Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess--possible role in bone homeostasis

Ueland, Thor; Bollerslev, Jens; Godang, Kristin; Müller, Fredrik; Ss, Frøland; Aukrust, Pål

doi:10.1530/eje.0.1450685

Cited by 117 publications

(96 citation statements)

References 30 publications

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“…23 Our OPG concentrations in plasma from HIV-infected subjects were different from previous data that reported a 52% increase of serum OPG in their cohort of HIV subjects. 57 Although OPG concentrations were measured by the same set of anti-OPG antibodies, two major differences between both studies can, however, explain this discrepancy. Firstly, our OPG evaluation was performed on plasma from HIV individuals instead of serum in Ueland et al's report.…”

Section: Discussionmentioning

confidence: 97%

Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro

Chakravarti

Marceau

Flamand

et al. 2008

Laboratory Investigation

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Osteoprotegerin (OPG) acts as a decoy receptor for receptor activator of nuclear factor-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG regulates bone remodeling and the immune response. The primary objective was to decipher, among human peripheral blood mononuclear leukocytes (PBML) that produce OPG, the subset(s) responsible for this synthesis and its regulation. To this end, normal human PBML and CD4-, 8-, 19-, 14-enriched subpopulations were studied in vitro for OPG synthesis. PBML were subjected to adherence and immunomagnetic separation, and OPG expression was analyzed by PCR, northern and western blotting, and ELISA. The antiapoptotic effects of OPG were studied on TRAIL-stimulated RPMI 8226 myeloma cells. OPG was time-dependently produced by primary CD4 þ T lymphocytes exclusively. OPG secretion was upregulated by anti-CD3 antibody stimulation or incubation with interleukin (IL)-4, IL-1b, TNF-a, GM-CSF, and vitamin D 3 . In contrast, IL-10 inhibited the basal and IL-4-induced production of OPG by T cells. Conditioned media from activated T lymphocytes decreased TRAIL-induced apoptosis of RPMI 8226 cells. This effect was reversed by addition of RANKL to the T-cell conditioned media. As human immunodeficiency virus-1 (HIV-1) targets CD4 þ T cells, we evaluated the effects of recombinant HIV-1 gp120 proteins on OPG synthesis. The gp120 from three different HIV-1 strains significantly reduced the basal output of OPG from T cells. Furthermore, all four protease inhibitors (PIs) used in highly active antiretroviral therapy decreased OPG synthesis by human blood T cells, nelfinavir being the most efficient PI. The simultaneous presence of an HIV-1 gp120 and a PI abrogated the basal output of OPG. In conclusion, these results highlight a new role for T lymphocytes involved in pathologies. Activated CD4 þ T cells could, through OPG release, have a paracrine effect on adjacent cells and contribute to reduce the local process of bone remodeling and cellular apoptosis.

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Section: Discussionmentioning

confidence: 97%

Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro

Chakravarti

Marceau

Flamand

et al. 2008

Laboratory Investigation

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“…Thus, OPG may be released from storage during excess resorption or released from osteoblasts directly to attenuate osteoclastic activity and compensate for increased bone resorption by binding RANKL and blocking RANK activation. Still, OPG does not seem to be a marker of bone turnover since serum OPG levels were normal in patients with acromegaly, as well as GHD (62). Furthermore, no changes in serum OPG were seen during GH substitution in aoGHD women (29) or elderly (63).…”

Section: Gh/igf-i and The Opg/rank/rankl Axismentioning

confidence: 95%

GH/IGF-I and bone resorption in vivo and in vitro

Ueland

2005

eur j endocrinol

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IGF-I may act as one of several coupling agents by activating bone formation and bone resorption. In vivo studies in normal subjects, postmenopausal women and patients with excess or diminished GH production (acromegaly and GHD) indicate that both GH and IGF-I activate osteoclasts, but that GH has a more pronounced effect, independently of IGF-I. In vitro, GH and IGF receptors have been demonstrated on osteoclasts and both GH and IGF-I may directly modify osteoclast function and activity. In addition to direct effects on osteoclasts, GH and IGF-I may affect bone resorption indirectly by stimulating release of paracrine mediators that regulate osteoclastic resorption (cytokines). Critical for the bone resorptive process is the balance between OPG and RANKL, which is regulated by many systemic factors. In vivo and in vitro, GH/IGF-I may modulate this balance but these studies are difficult to interpret, reflecting the complexity of this system. Increased OPG expression may possibly protect against GH/IGF-I-induced bone resorption and potentially be important for the long-term beneficial effects of GH replacement. Further studies investigating the OPG/RANKL ratio and system in experimental and transgenic GH/IGF models may clarify these issues.

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“…Also, the number of bleeding events was not sufficient for subgroup analysis, evaluating the association between osteoprotegerin levels and different types of bleeding. Finally, although we evaluated interactions between osteoprotegerin levels and outcomes by several subgroups (eg, diabetes mellitus status and type of ACS), increased osteoprotegerin levels have been observed in a wide range of diseases and comorbidities,23, 33 also associated with adverse outcome (eg, aortic stenosis33). Because we were unable to account for these diseases and comorbidities, we cannot exclude that they would influence our results.…”

Section: Discussionmentioning

confidence: 99%

“…The venous blood was centrifuged, and the plasma samples were locally frozen in aliquots and stored at −70°C in a central repository at Uppsala Biobank until biochemical analyses were performed. Osteoprotegerin concentrations were determined by enzyme‐linked immunoassay (R&D Systems, Stillwater, MN), as previously described and validated 23. Briefly, wells were coated overnight with monoclonal mouse anti‐human osteoprotegerin antibody in sterile PBS.…”

Section: Methodsmentioning

confidence: 99%

Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes: Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

Ueland

Åkerblom

Ghukasyan

et al. 2018

JAHA

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BackgroundElevated levels of osteoprotegerin, a secreted tumor necrosis factor–related molecule, might be associated with adverse outcomes in patients with coronary artery disease. We measured plasma osteoprotegerin concentrations on hospital admission, at discharge, and at 1 and 6 months after discharge in a predefined subset (n=5135) of patients with acute coronary syndromes in the PLATO (Platelet Inhibition and Patient Outcomes) trial.Methods and ResultsThe associations between osteoprotegerin and the composite end point of cardiovascular death, nonprocedural spontaneous myocardial infarction or stroke, and non–coronary artery bypass grafting major bleeding during 1 year of follow‐up were assessed by Cox proportional hazards models. Event rates of the composite end point per increasing quartile groups at baseline were 5.2%, 7.5%, 9.2%, and 11.9%. A 50% increase in osteoprotegerin level was associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI], 1.21–1.42) for the composite end point but was not significant in adjusted analysis (ie, clinical characteristics and levels of C‐reactive protein, troponin T, NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide], and growth differentiation factor‐15). The corresponding rates of non–coronary artery bypass grafting major bleeding were 2.4%, 2.2%, 3.8%, and 7.2%, with an unadjusted HR of 1.52 (95% CI, 1.36–1.69), and a fully adjusted HR of 1.26 (95% CI, 1.09–1.46). The multivariable association between the osteoprotegerin concentrations and the primary end point after 1 month resulted in an HR of 1.09 (95% CI, 0.89–1.33); for major bleeding after 1 month, the HR was 1.33 (95% CI, 0.91–1.96).ConclusionsIn patients with acute coronary syndrome treated with dual antiplatelet therapy, osteoprotegerin was an independent marker of major bleeding but not of ischemic cardiovascular events. Thus, high osteoprotegerin levels may be useful in increasing awareness of increased bleeding risk in patients with acute coronary syndrome receiving antithrombotic therapy.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

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Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess--possible role in bone homeostasis

Cited by 117 publications

References 30 publications

Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro

Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro

GH/IGF-I and bone resorption in vivo and in vitro

Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes: Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

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