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At least 19 recordsLinked to original sources
PubMed2001

Osteoprotegerin and osteoprotegerin-ligand balance: a new paradigm in bone metabolism providing new therapeutic targets.

Osteoprotegerin-ligand, also called Osteoclast Differentiation Factor or RANK-ligand, its receptor RANK and its decoy receptor Osteoprotegerin are key molecules regulating osteoclast differentiation and activation. In this view we discuss structure and expression of these molecules, the genetic models addressing their function and their role in in vivo models of osteoclast differentiation and activation. The new paradigm that has evolved from these studies, is not only important in normal bone homeostasis but also appears to play a role in different diseases that affect the skeleton, such as osteoporosis, inflammatory joint disease and cancer. It has opened a new era in bone research by increasing our molecular knowledge and providing new therapeutic targets in bone disease.

Bone Diseases, Metabolic↗
PubMed2000

Effect of osteoprotegerin and osteoprotegerin ligand on osteoclast formation by arthroplasty membrane derived macrophages.

OBJECTIVE: Osteoprotegerin ligand (OPGL) is a newly discovered molecule, which is expressed by osteoblasts/bone stromal cells. This ligand and M-CSF are now known to be essential for osteoclast differentiation from marrow and circulating precursors. This study examined whether OPGL and its soluble receptor osteoprotegerin (OPG), influenced osteoclast formation from human arthroplasty derived macrophages, to determine if the effects of OPGL and OPG on these cells could contribute to the osteolysis of aseptic loosening. METHODS: OPGL (+/- dexamethasone/M-CSF) was added to cultures of macrophages isolated from the pseudomembrane of loosened hip arthroplasties incubated on glass coverslips and dentine slices. OPG was added to cocultures of arthroplasty derived macrophages and UMR106 osteoblast-like cells. Osteoclast differentiation in long term cultures was assessed by expression of macrophage (CD14) and osteoclast markers (tartrate resistant acid phosphatase (TRAP), vitronectin receptor (VNR) and lacunar resorption). RESULTS: In the absence of osteoblastic cells, the addition of OPGL alone was sufficient to induce differentiation of macrophages (CD14(+), TRAP(-), VNR(-)) into TRAP(+) and VNR(+) multinucleated cells, capable of extensive lacunar resorption. OPG was found to inhibit osteoclast formation by arthroplasty macrophages in a dose dependent manner. OPG (100 ng/ml) more than halved the formation of TRAP(+) and VNR(+) cells and the extent of lacunar resorption in co-cultures of UMR106 cells and arthroplasty macrophages. CONCLUSIONS: This study has shown that macrophages, isolated from the pseudomembrane surrounding loose arthroplasty components, are capable of differentiating into osteoclastic bone resorbing cells and that OPGL is required for this to occur. OPG inhibits this process, most probably by interrupting the cell-cell interaction between osteoblasts and mononuclear phagocyte osteoclast precursors present in the pseudomembrane.

Aged↗
PubMed2000

The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption.

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-kappa 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.

Animals↗
PubMed2001

Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing.

Fracture healing is a unique biological process regulated by a complex array of signaling molecules and proinflammatory cytokines. Recent evidence for the role of tumor necrosis family members in the coupling of cellular functions during skeletal homeostasis suggests that they also may be involved in the regulation of skeletal repair. The expression of a number of cytokines and receptors that are of functional importance to bone remodeling (osteoprotegerin [OPG], macrophage colony-stimulating factor [M-CSF], and osteoprotegerin ligand [receptor activator of NF-kappaB ligand (RANKL)]), as well as inflammation (tumor necrosis factor alpha [TNF-alpha] and its receptors, and interleukin-1alpha [IL-1alpha] and -beta and their receptors) were analyzed over a 28-day period after the generation of simple transverse fractures in mouse tibias. OPG was expressed constitutively in unfractured bones and elevated levels of expression were detected throughout the repair process. It showed two distinct peaks of expression: the first occurring within 24 h after fracture and the second at the time of peak cartilage formation on day 7. In contrast, the expression of RANKL was nearly undetectable in unfractured bones but strongly induced throughout the period of fracture healing. The peak in expression of RANKL did not correlate with that of OPG, because maximal levels of expression were seen on day 3 and day 14, when OPG levels were decreasing. M-CSF expression followed the temporal profile of RANKL but was expressed at relatively high basal levels in unfractured bones. TNF-alpha, lymphotoxin-beta (LT-beta), IL-1alpha, and IL-1beta showed peaks in expression within the first 24 h after fracture, depressed levels during the period of cartilage formation, and increased levels of expression on day 21 and day 28 when bone remodeling was initiated. Both TNF-alpha receptors (p55 and p75) and the IL-1RII receptor showed identical patterns of expression to their ligands, while the IL-1R1 was expressed only during the initial period of inflammation on day 1 and day 3 postfracture. Both TNF-alpha and IL-1alpha expression were localized primarily in macrophages and inflammatory cells during the early periods of inflammation and seen in mesenchymal and osteoblastic cells later during healing. TNF-alpha expression also was detected at very high levels in hypertrophic chondrocytes. These data imply that the expression profiles for OPG, RANKL, and M-CSF are tightly coupled during fracture healing and involved in the regulation of both endochondral resorption and bone remodeling. TNF-alpha and IL-1 are expressed at both very early and late phases in the repair process, which suggests that these cytokines are important in the initiation of the repair process and play important functional roles in intramembraneous bone formation and trabecular bone remodeling.

Animals↗
PubMed2006

[Effects of soybean isoflavones on expression levels of osteoprotegerin and osteoprotegerin ligand mRNAs in bone tissues of ovariectomized rats].

OBJECTIVE: To investigate the effects of soybean isoflavones (SI) on expression levels of osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL) mRNAs in bone tissues of ovariectomized rats, and to discuss the mechanism of soybean isoflavaones in preventing and treating postmenopausal osteoporosis (PMO). METHODS: Thirty adult SD rats were randomly divided into 3 groups: sham-operation group, untreated group and SI-treated group. The rats in the last two groups were bilaterally ovariectomized. The bone density of L(3) to L(6) vertebrae was detected after 12-week intervention. Total RNA was extracted from femur head and the expression levels of OPG and OPGL mRNAs were examined by real-time quantitative polymerase chain reaction. RESULTS: SI could increase the bone density of lumbar vertebrae in ovariectomized rats, up-regulate the expression level of OPG mRNA and down-regulate the ratio of OPGL mRNA/OPG mRNA, but exert no significant effect on the expression of OPGL mRNA. CONCLUSION: The therapeutic effects of SI on PMO may be related to regulating the expression levels of OPG and OPGL mRNAs, and the ratio of OPGL mRNA/OPG mRNA.

Animals↗
PubMed2003

[The effects of 17 beta-estradiol on the expression of osteoprotegerin, the ligand of osteoprotegerin and related cytokines in osteosarcoma MG63 cells].

OBJECTIVE: To observe the regulative effects of 17 beta-estradiol (17 beta-E(2)) and ICI 182780 on the expression of osteoprotegerin (OPG), the ligand of osteoprotegerin (OPGL) and the related cytokines [macrophage colony-stimulating factor (M-CSF), TRAIL and transforming growth factor beta(TGF beta)] in MG63 cells. METHODS: The expression of OPG, OPGL, M-CSF, TRAIL and TGF beta mRNA was examined by reverse transcriptase (RT)-PCR. The expression of OPG and OPGL protein was measured with Western blot. RESULTS: (1) 17 beta-E(2) up-regulated the expression of OPG and TGF beta but down-regulated OPGL, M-CSF and TRAIL expression in MG63 cells. (2) ICI 182780 showed varied transactivating capability when regulating the expression of OPG, OPGL, TRAIL, M-CSF and TGF beta genes in MG63 cells. CONCLUSIONS: (1) One of the key pathogenetic factors of postmenopausal osteoporosis is that estrogen deficiency leads to the decreasing expression of OPG and TGF beta but the increasing expression of some bone-resorbing cytokines such as OPGL, M-CSF and TRAIL in osteoblasts, then stimulation of osteoclast differentiation and activity which potentiates bone resorption and bone loss; (2) ICI 182780 shows partial transactivating activity in osteoblasts, so it should belong to a kind of selective estrogen receptor modulators.

Apoptosis Regulatory Proteins↗
PubMed2004

[Effects of parathyroid hormone on osteoprotegerin expression and osteoprotegerin ligand and their related cytokines in human osteoblasts].

OBJECTIVE: To investigate the pathway and mechanism of parathyroid hormone (PTH) in regulating bone resorption. METHODS: We observed the regulative effects of PTH on the expression of osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL) and their related cytokines (M-CSF and TRAIL) in human osteoblasts (HOBs). The expressions of OPG, OPGL, M-CSF, and TRAIL mRNA were determined by RT-PCR. The expressions of OPG and OPGL proteins were measured by Western blotting. RESULTS: PTH down-regulated the expression of OPG but up-regulated the expressions of OPGL, M-CSF and TRAIL in HOBs. CONCLUSION: PTH can promote the bone resorption by decreasing the expression of OPG, increasing the expressions of some bone-resorbing cytokines such as OPGL, M-CSF, and TRAIL in osteoblasts, and then stimulating the osteoclast differentiation and activity.

Cells, Cultured↗
PubMed2005

Using the ratio of serum osteoprotegerin ligand to osteoprotegerin to evaluate renal osteodystrophy in dialysis patients.

Osteoclast function is important in the development of renal osteodystrophy (ROD). Osteoclast activity is modulated by the osteoprotegerin ligand-osteoprotegerin (OPGL/OPG) system. In the present study, we checked levels of serum OPG and soluble OPGL in dialyzed patients and correlated those levels with routinely measured parameters of bone metabolism. The study was carried out in 39 patients on hemodialysis (HD) and 29 on peritoneal dialysis (PD). The control group included 13 healthy volunteers. Patients on HD had lower OPGL (p = 0.027) and higher OPG (p = 0.000) levels than control subjects did [OPGL: 0.6 pmol/L (median) and 0.0 - 10.0 pmolL (range) vs. 1.9 pmo1/L (median) and 0.0 - 10.5 pmol/L (range); OPG: 7.7 pmol/L (median) and 0.9 - 16.5 pmol/L (range) vs. 2.2 pmol/L (median) and 1.0- 3.9 pmol/L (range)]. Patients on PD differed from controls only in OPG level [4.0 pmol/L (median) and 2.1 - 13.4 pmol/L (range), p = 0.043]. Patients on HD and on PD both had a lower OPGL/OPG ratio than did the control subjects [HD: 0.09 (median) and 0.00 - 1.45 (range), p = 0.000; PD: 0.35 (median) and 0.00 - 3.89 (range), p = 0.018; controls: 1.07 (median) and 0.00 - 5.14 (range)]. Patients on HD did not differ from patients on PD in levels of OPGL and OPGL/OPG, but they had a higher OPG level (p = 0.001). Patients on HD also showed significantly higher total alkaline phosphatase (ALP) activity and higher inorganic phosphate (iP), but lower total calcium and blood pH. In PD patients, OPGL and OPG both correlated with pH (OPGL positively and OPG negatively). In HD patients, OPGL showed a positive correlation with ALP and a negative correlation with calcium; OPG correlated positively with iP In 36 patients on HD (92.3%) and 15 patients on PD (51.7%), OPG was elevated above the normal value. Differences in serum OPG and OPGL/OPG ratio between groups of dialyzed patients and of control subjects indicate that ROD is more advanced in HD patients than in PD patients. Higher serum OPG and lower serum OPGL in the HD group is probably an effect of higher osteoclast activity. In about 50% of PD patients, osteoclast function is also disturbed, as indicated by elevated OPG levels.

Alkaline Phosphatase↗
PubMed2000

Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-kappaB in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation.

Giant cell tumor of bone (GCT) is a rare primary osteolytic tumor of bone that is characterized by massive tissue destruction at the epiphysis of long bones. There is no evidence that tumor cells themselves are capable of bone destruction; instead, it appears that the tumor cells of GCT act by promoting osteoclastogenesis and, as a consequence, osteoclastic bone resorption. However, the mechanism by which this is achieved is not understood. Here we attempted to determine whether osteoprotegerin ligand (OPGL), the factor that is necessary and essential for osteoclastogenesis, is involved in tumor cell-recruited osteoclast-like giant cell formation in GCT. Using fluorescence in situ hybridization, we sought to determine mRNA expression of OPGL, its receptor RANK, and its decoy receptor OPG in three major cell types of GCT. We demonstrated that OPG mRNA was expressed in all three cell types of GCT, OPGL transcripts were mainly detected in spindle-shaped stromal-like tumor cells, whereas RANK was expressed only in macrophage-like mononuclear cells and multinuclear osteoclast-like giant cells. By semiquantitative RT-PCR, we also showed that the level of OPGL mRNA in GCT is much higher than that in normal bone and osteogenic osteosarcoma. In contrast, a similar level of OPG transcripts was detected in these three kinds of tissues, and RANK mRNA was detectable only in GCT tissues. We have further examined the regulation of gene expression of OPGL and OPG in tumor cells in response to osteotropic hormones. Administration of 1,25(OH)(2)D(3) and dexamethasone resulted in maximum up-regulation of OPGL level and down-regulation of OPG level in cultured GCT stromal-like tumor cells and the mouse bone marrow-derived ST-2 stromal cell line. Furthermore, we have shown that tumor cells of GCT induce differentiation of RANK-expressing myeloid RAW(264.7) cells into osteoclast-like cells in the presence of 1,25(OH)(2)D(3) and dexamethasone. Our findings suggest that OPGL is involved in the tumor cell-induced osteoclast-like cell formation in GCT. The ratio of OPGL/OPG by tumor cells may contribute to the degree of osteoclastogenesis and bone resorption.

Animals↗
PubMed2005

Effects of osteoprotegerin administration on osteoclast differentiation and trabecular bone structure in osteoprotegerin-deficient mice.

Osteoprotegerin (OPG)-deficient mice exhibit severe bone loss including the destruction of growth plate cartilage. Using OPG-deficient mice, we attempted to clarify the differentiation and ultrastructure of osteoclasts located on the destroyed growth plate cartilage and trabecular bone matrix in long bones. In (-/-) homozygous OPG knockout mice, adjacent to the growth plate cartilage, the formation of bone trabeculae without a calcified cartilaginous core resulted in an irregular chondrocyte distribution in the growth plate cartilage. At the metaphyseal ossification center, TRAP-positive osteoclasts showed unusual localization on both type-II collagen-positive cartilage and type-I collagen-positive bone matrix. Osteoclasts located on cartilage matrix lacked a typical ruffled border structure, but formed resorption lacunae. During growth plate cartilage destruction, osteoclasts formed ruffled border structures on bone matrix deposited on the remaining cartilage surfaces. These findings suggest that, in OPG (-/-) mice, osteoclast structure differs, depending on the matrix of either cartilage or bone. Then, we examined the effects of OPG administration on the internal trabecular bone structure and osteoclast differentiation in OPG (-/-) mice. OPG administration to OPG (-/-) mice significantly inhibited trabecular bone loss and maintained the internal trabecular bone structure, but did not reduce the osteoclast number on bone trabeculae. For most osteoclasts, OPG administration caused disappearance or reduction of the ruffled border, but induced neither necrotic nor apoptotic damages. These results suggest that OPG administration is an effective means of maintaining the internal structure and volume of trabecular bone in metabolic bone diseases by inhibition of osteoclastic bone resorption.

Acid Phosphatase↗
PubMed2006

Serum levels of osteoprotegerin and osteoprotegerin polymorphisms in Gaucher disease.

Bone involvement in Gaucher disease causes disability and reduced quality of life; loss of function and pain are important indications for enzyme replacement therapy. The purpose of this study was to ascertain whether osteoprotegerin (OPG), which decreases osteoclast activity, is indicative of incipient bone involvement by comparing OPG serum levels to Gaucher disease severity (SSI) and bone mineral density (BMD), and to correlate bone and disease markers to OPG polymorphisms: OPG1-2(A163G), OPG3-4(T129C) and OPG5-6(C1217T). Of 554 patients, 173 Ashkenazi Jewish patients with non-neuronopathic Gaucher disease were enrolled and 32 healthy Ashkenazi Jews served as controls. Serum OPG levels were detected by enzyme-linked immunosorbent assay and BMD was obtained by dual X-ray absorptiometry. OPG polymorphisms were determined in 63 randomly chosen patients. Serum OPG values for patients were not greater than in controls, but showed a statistically significant trend to increase with age (P = 0.057). No correlation existed between OPG levels and BMD or with genotype or other disease markers. A significant correlation was noted between OPG5-6 genotype and SSI. A significant difference was found between the allele distributions of each OPG polymorphism when compared with Caucasians and Ashkenazi Jews. OPG levels probably do not predict BMD in Gaucher disease and hence are not indicative of osteoporosis in Gaucher disease.

Adolescent↗
PubMed1999

Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis.

Osteoporosis is a serious complication of systemic glucocorticoid use. However, while glucocorticoids increase bone resorption in vitro and in vivo, the mechanism(s) of this effect are at present unclear. Recent studies have identified the osteoprotegerin (OPG) ligand (OPG-L) as the final effector of osteoclastogenesis, an action that is opposed by the soluble neutralizing receptor, OPG. Thus, we assessed glucocorticoid regulation of OPG and OPG-L in various human osteoblastic lineage cells using Northern analysis, RT-PCR, and ELISA. Dexamethasone inhibited constitutive OPG messenger RNA (mRNA) steady-state levels by 70-90% in primary (MS) and immortalized stromal cells (hMS), primary trabecular osteoblasts (hOB), immortalized fetal osteoblasts (hFOB), and osteosarcoma cells (MG-63). In hFOB cells, dexamethasone inhibited constitutive OPG mRNA steady-state levels in a dose- and time-dependent fashion by 90%, and also suppressed cytokine-stimulated OPG mRNA steady-state levels. Dexamethasone-induced inhibition of OPG mRNA levels was not affected by the protein synthesis inhibitor, cycloheximide, and was shown to be due to inhibition of OPG gene transcription using a nuclear run-on assay. Moreover, dexamethasone also dose dependently (10(-10) M-10(-7) M) inhibited constitutive OPG protein concentrations in the conditioned medium of hFOB cells from 2.59 +/- 0.02 ng/ml (control) to 0.30 +/- 0.01 ng/ml (88% inhibition; P < 0.001 by ANOVA). Concurrently, dexamethasone stimulated OPG-L mRNA steady-state levels in MS and hFOB cells by 2- and 4-fold, respectively. Treatment of murine marrow cultures with conditioned medium harvested from dexamethasone-treated MG-63 cells increased tartrate-resistant acid phosphatase (TRAP) activity by 54% (P < 0.005) compared with medium harvested from control-treated cells (in the presence of OPG-L and macrophage colony-stimulating factor). Moreover, dexamethasone (10(-8) M) promoted osteoclast formation in vitro, as assessed by a 2.5-fold increase of TRAP activity in cell lysates (P < 0.001) and the appearance of TRAP-positive multinucleated cells. Our data are thus consistent with the hypothesis that glucocorticoids promote osteoclastogenesis by inhibiting OPG and concurrently stimulating OPG-L production by osteoblastic lineage cells, thereby enhancing bone resorption.

Carrier Proteins↗
PubMed1999

Osteoprotegerin and osteoprotegerin ligand effects on osteoclast formation from human peripheral blood mononuclear cell precursors.

Osteoprotegerin (OPG) and its ligand (OPGL) negatively and positively regulate osteoclastogenesis in the mouse. OPG inhibits osteoclastogenesis by sequestering its ligand, OPGL, the osteoclast differentiation and activation factor. This study demonstrates the effects of soluble muOPGL and huOPG on the developing human osteoclast phenotype, on bone slices, using peripheral blood mononuclear cells (PBMCs), cultured for 2 weeks, without stromal cells. OPGL (2-50 ng/ml), in combination with CSF-1, hydrocortisone (HC), and 1,25(OH)2D3, increases the size of osteoclast-like cells on bone, as defined by the acquisition of osteoclast markers: vitronectin receptor (VR), tartrate-resistant acid phosphatase (TRAP), multinuclearity, and bone resorption. By 14 days, with 20 ng/ml OPGL, the largest cells/10x field have achieved an average diameter of 163+/-38 microm, but only approximately 10-20 microm in its absence and the number of osteoclast-like cells/mm2 bone surface is about 128. By scanning electron microscopy, OPGL-treated (20-ng/ml) cultures contain small osteoclast-like cells on bone with ruffled "apical" surfaces by day 7; by day 15, large osteoclast-like cells are spread over resorption lacunae. At 15 ng/ml OPGL, about 37% of the bone slice area is covered by resorption lacunae. OPG (5-250 ng/ml) antagonizes the effects of OPGL on the morphology of the osteoclast-like cells that form, as well as bone erosion. For cells grown on plastic, Cathepsin K mRNA levels, which are barely detectable at plating, are elevated 7-fold, by 5 days, in the presence, not the absence, of OPGL (20 ng/ml) + CSF-1 (25 ng/ml). Similar findings are observed in experiments performed in the absence of HC and 1,25(OH)2D3, indicating that HC and 1,25(OH)2D3 are not needed for OPGL-induced osteoclast differentiation. In conclusion, this study confirms a pivotal role for OPGL and OPG in the modulation of human osteoclast differentiation and function, suggesting a use for OPG for treating osteoclast-mediated bone disease in humans.

Animals↗
PubMed2006

Osteoprotegerin and bone mineral density in hemodialysis patients.

INTRODUCTION: Osteoprotegerin is a soluble glycoprotein that belongs to the tumor-necrosis-factor receptor superfamily. In vitro, osteoprotegerin blocks osteoclastogenesis in a dose-dependent manner. The serum osteoprotegerin level shows a positive correlation with bone metabolism markers and a negative correlation with bone mineral density in healthy persons, but these relationships are unclear in hemodialysis patients. We investigated the role of osteoprotegerin in bone loss in hemodialysis patients. METHODS: We measured baseline serum osteoprotegerin, bone metabolism markers, and bone mineral density in hemodialysis patients. A total of 201 patients (114 men and 87 women) were followed for 12 months, and bone mineral density was measured again to calculate the annual percent change in bone mineral density. Serum osteoprotegerin was also measured in 20 healthy persons. RESULTS: The osteoprotegerin levels of the hemodialysis patients were about three times higher than those of the healthy controls. The osteoprotegerin level showed a negative correlation with various bone metabolism markers. In multiple regression analysis, the annual percent change in bone mineral density showed a positive correlation with osteoprotegerin level, while there was a negative correlation with duration of hemodialysis and intact parathyroid hormone level. The osteoprotegerin levels of the hemodialysis patients were about three times higher than those of the healthy controls. The osteoprotegerin level showed a negative correlation with various bone metabolism markers. In multiple regression analysis, the annual percent change in bone mineral density showed a positive correlation with osteoprotegerin level, while there was a negative correlation with duration of hemodialysis and intact parathyroid hormone level. CONCLUSIONS: These correlations of osteoprotegerin are opposite to those found in healthy persons. However, osteoprotegerin might act to prevent bone loss even in hemodialysis patients.

Absorptiometry, Photon↗
PubMed2000

Osteoprotegerin inhibits tumor-induced osteoclastogenesis and bone tumor growth in osteopetrotic mice.

Osteoprotegerin and osteoprotegerin ligand have recently been identified as novel proteins that inhibit and stimulate, respectively, osteoclast formation. We examined the possibility that osteoprotegerin would inhibit cancer-induced osteoclastogenesis and cancer growth in bone. An experimental model was used in which osteolytic tumors are known to stimulate osteoclastogenesis and grow in femora of osteoclast-deficient mice (op/op). Osteoprotegerin treatment decreased the number of osteoclasts by 90% (p < 0.0007) at sites of tumor in a dose-dependent manner and decreased bone tumor area by greater than 90% (p < 0.003). The mechanisms through which osteoprotegerin decreased osteoclast formation in tumor-bearing animals included (a) an osteoprotegerin-mediated, systemic reduction in the number of splenic and bone marrow-residing osteoclast precursor cells, (b) a decrease in the number of osteoclast precursor cells at sites of tumor as detected by cathepsin K and receptor activator of NFkappaB mRNA expression, and (c) a decrease in osteoprotegerin ligand mRNA at sites of tumor. These findings suggest that osteoprotegerin treatment, in addition to having direct antagonistic effects on endogenous osteoprotegerin ligand, decreases the number of osteoclast precursors and reduces production of osteoprotegerin ligand at sites of osteolytic tumor.

Animals↗
PubMed2004

Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease.

BACKGROUND: Osteoprotegerin is a novel member of the tumor necrosis factor receptor superfamily and a soluble decoy receptor of the receptor activator of nuclear factor-kappaB ligand. Recent experimental research has implicated osteoprotegerin in atherogenesis, but epidemiological confirmation of this concept is sparse. METHODS AND RESULTS: As part of the prospective, population-based Bruneck Study, severity, initiation, and progression of atherosclerosis were assessed in carotid arteries. Cases of incident cardiovascular disease and vascular mortality were carefully recorded over a 10-year period (1990 to 2000). Osteoprotegerin levels were measured in samples obtained at baseline and during follow-up. Serum osteoprotegerin showed a strong association with numerous vascular risk factors, including age, diabetes, markers of systemic inflammation, chronic infection, and smoking. In multivariate analyses, osteoprotegerin was significantly related to severity and 10-year progression of carotid atherosclerosis. Furthermore, a high level of osteoprotegerin was an independent risk factor for incident cardiovascular disease (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 2.2 [1.3 to 3.8]; P=0.001) and vascular mortality (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 3.1 [1.2 to 8.2]; P=0.010) but not for mortality due to nonvascular causes. CONCLUSIONS: Osteoprotegerin is an independent risk factor for the progression of atherosclerosis and onset of cardiovascular disease.

Aged↗