INT158978

Context Info Confidence 0.78 First Reported 2004 Last Reported 2009 Negated 0 Speculated 0 Reported most in Body Documents 19 Total Number 21 Disease Relevance 11.80 Pain Relevance 3.32

signal transduction (TNFRSF11B) extracellular region (TNFRSF11B) proteinaceous extracellular matrix (TNFRSF11B) extracellular matrix organization (TNFRSF11B)

Anatomy Link Frequency neutrophils 7 osteoblasts 4 chondrocytes 1 peritoneal fluid 1 plasma 1 TNFRSF11B (Homo sapiens)

Pain Link Frequency Relevance Heat Osteoarthritis 142 99.38 cytokine 142 98.96 rheumatoid arthritis 437 98.76 Pain 25 97.36 Inflammation 250 94.32 endometriosis 5 94.28 visual analogue scale 2 82.96 metalloproteinase 10 81.20 Pain score 1 78.08 antagonist 19 71.56

Disease Link Frequency Relevance Heat Osteoporosis 320 100.00 Cancer 271 100.00 Necrosis 79 100.00 Osteoarthritis 143 99.38 Rheumatoid Arthritis 437 98.76 Osteolysis 48 97.82 Pain 21 97.36 Apoptosis 72 96.88 Reprotox - General 3 3 95.98 INFLAMMATION 246 94.32

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Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

CONCLUSION: Pronounced effects of celecoxib on cell viability (reduction), oxygen consumption (stimulation), GLUT-1 mRNA expression (stimulation) and OPG protein secretion (inhibition) in osteoblastic cells were observed only at 50microM-a concentration not reached by therapeutic doses giving plasma concentrations less than 10microM.

Localization (secretion) of OPG in plasma

1) Confidence 0.78 Published 2009 Journal Clin. Exp. Rheumatol. Section Body Doc Link 19327236 Disease Relevance 0 Pain Relevance 0

We also showed that celecoxib at 50microM significantly inhibits OPG protein secretion leading to a compensative increase of mRNA expression.

Localization (secretion) of OPG

2) Confidence 0.78 Published 2009 Journal Clin. Exp. Rheumatol. Section Body Doc Link 19327236 Disease Relevance 0.05 Pain Relevance 0

Effects on cellular oxygen consumption were measured amperometrically using a Clark electrode. mRNA expression of GLUT-1 and OPG was determined by RT-PCR; OPG protein secretion by ELISA and HIF-1alpha protein expression by immunoblotting.

Localization (secretion) of OPG

3) Confidence 0.78 Published 2009 Journal Clin. Exp. Rheumatol. Section Body Doc Link 19327236 Disease Relevance 0.08 Pain Relevance 0

We previously demonstrated that OA subchondral bone osteoblasts can be discriminated into two subgroups and that both OPG and RANKL expression levels, and consequently the expression ratio of OPG/RANKL, differ according to the metabolic state of human OA subchondral bone osteoblasts: OPG/RANKL is decreased in L- and increased in H-OA osteoblasts[11].

Localization (decreased) of OPG in osteoblasts associated with osteoarthritis

4) Confidence 0.74 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC2246236 Disease Relevance 0.95 Pain Relevance 0.40

Endometriosis affects 10-20% of women during reproductive age and is a common cause of infertility and pain leading to work absenteeism and reduced quality of life.The objective of this study was to investigate the association between the presence and concentration of interleukin-8 (IL-8), RANTES, osteoprotegerin (OPG), pregnancy-associated plasma protein A (PAPP-A), tumour necrosis factor-alpha (TNF-alpha), midkine and glycodelin in the peritoneal fluid (PF) and the intensity of pain reported by patients undergoing laparoscopy in our clinic.

Localization (midkine) of osteoprotegerin in peritoneal fluid associated with pain, endometriosis, necrosis, reprotox - general 3 and cancer

5) Confidence 0.73 Published 2009 Journal Gynecol. Endocrinol. Section Abstract Doc Link 19903048 Disease Relevance 1.17 Pain Relevance 0.76

In contrast, PBMLs cultured under similar conditions secreted RANK-L and OPG in the supernatants (data not shown), confirming that neutrophils and PBMLs expressed RANK-L and OPG differently.

Localization (secreted) of OPG in neutrophils

6) Confidence 0.71 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1906801 Disease Relevance 0.29 Pain Relevance 0.18

The high concentrations of OPG measured in SF from patients with RA (see Results section) could be related to the capacity of neutrophils, which are present in large numbers, to release OPG (Figure 2c).

Localization (release) of OPG in neutrophils associated with rheumatoid arthritis

7) Confidence 0.62 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1906801 Disease Relevance 0.63 Pain Relevance 0.26

Incubation of healthy blood neutrophils in CM or SM conditions for up to 3 days did not modify the membrane expression of RANK-L as evaluated by cytofluorometry and did not stimulate the release of detectable amounts of OPG in neutrophil supernatants as measured by EIA (data not shown).

Localization (release) of OPG in neutrophil

8) Confidence 0.62 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1906801 Disease Relevance 0.06 Pain Relevance 0.03

In vitro, the maximal concentration of OPG released by neutrophils in the presence of IL-4, TNF-?

Localization (released) of OPG in neutrophils

9) Confidence 0.62 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1906801 Disease Relevance 0.79 Pain Relevance 0.26

Moreover, the same SF neutrophils obtained from patients with RA and incubated for up to 4 days in CM showed a time-dependent release and accumulation of OPG in supernatants (Figure 2c).

Localization (release) of OPG in neutrophils associated with rheumatoid arthritis

10) Confidence 0.57 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1906801 Disease Relevance 0.72 Pain Relevance 0.36

In vitro, the maximal concentration of OPG released by neutrophils in the presence of IL-4, TNF-?

Localization (released) of OPG in neutrophils

11) Confidence 0.57 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1906801 Disease Relevance 0.79 Pain Relevance 0.26

In contrast, SF neutrophils from patients with RA not only express the membrane-associated form of RANK-L but also express RANK and secrete OPG.

Localization (secrete) of OPG in neutrophils associated with rheumatoid arthritis

12) Confidence 0.54 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1906801 Disease Relevance 0.59 Pain Relevance 0.29

M-CSF and OPG are produced and released by activated osteoblasts, chondrocytes, and fibroblasts [2, 4–6].

Localization (released) of OPG in osteoblasts

13) Confidence 0.35 Published 2009 Journal Mediators of Inflammation Section Body Doc Link PMC2829618 Disease Relevance 0.19 Pain Relevance 0.08

Osteolysis is characterized by an increase in the ratio of RANKL to OPG; tumor-secreted factors that have been implicated in osteolysis increase this ratio by up-regulating the RANKL expression on osteoblasts/stromal cells or by downregulating OPG secretion [26,34,41].

Localization (secretion) of OPG in stromal cells associated with cancer and osteolysis

14) Confidence 0.32 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1924520 Disease Relevance 1.45 Pain Relevance 0.05

Osteoprotegerin (OPG) is a secreted soluble member of the tumor necrosis factor receptor superfamily (TNFR), also known as osteoclastogenesis inhibitory factor (OCIF) 54,55.

Localization (secreted) of OPG associated with necrosis and cancer

15) Confidence 0.30 Published 2004 Journal International Journal of Medical Sciences Section Body Doc Link PMC1074710 Disease Relevance 0.51 Pain Relevance 0

Osteoprotegerin (OPG) is a secreted soluble member of the tumor necrosis factor receptor superfamily (TNFR), also known as osteoclastogenesis inhibitory factor (OCIF) 54,55.

Localization (secreted) of Osteoprotegerin associated with necrosis and cancer

16) Confidence 0.30 Published 2004 Journal International Journal of Medical Sciences Section Body Doc Link PMC1074710 Disease Relevance 0.51 Pain Relevance 0

OPG – the third member of the triad – is a secreted TNF receptor that acts as a soluble decoy receptor for RANKL and TNF-related apoptosis-inducing ligand (TRAIL) [39,40].

Localization (secreted) of OPG associated with apoptosis

17) Confidence 0.30 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1924520 Disease Relevance 0.62 Pain Relevance 0.03

M-CSF and OPG are produced and released by activated osteoblasts, chondrocytes, and fibroblasts [2, 4–6].

Localization (released) of OPG in fibroblasts

18) Confidence 0.12 Published 2009 Journal Mediators of Inflammation Section Body Doc Link PMC2829618 Disease Relevance 0.19 Pain Relevance 0.08

M-CSF and OPG are produced and released by activated osteoblasts, chondrocytes, and fibroblasts [2, 4–6].

Localization (released) of OPG in chondrocytes

19) Confidence 0.12 Published 2009 Journal Mediators of Inflammation Section Body Doc Link PMC2829618 Disease Relevance 0.19 Pain Relevance 0.08

Osteolysis is characterized by an increase in the ratio of RANKL to OPG; tumor-secreted factors that have been implicated in osteolysis increase this ratio by up-regulating the RANKL expression on osteoblasts/stromal cells or by downregulating OPG secretion [26,34,41].

Localization (secretion) of OPG in osteoblasts associated with cancer and osteolysis

20) Confidence 0.11 Published 2007 Journal Arthritis Res Ther Section Body Doc Link PMC1924520 Disease Relevance 1.45 Pain Relevance 0.05

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