A comparative study of serum and synovial fluid lipoprotein levels in patients with various arthritides

doi:10.1016/j.cca.2011.10.019

Clinica Chimica Acta

Volume 413, Issues 1–2, 18 January 2012, Pages 303-307

https://doi.org/10.1016/j.cca.2011.10.019 Get rights and content

Abstract

The aim of this study was to investigate apolipoprotein (apo) A-I, apo B, lipoprotein (Lp) (a), HDL-cholesterol (C), LDL-C, triglycerides (TG) and total cholesterol (TC) values in the serum and synovial fluid (SF) of untreated rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA) patients.

Methods

Paired SF and serum samples were collected simultaneously from 14 patients with RA, 14 with PsA, and 16 with OA and tested for apo A-I, apo B, HDL-C, LDL-C, Lp(a), TC and TG. Serum C reactive protein (CRP) and amyloid A (SAA) levels were also determined.

Results

The inflammatory arthritis patients had higher SF lipid levels with the exception of HDL. Reflecting increased synovial permeability, the lipid SF/serum ratio was always higher in RA and PsA with respect to OA patients. The positive correlation between serum and SF apo A-I, apo B, HDL-C, TG, and Lp(a) levels confirmed that there is lipoprotein diffusion into the SF.

RA and PsA patients had lower concentrations of all serum lipids except for Lp(a) with respect to OA patients. The levels in the RA patients were similar to those in healthy matched controls, while the PsA patients had significantly lower apo A-I and HDL levels and higher apo B and LDL values.

Conclusions

Lipid diffusion into the joint cavity, which largely depends on the degree of inflammation, may contribute to modulating local inflammatory processes.

Highlights

► Apolipoproteins, lipoproteins and lipids in synovial fluid of arthritis patients. ► Lipoproteins diffuse into the synovial fluid depending on the degree of inflammation. ► Higher synovial fluid lipid levels in inflammatory arthritis. ► The lipid synovial fluid/serum ratio reflects the synovial permeability. ► The lipid synovial fluid/serum ratio is always lower in osteoarthritis.

Introduction

Inflammatory arthritides, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are associated with multiple alterations in lipid metabolism [1]. It is widely held that acute-phase responses lead to higher serum triglyceride (TG) and lower HDL-cholesterol (HDL-C) concentrations.

Alterations in total cholesterol (TC) and LDL-cholesterol (LDL-C) also seem to occur. The wide range of fluctuations in lipid levels, which are mediated by cytokines, are connected to host defense and tissue repair [2], but when inflammation become chronic these alterations may contribute to the development of cardiovascular disease [3], [4].

It has been postulated that apolipoproteins (apo) and lipoproteins play an important role in modulating both acute and chronic inflammation [5]. HDL, in particular, has an antiinflammatory effect by inhibiting production of pro-inflammatory cytokines induced by T cell contact [6]. At the joint level, inflammation causes increased synovial permeability thereby allowing proteins and lipids to pass into the synovial fluid (SF).

We have recently demonstrated that patients affected with chronic inflammatory arthritides have higher apo A-I and TC SF levels, inversely correlated to local inflammatory indices such as white blood cell (WBC) count and IL-1ß, than do osteoarthritis (OA) patients [7].

Synovial lipoprotein concentrations appear to be correlated to their respective serum levels [8], but the interrelationship of synovial and serum values, their connection to synovial/systemic inflammation, and how individual lipids are affected have yet to be delineated.

The current work is an attempt to define in various arthritides the relationships between lipoproteins, inflammation severity, and synovial membrane permeability to single lipids, expressed as the ratio between synovial and serum concentrations. We have thus investigated SF and serum apo A-I, apo B, lipoprotein (Lp) (a), HDL-C, LDL-C, TG and TC levels in untreated RA, PsA, and OA patients.

Section snippets

Patients

Fourteen patients with RA, 14 with PsA, and 16 with OA attending the Outpatient Clinic of the Rheumatology Unit of the University of Padova Medical Center for diagnosis and/or treatment took part in this study. All the patients fulfilled the established diagnostic criteria for their respective diseases [9], [10], [11]. Patients with thyroid dysfunction, diabetes, renal disease, impaired hepatic function (aminotransferase levels > 2 × upper normal limits) or a history of alcohol abuse or smoking

Results

Patients' demographic and clinical characteristics as well as SF inflammatory indices are outlined in Table 1.

The age and disease duration in the OA, RA, and PsA groups were not significantly different. Serum CRP and SAA levels as well as SF WBC and PMN were significantly lower in the OA than in the RA and PsA patients (p < 0.05).

Discussion

Markedly different from those found in plasma, lipid levels are extremely low in normal human SF [13]. During inflammation, synovial permeability increases allowing proteins to enter the joint cavity. Depending on the degree of inflammation, protein SF/serum ratios increase reflecting diffusion of almost all proteins into the SF [14].

As far as larger molecules are concerned, both apo and lipoproteins seem to be able to flow through the synovial barrier and to enter into the SF cavity [8].

List of abbreviations

rheumatoid arthritis

PsA

psoriatic arthritis

osteoarthritis

HDL-C

high density lipoprotein-cholesterol

LDL-C

low density lipoprotein-cholesterol

total cholesterol

triglycerides

apo A-I

apolipoprotein A-I

apo B

apolipoprotein B

Lp(a)

lipoprotein (a)

synovial fluid

WBC

white blood cell

CRP

C-reactive protein

SAA

serum amyloid A

PMN

polymorphonuclear leukocytes

Acknowledgments

The authors are grateful to Mrs. Linda Inverso Moretti for editing the English version of this manuscript.

References (31)

E. Esteve et al.
Dyslipidemia and inflammation: an evolutionary conserved mechanism
Clin Nutr
(2005)
N. Busso et al.
Plasma apolipoprotein(a) co-deposits with fibrin in inflammatory arthritic joints
Am J Pathol
(2001)
P.E. Prete et al.
The contribution of synovial fluid lipoproteins to the chronic synovitis of rheumatoid arthritis
Prostaglandins
(1997)
L. Ananth et al.
Apolipoproteins A-I and B and cholesterol in synovial fluid of patients with rheumatoid arthritis
Metabolism
(1993)
J. Wang et al.
Native, oxidized lipoprotein(a) and lipoprotein(a) immune complex in patients with active and inactive rheumatoid arthritis: plasma concentrations and relationship to inflammation
Clin Chim Acta
(2008)
O. Kimhi et al.
Prevalence and risk factors of atherosclerosis in patients with psoriatic arthritis
Semin Arthritis Rheum
(2007)
N. Hyka et al.
Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes
Blood
(2001)
A.J. Wilhelm et al.
Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr−/−, ApoA-I−/− mice
J Biol Chem
(2010)
T.E. Toms et al.
Dyslipidaemia in rheumatoid arthritis: the role of inflammation, drugs, lifestyle and genetic factors
Curr Vasc Pharmacol
(2010)
L.S. Tam et al.
Cardiovascular risk profile of patients with psoriatic arthritis compared to controls—the role of inflammation
Rheumatology (Oxford)
(2008)

C. Han et al.

Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

J Rheumatol

(2006)

B. Bresnihan et al.

Apolipoprotein A-I infiltration in rheumatoid arthritis synovial tissue: a control mechanism of cytokine production?

Arthritis Res Ther

(2004)

L. Gruaz et al.

Blockade of T cell contact-activation of human monocytes by high-density lipoproteins reveals a new pattern of cytokine and inflammatory genes

PLoS One

(2010)

F. Oliviero et al.

Apolipoprotein A-I and cholesterol in synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis

Clin Exp Rheumatol

(2009)

F.C. Arnett et al.

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

Arthritis Rheum

(1988)

Cited by (67)

Metabolic phenotypes reflect patient sex and injury status: A cross-sectional analysis of human synovial fluid
2023, Osteoarthritis and Cartilage
Osteoarthritis is a heterogeneous disease. The objective was to compare differences in underlying cellular mechanisms and endogenous repair pathways between synovial fluid (SF) from male and female participants with different injuries to improve the current understanding of the pathophysiology of downstream post-traumatic osteoarthritis (PTOA).
SF from n = 33 knee arthroscopy patients between 18 and 70 years with no prior knee injuries was obtained pre-procedure and injury pathology assigned post-procedure. SF was extracted and analyzed via liquid chromatography-mass spectrometry metabolomic profiling to examine differences in metabolism between injury pathologies (ligament, meniscal, and combined ligament and meniscal) and patient sex. Samples were pooled and underwent secondary fragmentation to identify metabolites.
Different knee injuries uniquely altered SF metabolites and downstream pathways including amino acid, lipid, and inflammatory-associated metabolic pathways. Notably, sexual dimorphic metabolic phenotypes were examined between males and females and within injury pathology. Cervonyl carnitine and other identified metabolites differed in concentrations between sexes.
These results suggest that different injuries and patient sex are associated with distinct metabolic phenotypes. Considering these phenotypic associations, a greater understanding of metabolic mechanisms associated with specific injuries, sex, and PTOA development may yield data regarding how endogenous repair pathways differ between male and female injury types. Ongoing metabolomic analysis of SF in injured male and female patients can be performed to monitor PTOA development and progression.
Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases
2021, Cell Metabolism
High levels of cholesterol are generally considered to be associated with atherosclerosis. In the past two decades, however, a number of studies have shown that excess cholesterol accumulation in various tissues and organs plays a critical role in the pathogenesis of multiple diseases. Here, we summarize the effects of excess cholesterol on disease pathogenesis, including liver diseases, diabetes, chronic kidney disease, Alzheimer’s disease, osteoporosis, osteoarthritis, pituitary-thyroid axis dysfunction, immune disorders, and COVID-19, while proposing that excess cholesterol-induced toxicity is ubiquitous. We believe this concept will help broaden the appreciation of the toxic effect of excess cholesterol, and thus potentially expand the therapeutic use of cholesterol-lowering medications.
Novel high-intensive cholesterol-lowering therapies do not ameliorate knee OA development in humanized dyslipidemic mice
2021, Osteoarthritis and Cartilage
Citation Excerpt :
A recent meta-analysis found a significantly increased prevalence and risk of overall CVD in OA patients compared to non-OA controls3, while others did not observe this association4. Although some studies show that OA patients have significantly higher levels of LDL-C5,6, the role of an impaired lipid metabolism in OA pathology remains unclear. Increased total cholesterol (TC) levels were recently associated with increased risk of generalized OA1,7, while others found no association with LDL-C or TC8 and even describe protective effects of high-density lipoprotein cholesterol (HDL-C).
High systemic cholesterol levels have been associated with osteoarthritis (OA) development. Therefore, cholesterol lowering by statins has been suggested as a potential treatment for OA. We investigated whether therapeutic high-intensive cholesterol-lowering attenuated OA development in dyslipidemic APOE∗3Leiden.CETP mice.
Female mice (n = 13–16 per group) were fed a Western-type diet (WTD) for 38 weeks. After 13 weeks, mice were divided into a baseline group and five groups receiving WTD alone or with treatment: atorvastatin alone, combined with PCSK9 inhibitor alirocumab and/or ANGPTL3 inhibitor evinacumab. Knee joints were analysed for cartilage degradation, synovial inflammation and ectopic bone formation using histology. Aggrecanase activity in articular cartilage and synovial S100A8 expression were determined as markers of cartilage degradation/regeneration and inflammation.
Cartilage degradation and active repair were significantly increased in WTD-fed mice, but cholesterol-lowering strategies did not ameliorate cartilage destruction. This was supported by comparable aggrecanase activity and S100A8 expression in all treatment groups. Ectopic bone formation was comparable between groups and independent of cholesterol levels.
Intensive therapeutic cholesterol lowering per se did not attenuate progression of cartilage degradation in dyslipidemic APOE∗3Leiden.CETP mice, with minor joint inflammation. We propose that inflammation is a key feature in the disease and therapeutic cholesterol-lowering strategies may still be promising for OA patients presenting both dyslipidemia and inflammation.
Liver X receptors conserve the therapeutic target potential for the treatment of rheumatoid arthritis
2021, Pharmacological Research
Rheumatoid arthritis (RA) is a chronic multi-system autoimmune disease with extremely complex pathogenesis. Significantly altered lipid paradox related to the inflammatory burden is reported in RA patients, inducing 50% higher cardiovascular risks. Recent studies have also demonstrated that lipid metabolism can regulate many functions of immune cells in which metabolic pathways have altered. The nuclear liver X receptors (LXRs), including LXRα and LXRβ, play a central role in regulating lipid homeostasis and inflammatory responses. Undoubtedly, LXRs have been considered as an attractive therapeutic target for the treatment of RA. However, there are some contradictory effects of LXRs agonists observed in previous animal studies where both pro-inflammatory role and anti-inflammatory role were revealed for LXRs activation in RA. Therefore, in addition to updating the knowledge of LXRs as the prominent regulators of lipid homeostasis, the purpose of this review is to summarize the effects of LXRs agonists in RA-associated immune cells, to explore the underlying reasons for the contradictory therapeutic effects of LXRs agonists observed in RA animal models, and to discuss future strategy for the treatment of RA with LXRs modulators.
The influence of sample collection, handling and low temperature storage upon NMR metabolic profiling analysis in human synovial fluid
2021, Journal of Pharmaceutical and Biomedical Analysis
The impact of metabolism upon the altered pathology of joint disease is rapidly becoming recognized as an important area of study. Synovial joint fluid is an attractive and representative biofluid of joint disease. A systemic review revealed little evidence of the metabolic stability of synovial joint fluid collection, handling or storage, despite recent reports characterizing the metabolic phenotype in joint disease. We aim to report the changes in small molecule detection within human synovial fluid (HSF) using nuclear magnetic resonance (NMR) spectroscopy at varying storage temperatures, durations and conditions. HSF was harvested by arthrocentesis from patients with isolated monoarthropathy or undergoing joint replacement (n = 30). Short-term storage (0−12 h, 4°C & 18°C) and the effect of repeated freeze-thaw cycles (-80°C to 18°C) was assessed. Long-term storage was evaluated by early (-80°C, <21days) and late analysis (-80°C, 10−12 months). 1D NMR spectroscopy experiments, NOESYGPPR1D and CPMG identified metabolites and semi-quantification was performed. Samples demonstrated broad stability to freeze-thaw cycling and refrigeration of <4 h. Short-term room temperature or refrigerated storage showed significant variation in 2-ketoisovalerate, valine, dimethylamine, succinate, 2-hydroxybutyrate, and acetaminophen glucuronide. Lipid and macromolecule detection was variable. Long-term storage demonstrated significant changes in: acetate, acetoacetate, creatine, N,N-dimethylglycine, dimethylsulfone, 3-hydroxybutyrate and succinate. Changeable metabolites during short-term storage appeared to be energy-synthesis intermediates. Most metabolites were stable for the first four hours at room temperature or refrigeration, with notable exceptions. We therefore recommend that HSF samples should be kept refrigerated for no more than 4 hours prior to freezing at -80°C. Furthermore, storage of HSF samples for 10-12 months before analysis can affect the detection of selected metabolites.
S100 family proteins in inflammation and beyond
2020, Advances in Clinical Chemistry
Citation Excerpt :
S100A8 and S100A9 have been shown to promote synovial activation, cartilage degradation, and osteophyte formation [65,203,352] in a canonical Wnt pathway-dependent manner [353,354] and inhibition of S100A9 using paquinimod (ABR-215757) [355], reduces OA pathology [356]. Several studies have demonstrated higher serum levels of LDL in OA patients compared to healthy patients [357,358]. High LDL levels can aggravate OA pathology by inducing production of S100A8/A9 by activated macrophages leading to increased synovial activation, cartilage destruction and enthesophyte/osteophyte formation [359,360].
The S100 family proteins possess a variety of intracellular and extracellular functions. They interact with multiple receptors and signal transducers to regulate pathways that govern inflammation, cell differentiation, proliferation, energy metabolism, apoptosis, calcium homeostasis, cell cytoskeleton and microbial resistance. S100 proteins are also emerging as novel diagnostic markers for identifying and monitoring various diseases. Strategies aimed at targeting S100-mediated signaling pathways hold a great potential in developing novel therapeutics for multiple diseases. In this chapter, we aim to summarize the current knowledge about the role of S100 family proteins in health and disease with a major focus on their role in inflammatory conditions.

View all citing articles on Scopus

View full text

A comparative study of serum and synovial fluid lipoprotein levels in patients with various arthritides

Abstract

Methods

Results

Conclusions

Highlights

Introduction

Section snippets

Patients

Results

Discussion

List of abbreviations

Acknowledgments

Clin Nutr

Am J Pathol

Prostaglandins

Metabolism

Clin Chim Acta

Semin Arthritis Rheum

Blood

J Biol Chem

Dyslipidaemia in rheumatoid arthritis: the role of inflammation, drugs, lifestyle and genetic factors

Curr Vasc Pharmacol

Cardiovascular risk profile of patients with psoriatic arthritis compared to controls—the role of inflammation

Rheumatology (Oxford)

Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

J Rheumatol

Apolipoprotein A-I infiltration in rheumatoid arthritis synovial tissue: a control mechanism of cytokine production?

Arthritis Res Ther

Blockade of T cell contact-activation of human monocytes by high-density lipoproteins reveals a new pattern of cytokine and inflammatory genes

PLoS One

Apolipoprotein A-I and cholesterol in synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis

Clin Exp Rheumatol

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

Arthritis Rheum