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PubMed: 30505280

Title
α<sub>1</sub>-Microglobulin Protects Against Bleeding-Induced Oxidative Damage in Knee Arthropathies.
Journal
Frontiers in physiology
Volume
9
Issue
None
Pages
1596
Date
2018-01-01
Authors
Gram M | Larsson S | Lohmander LS | Struglics A | Åkerström B

Evidence 6acd0c3f9b
JSON

Expression and synthesis of A1M has been shown to be upregulated in cells after exposure to heme and ROS (Olsson et al., 2007, 2011).

a(CHEBI:heme) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

a(MESH:"Reactive Oxygen Species") positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence ed7cb01763
JSON

This is consistent with our findings here that both heme and Hb were associated with increased levels of synovial fluid A1M.

a(CHEBI:heme) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence fb6c55db12
JSON

These novel data support a role for A1M in the protection against oxidative damage due to extracellular Hb and heme in the joint in various knee arthropathies.

a(CHEBI:heme) increases path(HM:"Oxidative damage") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:HBB) increases path(HM:"Oxidative damage") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) decreases path(HM:"Oxidative damage") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence cda8d0d2a5
JSON

As a part of the inflammatory response after injury, oxidative stress due to formation of reactive oxygen species (ROS) is involved both in direct damage of cartilage components and as integral factors in cell signaling leading to cartilage degradation (Henrotin et al., 2003).

a(MESH:"Reactive Oxygen Species") positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

a(MESH:"Reactive Oxygen Species") increases bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

bp(GO:"inflammatory response") positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

bp(MESH:"Oxidative Stress") increases path(MESH:Osteoarthritis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence b2080b2b2f
JSON

However, with A1M increased in both synovial fluid and serum in AIA, the present study further suggests that, in addition to heme and ROS, A1M may be regulated by inflammatory cytokines.

a(MESH:Cytokines) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
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MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) positiveCorrelation a(MESH:Cytokines) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence 2657b911c2
JSON

Lately, much evidence has emerged to support a central role for participation of local inflammatory pathways in the disease processes (Scanzello, 2017), particularly so after knee injury (Goldring and Otero, 2011).

bp(GO:"inflammatory response") positiveCorrelation path(MESH:"Knee Injuries") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

path(MESH:"Knee Injuries") positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence f17fb73916
JSON

Oxidation of proteins result in stable carbonyl groups on amino acid side chains, and protein carbonyl content is one of the most widely used marker of protein oxidation and a general indicator of oxidative stress (Dalle-Donne et al., 2003).

bp(GO:"protein oxidation") positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

bp(MESH:"Oxidative Stress") positiveCorrelation bp(GO:"protein oxidation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence 7d13016300
JSON

Obesity, genetic factors, and aging are some of the most prominent risk factors (Sharma et al., 2006), and in the younger population, previous knee injury is an important contributor to increased prevalence of knee OA – as much as half of those sustaining a knee injury in their 20s had developed posttraumatic knee OA in the following 12 to 14 years (Lohmander et al., 2004, 2007; von Porat et al., 2004).

bp(GO:aging) positiveCorrelation path(MESH:"Osteoarthritis, Knee") View Subject | View Object

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Text Location
Introduction

bp(MESH:"Genetic Markers") positiveCorrelation path(MESH:"Osteoarthritis, Knee") View Subject | View Object

Appears in Networks:
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Text Location
Introduction

path(MESH:"Knee Injuries") positiveCorrelation path(MESH:"Osteoarthritis, Knee") View Subject | View Object

Appears in Networks:
Annotations
Text Location
Introduction

path(MESH:"Osteoarthritis, Knee") positiveCorrelation path(MESH:Obesity) View Subject | View Object

Appears in Networks:
Annotations
Text Location
Introduction

path(MESH:"Osteoarthritis, Knee") positiveCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
Text Location
Introduction

path(MESH:"Osteoarthritis, Knee") positiveCorrelation bp(MESH:"Genetic Markers") View Subject | View Object

Appears in Networks:
Annotations
Text Location
Introduction

path(MESH:"Osteoarthritis, Knee") positiveCorrelation path(MESH:"Knee Injuries") View Subject | View Object

Appears in Networks:
Annotations
Text Location
Introduction

path(MESH:Obesity) positiveCorrelation path(MESH:"Osteoarthritis, Knee") View Subject | View Object

Appears in Networks:
Annotations
Text Location
Introduction

Evidence aaa19e4d6b
JSON

In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress.

bp(MESH:"Oxidative Stress") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence e641b7a9c3
JSON

In addition to the obvious protective benefit of exogenous A1M binding and neutralizing cell-free Hb and heme, it may also be beneficial as a repair mechanism in already damaged cartilage, since in vitro studies showed that collagen fibrils were restored to normal by addition of recombinant A1M after destruction already had begun (Olsson et al., 2011).

bp(MESH:"Wound Healing") positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) positiveCorrelation bp(MESH:"Wound Healing") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence 498f87b9c8
JSON

Spontaneous decomposition of Hb via auto-oxidation leads to the formation of ROS, free heme groups and free iron, which are highly reactive and have the ability to damage lipids, proteins, and DNA (Olsson et al., 2012).

deg(p(HGNC:HBB)) positiveCorrelation complex(a(CHEBI:"iron(2+)"), a(CHEBI:heme), a(MESH:"Reactive Oxygen Species")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

complex(a(CHEBI:"iron(2+)"), a(CHEBI:heme), a(MESH:"Reactive Oxygen Species")) positiveCorrelation deg(p(HGNC:HBB)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence 8ef4ac8c22
JSON

On the extracellular level, within the circulation, haptoglobin (Hp) and hemopexin (Hpx) are two of the most prominent scavenger proteins, with antioxidative properties through their capacity to remove cell-free Hb (by Hp) and heme (by Hpx).

p(HGNC:HPX) decreases a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence 41abba760d
JSON

Another protein that in the last decade has been shown to play a central role as a protective protein against oxidative stress is a1-microglobulin (A1M) (Åkerström and Gram, 2014).

p(HGNC:AMBP) decreases bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence 862cb0c17b
JSON

Of particular interest for this investigation is that the expression of A1M has been shown to be up-regulated in several cells and tissues during oxidative stress conditions in response to elevated levels of ROS, Hb, and free heme (Olsson et al., 2007, 2011).

p(HGNC:AMBP) positiveCorrelation path(HM:"Oxidative damage") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

path(HM:"Oxidative damage") positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence 62e4b1e874
JSON

When adjusted for their respective absolute concentrations, the higher the proportion sf-A1M to sf-heme or sf-Hb, the less oxidative damage measured as protein carbonyl groups in synovial fluid.

p(HGNC:AMBP) decreases path(HM:"Oxidative damage") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence d44e66243f
JSON

Altogether, our best interpretation of these data is that increased levels of cell-free Hb and heme in synovial fluid early after injury triggered an increase in the synovial fluid A1M concentration that appeared to be protective of oxidative damage.

p(HGNC:AMBP) decreases path(HM:"Oxidative damage") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:"Knee Injuries") increases p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:"Knee Injuries") increases a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:"Knee Injuries") increases p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence efc2536215
JSON

The highest concentrations of A1M, both in synovial fluid and serum, were found in the AIA (Figure 1A).

p(HGNC:AMBP) positiveCorrelation path(MESH:Arthritis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Results

path(MESH:Arthritis) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Results

Evidence 89703a32bd
JSON

Our study extends those findings to include elevated A1M in both serum and synovial fluid as a biomarker of AIA, as suggested by the ROC-curves with AUCs close to 0.8.

p(HGNC:AMBP) positiveCorrelation path(MESH:Arthritis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:Arthritis) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence 3c3c6875f6
JSON

Finally, we note that in AIA A1M is increased both locally in the joint fluid and systemically in serum, whereas in knee injury A1M is increased only in the joint fluid.

p(HGNC:AMBP) positiveCorrelation path(MESH:Arthritis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) positiveCorrelation path(MESH:"Osteoarthritis, Knee") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:"Osteoarthritis, Knee") positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:Arthritis) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence 6eab4ef3a2
JSON

In serum, the A1M concentration in the AIA group was between 1.3- and 1.4-fold higher compared to the injury and osteoarthritis groups (p = 0.035 and 0.030, respectively), whereas the 1.2-fold higher mean concentration compared to the reference group was not statistically significan (p = 0.15; Figure 1A).

p(HGNC:AMBP) positiveCorrelation path(MESH:Hemorrhage) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Results

path(MESH:Hemorrhage) increases path(HM:"Oxidative damage") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Results

path(MESH:Hemorrhage) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Results

Evidence 9d627465fb
JSON

There are many examples of studies that have shown increased A1M in serum or urine to be a biomarker of diseases such as preeclampsia (Anderson et al., 2011, 2016; Gram et al., 2015), and kidney failure (Terzi et al., 2014; Kang et al., 2015).

p(HGNC:AMBP) positiveCorrelation path(HP:Preeclampsia) View Subject | View Object

Appears in Networks:
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MeSH
Serum
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:AMBP) positiveCorrelation path(MESH:"Kidney Failure, Chronic") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Serum
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(HP:Preeclampsia) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Serum
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:"Kidney Failure, Chronic") positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Serum
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence f4d3bcc9cc
JSON

In similarity with both studies, we found detectable concentrations of A1M in synovial fluid in subjects with knee OA.

p(HGNC:AMBP) positiveCorrelation path(MESH:"Osteoarthritis, Knee") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:"Osteoarthritis, Knee") positiveCorrelation p(HGNC:AMBP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

Evidence 3524c977d4
JSON

A major intracellular antioxidant is heme oxygenase-1 (HO-1) which, through its heme-degrading activity, plays a critical role in the protection of cells.

p(HGNC:HMOX1) increases deg(a(CHEBI:heme)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

Evidence 62a06a1fbf
JSON

Knee osteoarthritis (OA) is the most common joint disease and is a major cause of pain and disability in the older population worldwide (Liu et al., 2015).

path(MESH:"Osteoarthritis, Knee") positiveCorrelation path(MESH:Pain) View Subject | View Object

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Text Location
Introduction

path(MESH:Pain) positiveCorrelation path(MESH:"Osteoarthritis, Knee") View Subject | View Object

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Text Location
Introduction

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