases in OPG protein levels were observed in osteosarcoma cell culture media after 3 days of 2-ME treatment. The effect of 2-ME on osteosarcoma cells was ligand-specific as parent estrogen, 17,-estradiol and a tumorigenic estrogen metabolite, 16,-hydroxyestradiol, which do not affect osteosarcoma cell cycle and cell death, had no effect on OPG protein expression. Furthermore, co-treating osteosarcoma cells with OPG protein did not further enhance 2-ME-mediated anti-tumor effects. OPG-released in 2-ME-treated cultures led to an increase in osteoblastic activity and a decrease in osteoclast number, respectively. These findings suggest that OPG is not directly involved in 2-ME-mediated anti-proliferative effects in osteosarcoma cells, but rather participates in anti-resorptive functions of 2-ME in bone tumor environment. J. Cell. Biochem. 109: 950,956, 2010. © 2010 Wiley-Liss, Inc. [source] Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2009Tilman D. Rachner Abstract Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-,B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). While RANKL is essential for osteoclastogenesis and facilitates breast cancer migration into bone, TRAIL promotes breast cancer apoptosis. We analyzed the expression of OPG and TRAIL and its modulation in estrogen receptor-positive MCF-7 cells and receptor-negative MDA-MB-231 cells. In both cells, OPG mRNA levels and protein secretion were dose- and time-dependently enhanced by interleukin (IL)-1, and suppressed by dexamethasone. In contrast to MCF-7 cells, MDA-MB-231 abundantly expressed TRAIL mRNA, which was enhanced by IL-1, and inhibited by dexamethasone. TRAIL activated pro-apoptotic caspase-3, -7, and poly-ADP-ribose polymerase and decreased cell numbers of MDA-MB-231, but had no effect on MCF-7 cells. Gene silencing siRNA directed against OPG resulted in a 31% higher apoptotic rate compared to non-target siRNA-treated MDA-MB-231 cells. Furthermore, TRAIL induced significantly less apoptosis in cells cultured in conditioned media (containing OPG) compared to cells exposed to TRAIL in fresh medium lacking OPG (P,<,0.01) and these protective effects were reversed by blocking OPG with its specific ligand RANKL (P,<,0.05). The association between cancer cell survival and OPG production by MDA-MB-231 cells was further supported by the finding, that modulation of OPG secretion using IL-1, or dexamethasone prior to TRAIL exposure resulted in decreased and increased rate of apoptosis, respectively (P,<,0.05). Thus, OPG secretion by breast cancer cells is modulated by cytokines and dexamethasone, and may represent a critical resistance mechanism that protects against TRAIL-induced apoptosis. J. Cell. Biochem. 108: 106,116, 2009. © 2009 Wiley-Liss, Inc. [source] DNA methylation and histone modification regulate silencing of OPG during tumor progression,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2009Tung-Ying Lu Abstract The identification of molecules that are down-regulated in malignant phenotype is important for understanding tumor biology and their role in tumor suppression. We compared the expression profile of four normal nasal mucosal (NNM) epithelia and a series of nasopharyngeal cancinoma (NPC) cell lines using cDNA microarray and confirmed the actual expression of the selected genes, and found osteoprotegerin (OPG) to be ubiquitously deficient in NPC cells. We also found OPG to be down-regulated in various cancer cell lines, including oral, cervical, ovarian, lung, breast, pancreas, colon, renal, prostate cancer, and hepatoma. Administration of recombinant OPG (rOPG) brought about a reduction in cancer cell growth through apoptotic mechanism. We generated eleven monoclonal antibodies (MAbs) against OPG to study OPG's expression and biological functions in cancer cells. OPG was detected in the tumor stromal regions, but not in the cancer cell per se in surgical specimens of liver cancer. Quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR) revealed that OPG was down-regulated in NPC tissues compared with normal nasal polyp (NNP) tissues. In addition, we showed OPG silencing to be associated with promoter methylation as well as histone modifications. In OPG-silenced cancer cell lines, the OPG gene promoter CpG dinucleotides were highly methylated. Compared to normal cells, silenced OPG gene in cancer cells were found to have reduced histone 3 lysine 4 tri-methylation (H3K4me3) and increased histone 3 lysine 27 tri-methylation (H3K27me3). Taken together, these results suggest that OPG silencing in carcinoma cancer cells occurs through epigenetic repression. J. Cell. Biochem. 108: 315,325, 2009. © 2009 Wiley-Liss, Inc. [source] TNF receptor type 1 regulates RANK ligand expression by stromal cells and modulates osteoclastogenesisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2004Yousef Abu-Amer Abstract TNF, is a major osteoclastogenic cytokine and a primary mediator of inflammatory osteoclastogenesis. We have previously shown that this cytokine directly targets osteoclasts and their precursors and that deletion of its type-1 receptor (TNFr1) lessens osteoclastogenesis and impacts RANK signaling molecules. Osteoclastogenesis is primarily a RANK/RANKL-dependent event and occurs in an environment governed by both hematopoietic and mesenchymal compartments. Thus, we reasoned that TNF/TNFr1 may regulate RANKL and possibly RANK expression by stromal cells and osteoclast precursors (OCPs), respectively. RT-PCR experiments reveal that levels of RANKL mRNA in WT stromal cells are increased following treatment with 1,25-VD3 compared to low levels in TNFr1-null cells. Expression levels of OPG, the RANKL decoy protein, were largely unchanged, thus supporting a RANKL/OPG positive ratio favoring WT cells. RANK protein expression by OCPs was lower in TNFr1-null cells despite only subtle differences in mRNA expression in both cell types. Mix and match experiments of different cell populations from the two mice phenotypes show that WT stromal cells significantly, but not entirely, restore osteoclastogenesis by TNFr1-null OCPs. Similar results were obtained when the latter cells were cultured in the presence of exogenous RANKL. Altogether, these findings indicate that in the absence of TNFr1 both cell compartments are impaired. This was further confirmed by gain of function experiments using TNFr1- null cultures of both cell types at which exogenous TNFr1 cDNA was virally expressed. Thus, restoration of TNFr1 expression in OCPs and stromal cells was sufficient to reinstate osteoclastogenesis and provides direct evidence that TNFr1 integrity is required for optimal RANK-mediated osteoclastogenesis. © 2004 Wiley-Liss, Inc. [source] Markers of bone destruction and formation and periodontitis in type 1 diabetes mellitusJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 8 2009David F. Lappin Abstract Aim: To determine plasma concentrations of bone metabolism markers in type 1 diabetes mellitus patients and non-diabetic and to evaluate the influence of periodontitis on biomarkers of bone formation in these patient groups. Methods: Plasma concentrations of receptor activator of nuclear factor- ,B ligand (RANKL), osteoprotegerin (OPG), C-terminal telopeptide of type 1 collagen and osteocalcin were measured in type 1 diabetes mellitus patients (n=63) and non-diabetics (n=38) who were also subdivided on the basis of their periodontal status. Results: Diabetics had significantly lower osteocalcin concentrations, lower RANKL to OPG ratios and higher OPG concentrations (as shown by other researchers) than non-diabetics. The ratio of RANKL to OPG was altered by the periodontal status. Osteocalcin had a negative correlation and OPG a positive correlation with the percentage of glycated haemoglobin in the blood. Conclusion: Because, osteocalcin, a biomarker of bone formation, is lower in patients with periodontitis and in patients with type 1 diabetes mellitus with and without periodontitis than in non-diabetics without periodontitis, this might indicate that diabetics are less able to replace bone lost during active bursts of periodontitis and explain the greater severity of disease seen in studies of patients with diabetes. [source] Saliva concentrations of RANKL and osteoprotegerin in smoker versus non-smoker chronic periodontitis patientsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 10 2008Nurcan Buduneli Abstract Objectives: To compare the salivary receptor activator of NF- ,B ligand (RANKL) and osteoprotegerin (OPG) concentrations in smokers versus non-smokers with chronic periodontitis. Material and Methods: Whole saliva samples were obtained from 67 untreated chronic periodontitis patients, of whom 34 were smokers, and from 44 maintenance patients, of whom 22 were smokers. Full-mouth clinical periodontal measurements were recorded. Saliva cotinine, sRANKL and OPG concentrations were determined by ELISA. Statistical analysis was performed using the Mann,Whitney U test, Bonferroni's correction for multiple comparisons and Spearman's correlations. Results: Untreated smokers exhibited significantly higher values of clinical periodontal recordings than untreated non-smokers (all p<0.05). Salivary cotinine level correlated with clinical attachment level (p=0.023). Smoker versus non-smoker maintenance groups showed no significant differences in clinical parameters. There were significant differences in sRANKL and OPG concentrations between untreated and maintenance groups (all p<0.01). Salivary OPG concentration was significantly lower (all p<0.01) and the sRANKL/OPG ratio was higher (all p<0.01) in smokers than in non-smokers. OPG concentration correlated positively with probing depth, clinical attachment level and bleeding on probing (all p<0.005) and negatively with pack-year, and cotinine level (p<0.05). Conclusion: Salivary RANKL and OPG concentrations are suggested to be affected by smoking as not only the untreated but also the treated smokers exhibited higher RANKL and lower OPG concentrations than non-smokers. [source] Gingival crevicular fluid levels of RANKL and OPG in periodontal diseases: implications of their relative ratioJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 5 2007Nagihan Bostanci Abstract Aim: Receptor activator of NF-,B ligand (RANKL) and osteoprotegerin (OPG) are a system of molecules that regulate bone resorption. This study aims to compare the levels of RANKL, OPG and their relative ratio in gingival crevicular fluid (GCF) of healthy and periodontal disease subjects. Material and Methods: GCF was obtained from healthy (n=21), gingivitis (n=22), chronic periodontitis (n=28), generalized aggressive periodontitis (n=25) and chronic periodontitis subjects under immunosuppressant therapy (n=11). RANKL and OPG concentrations in GCF were measured by enzyme-linked immunosorbent assays. Results: RANKL levels were low in health and gingivitis groups, but increased in all three forms of periodontitis. OPG levels were higher in health than all three periodontitis, or gingivitis groups. There were no differences in RANKL and OPG levels between chronic and generalized aggressive periodontitis groups, whereas these were lower in the immunosuppressed chronic periodontitis group. The RANKL/OPG ratio was significantly elevated in all three periodontitis forms, compared with health or gingivitis, and positively correlated to probing pocket depth and clinical attachment level. Conclusion: GCF RANKL and OPG levels were oppositely regulated in periodontitis, but not gingivitis, resulting in an enhanced RANKL/OPG ratio. This ratio was similar in all three periodontitis groups and may therefore predict disease occurrence. [source] | |||||||||||||||||||||||||||||||