Rheumatology 2016;55:16–24
doi:10.1093/rheumatology/kev270
Advance Access publication 31 July 2015
RHEUMATOLOGY
Review
High systemic levels of low-density lipoprotein
cholesterol: fuel to the flames in inflammatory
osteoarthritis?
Wouter de Munter1, Peter M. van der Kraan1, Wim B. van den Berg1 and
Peter L. E. M. van Lent1
R EV I E W
Abstract
There is increasing evidence that low-density lipoprotein (LDL) cholesterol plays a role in the pathology of
OA. Specifically, oxidized LDL (oxLDL), which has been shown to play an essential role during development of atherosclerosis, could be involved in processes such as synovial inflammation, cartilage destruction and bone deformations. OxLDL can activate synovial cells such as macrophages, endothelial cells
and synovial fibroblasts, resulting in release of growth factors, MMP and pro-inflammatory cytokines.
In this review article, we discuss the role of LDL and oxLDL in OA joint pathology and share our viewpoint
of possible mechanisms by which these proteins could influence the development and progression of OA.
The proposed theory could provide insight into the aetiopathology of OA and give rise to new potential
treatments.
Key words: osteoarthritis, cholesterol, low density lipoproteins, oxidized low density lipoproteins, metabolic
syndrome, synovium, inflammation, macrophages, joint pathology, statins.
Rheumatology key messages
High Levels of LDL-cholesterol are associated with development of (inflammatory) OA in both humans and mouse
OA models.
. Systemically lowering levels of oxidized LDL could be effective against inflammatory OA.
. Locally blocking oxidized LDL-mediated processes could be a potential therapy in OA patients.
.
Introduction
Already at the beginning of the last century, OA was seen
as a disease in which metabolic processes play a role. In
1937, Matthew B. Ray (senior physician of the British Red
Cross Clinic for Rheumatism) described OA patients as
‘well nourished individuals of a fairly robust type and frequently of a plethoric habit of body’ [1]. Fifty years earlier,
John Kent Spender of the Royal Mineral Water Hospital in
Bath, UK, described the first stage of OA as the early
synovial stage, hinting towards a theory in which synovial
pathology precedes other OA pathology, such as cartilage
damage and osteophyte formation [2]. During the 20th
century, however, OA was typically seen as a wearand-tear disease, and hardly any research was performed
concerning synovial involvement and systemic factors.
Nevertheless, over the past two decades, the paradigm
of OA has been shifting from a cartilage-specific disease
towards that of an organ disease, in which low-grade
inflammation and systemic pathology do play an important role. Several recent reviews discuss the role of
(systemic) inflammation in OA [3–5]. In this article, we postulate a role specifically for low-density lipoprotein (LDL)cholesterol in the pathology of inflammatory OA.
Methods
1
Experimental Rheumatology, Radboud University Medical Center,
Nijmegen, The Netherlands
Submitted 28 January 2015; revised version accepted 24 June 2015
Correspondence to: Peter L. E. M. van Lent, Radboud University
Medical Center, Experimental Rheumatology (272), PO Box 9101,
6500 HB Nijmegen, The Netherlands.
E-mail: [email protected]
Literature investigating the role of the metabolic syndrome, and specifically LDL-cholesterol, on innate
immunity was recapitulated and integrated with OA literature to form a literature-based hypothesis (Fig. 1). In
essence, we included literature based on (the combination
of) the search terms shown in Table 1 using the PubMed
! The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Pathological role of LDL in OA
FIG. 1 Hypothesized mechanism for aggravation of OA pathology by oxidized low-density lipoprotein
(A) OxLDL stimulation of chondrocytes results in MMP-3 secretion, COL10 production and increased mRNA expression
of ROS, Runx2 and VEGF. (B) Moreover, LDL-cholesterol can be oxidized during inflammatory OA, leading to activation
of synovial macrophages and endothelial cells. (C) These cells start to produce inflammatory and chemotactic factors,
stimulating monocyte influx and resulting in aggravated inflammation. (D) Additionally, oxLDL can stimulate fibroblasts to
produce catabolic enzymes and macrophages to produce growth factors such as TGF-b. COL10: type X collagen; EC:
endothelial cell; LDL: low-density lipoprotein; LOX-1: lectin-like oxLDL receptor-1; MCP-1: monocyte chemotactic protein 1; Mo: monocyte; MT: macrophage; oxLDL: oxidized low-density lipoprotein; Runx2: runt-related transcription
factor 2; ROS: reactive oxygen species; SR: scavenger receptor A/B.
TABLE 1 Basic search terms for literature
Disease
Determinant
Comparator
Outcome
Atherosclerosis
Osteoarthritis
Metabolic syndrome
Cholesterol
LDL
Oxidized LDL
Macrophages
Chondrocytes
Fibroblasts
Endothelial cells
Monocytes
Synovium
Cartilage
Bone
Inflammation
Infiltration
S100
Cytokines
Chemokines
Damage
Destruction
Metalloproteinases
Aggrecenases
Chondrogenesis
Osteophyte
Growth factors
Pain
Bone loss
LDL: low-density lipoprotein.
search engine. Non-English literature was excluded
from our search. The main focus of this hypothesis
article will be the effects of LDL and oxidized LDL
(oxLDL) on OA joint pathology, possible mechanisms by
which these proteins influence OA, and potential
treatments.
www.rheumatology.oxfordjournals.org
Risk factors for primary OA
OA is recognized as a disease that affects the whole joint,
including subchondral bone, ligaments, menisci, periarticular muscle, infrapatellar fat pad, synovial tissue and
articular cartilage [6, 7]. Articular cartilage mainly consists
17
Wouter de Munter et al.
of proteoglycans and collagen type II fibres, in which
chondrocytes are embedded. Homoeostasis of articular
cartilage is constantly balanced by complex interplay
between anabolic and catabolic processes. Failure to
maintain this balance (by either abnormal loading or
abnormal functioning of tissue) lies at the base of OA development and is characterized by release of cartilage
fragments, cytokines and catabolic enzymes that could
activate synovial cells and further enhance cartilage
degradation [7, 8]. OA is, however, not confined only to
the joint. Serum levels of proteins such as collagen type
II-associated products, COMP, MMPs, adipokines and
many more have been widely studied and shown to be
increased in OA patients compared with healthy controls
(extensively reviewed by Lotz et al. [9] and Hunter
et al.[10]). The Dutch Cohort Hip and Cohort Knee
(CHECK) study consists of early OA patients (aged between 45 and 65 years) who, on entry, had pain or stiffness of the knee or hip. They had not yet consulted their
physician for these symptoms, or the first appointment
occurred within 6 months before cohort entry. We recently
found that, even in these early patients, high plasma levels
of alarmins S100A8/100A9 (>200 ng/ml) increased odds
of disease progression (odds ratio 4.0) 2–5 years later,
whereas high ESR (up to 31 mm/h) and high levels
of CRP (up to 14 ng/l) were not predictive [11]. S100A8
(myeloid-related protein-8) and S100A9 (myeloid-related
protein-14) proteins are produced mainly by granulocytes,
monocytes and activated macrophages [12–14]. In addition to their function as inflammatory markers [15], these
proteins have also been shown to be involved in cartilage
damage and synovial activation during OA [16, 17].
Although most of the above-mentioned factors are
believed to be the result of, rather than causative for,
OA-related joint pathology, it suggests that OA is not
merely a local disease. The fact that basic inflammatory
markers, such as ESR and CRP, do not always reflect OA
pathology might preclude the disease as a common
inflammatory disease but does not exclude a systemic
component.
Moreover, there are systemic processes that have been
shown to increase the risk of primary human OA. Two of
these undeniably important risk factors are ageing and the
metabolic syndrome. Ageing could induce OA simply via
wear and tear, which means that long-term or excessive
loading locally increases vulnerability of the joint and, in
combination with systemic factors that increase susceptibility, such as weight and female sex, cause cartilage
damage [18]. Also, age could induce OA via chondrocyte
senescence. Shortening of telomerase length and
decrease of mitotic activity in chondrocytes limits the ability of these cells to form new cartilage [19], although this is
an unlikely cause of OA in a non-dividing tissue, such as
adult cartilage. A more recent theory is that, with age,
cartilage balance shifts from homeostasis towards terminal differentiation [20–23]. Finally, ageing also induces
low-grade systemic inflammation that could influence OA.
The word inflamm-ageing is often used these days,
describing a process in which continuous antigen load
18
acts as stressor and eventually results in low-grade systemic inflammation [24]. This low-grade inflammation is
coupled to increased levels of pro-inflammatory factors,
such as S100A8 and S100A9, that are also important
during OA processes [25].
A second important risk factor that is described for primary OA is the metabolic syndrome [26]. The metabolic
syndrome, also known as insulin resistance syndrome or
metabolic syndrome X, affects 22% of the United States
population, with a slightly higher prevalence in female
adults compared with males [27]. The metabolic syndrome includes a variety of conditions that, in combination, cause cardiovascular disease and diabetes. These
conditions are high blood pressure, decreased highdensity lipoprotein (HDL) levels, increased LDL and triglyceride levels, raised blood glucose levels and abdominal
obesity [28]. Obesity has been extensively associated with
OA, often leading to the theory that OA is induced via a
biomechanical link [29]; however, the association of obesity with development of OA in non-weight-bearing joints
[30–32] suggests a systemic mechanism, rather than plain
overloading. This, taken together with studies that report
no direct relation between obesity and OA [33, 34],
supports the recent theory in which the metabolic syndrome, rather than obesity itself, is seen as a risk factor
for OA [35, 36]. Obviously, the metabolic syndrome is
often accompanied by obesity and, in reality, both mechanisms (overloading and a systemic component) will contribute to initiation and aggravation of OA.
LDLs in OA
A study by Gierman et al. [37] showed a relationship
between metabolic stress and spontaneous development
of OA in mice. A high-fat diet increased cartilage damage
independently of body weight, and this effect could be
abolished by lowering cholesterol levels, suggesting a
cholesterol-mediated mechanism for cartilage damage
[37]. In a later study, this group also showed that a cholesterol-rich diet in a murine model for hyperlipidaemia and
atherosclerosis led to increased spontaneous cartilage
damage, further underlining an important role for total
cholesterol [38]. In both studies, the authors claim that
metabolic stress-induced inflammation is more likely to
be at the base of cholesterol-induced cartilage damage
than mechanical overload, because anti-inflammatory
intervention suppressed the development of OA. The evidence that atherosclerosis and OA are both associated
with the metabolic syndrome and that the cell types that
are important in the development of atherosclerosis (such
as macrophages and endothelial cells) [39] also play an
important role in OA pathology [40, 41] suggests that
LDL-cholesterol and LDL modifications (such as oxLDL)
play a role in OA pathology.
One of the features of the metabolic syndrome is
increased levels of LDL [42]. In the course of metabolic
syndrome, high levels of non-esterified fatty acids,
together with hyperinsulinaemia and low adiponectin
levels, provide substrate for increased production of
very low density lipoprotein (VLDL) in the liver. VLDL,
www.rheumatology.oxfordjournals.org
Pathological role of LDL in OA
with its associated apolipoprotein B, is converted to LDL
particles, which form the main transport vehicle of cholesterol from the liver to all other cells in the body.
Normally, HDL particles reverse cholesterol transport;
however, the metabolic syndrome is characterized by
low levels of HDL, thus resulting in increased LDL levels
[43]. LDL is internalized by cells via the LDL receptor
(LDLR), where it releases its cholesterol after lysosomal
hydrolysis. Cholesterol is an essential component of the
plasma membrane, serving a barrier function, modulating
fluidity and forming lipid rafts [44]. After taking up LDL,
LDLR production by the cell is decreased, blocking further
uptake of LDL and efficiently regulating intracellular cholesterol levels [45, 46]. As a result of this regulated LDL
uptake by cells and low levels of HDL, the serum levels of
LDL remain high in patients with the metabolic syndrome.
Although LDL has been extensively studied in the pathology of cardiovascular diseases [47, 48], it has gained
relatively little attention in clinical OA research.
Comparative analysis of serological parameters has
demonstrated that OA patients have significantly higher
serum LDL levels compared with age-, sex- and BMImatched healthy controls [49, 50].
Also in mice there is evidence that LDL is related to OA
pathology. Recently, we observed that increased LDL
levels (by LDLR deficiency or a cholesterol-rich diet), in
a model for inflammatory OA, increased pathology. Mice
with enhanced LDL levels showed increased synovial
S100A8 production and TGF-b signalling, suggesting synovial activation. Furthermore, we observed increased
ectopic bone formation, both at the bone margins and in
the collateral ligaments, due to increased levels of LDL
[51]. Although we proposed in that study a specific role
for oxLDL, the main focus was the indirect effects of high
LDL levels on OA processes. In vivo experiments specifically directed to oxLDL or oxLDLRs in the joint could provide conclusive evidence of oxLDL involvement.
Oxidation of LDL and its effects on
cellular level
A variety of factors have been proposed to induce LDL
oxidation [e.g. sphingomyelinase, reactive oxygen species
(ROS), secretory phospholipase-2, other lipases and
MPO]. Although the precise mechanism by which LDL is
oxidized in vivo is unknown, ROS is generally seen as the
main suspect [52–54]. OxLDL can be taken up by endothelial cells, fibroblasts and macrophages, among others,
via scavenger receptors (SR) such as SR-A [55], CD36
(SR-B) [56] and lectin-type oxLDL receptor 1 (LOX-1;
SR-E) [57, 58]. As these receptors lack the self-regulating
mechanism of LDLR, high levels of oxLDL could have farreaching effects on the cells that take up these molecules.
Different cell types have been described to respond upon
oxLDL uptake. Fibroblast stimulation by oxLDL is mainly
mediated via LOX-1, inducing production of MMP-1 and
MMP-3 [59]. Also, endothelial cells can be activated by
oxLDL via LOX-1, resulting in increased expression of
leucocyte adhesion molecules and enhanced secretion
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of chemoattractants such as chemokine (C-C motive)
ligand 2 [CCL2, also referred to as monocyte chemotactic
protein 1(MCP-1)] [60]. Mostly described, however, is
oxLDL uptake by macrophages via SR-A and CD36. A
review by Maiolino et al. [61] thoroughly discusses the
role of oxLDL uptake by macrophages and the different
effects on inflammation. Uptake of oxLDL by macrophages causes production of pro-inflammatory mediators
such as IL-6, IL-8, MCP-1 and S100A8/9 [51, 62], matrixdegrading proteinases MMP-1 and MMP-3 [63] and
growth factors such as TGF-b [51]. Very recently,
Hossain et al. [64] also reported that LOX-1, which is
normally expressed in relatively low levels on macrophages, potentially plays an important role in oxLDL
uptake by macrophages. Toll-like receptor 4-stimulation
strongly up-regulates surface expression of LOX-1 in
macrophages, resulting in elevated oxLDL uptake.
In addition to synovial cells, it has also been described
that chondrocytes exhibit LOX-1 receptors [65, 66].
Stimulation of chondrocytes by oxLDL results in intracellular ROS production [67], mediates intracellular MMP-3
accumulation and secretion [68] and up-regulates mRNA
levels of VEGF and mRNA and protein levels of MCP-1
[69, 70] (Fig. 1, mechanism A). Furthermore, Kishimoto
et al. [71] show that bovine chondrocytes, cultured with
oxLDL, increase expression of runt-related transcription
factor 2, resulting in hypertrophic, type X collagenproducing chondrocytes, thereby suggesting a possible
molecular mechanism by which oxLDL could lead to
terminal chondrocyte differentiation and cartilage destruction. Nevertheless, studies investigating the effect of
oxLDL directly on chondrocytes are scarce and are confined to in vitro experiments.
Oxidized LDL as a potential inducer of
OA pathology
Given that the same cells that have been described as
being affected by oxLDL in cardiovascular diseases,
such as macrophages, endothelial cells and fibroblasts,
are dominant cells within synovium, we postulate that
oxLDL can play an important role in OA pathology. A substantial population of OA patients develops synovitis, in
which cells such as synovial macrophages are suggested
to play a key role [3, 40, 72–74]. OxLDL could therefore be
a strong modulator of OA pathology. Figure 1 depicts a
putative pathway showing how oxLDL influences OA
pathology via activation of synovial cells. Increased
levels of oxLDL activate synovial cells such as macrophages, fibroblasts and endothelial cells via SRs (Fig. 1,
mechanism B). These cells are than able to produce inflammatory and chemotactic factors, stimulating monocyte influx and resulting in aggravated inflammation
(Fig. 1, mechanism C) [59, 60, 62, 63]. In mice, we have
already shown that increased accumulation of modified
LDL in synovium is associated with increased production
of S100A8 and S100A9 [51]. Additionally, oxLDL could
stimulate synovial fibroblasts to produce catabolic
enzymes, as described by Ishikawa et al. [59] and
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Wouter de Munter et al.
TABLE 2 Evidence for involvement of low-density lipoprotein in OA (in order of appearance in main text)
Reference
Gierman et al. [37]
Gierman et al. [38]
Mishra et al. [49];
Oliviero et al. [50]
de Munter et al. [51]
Ishikawa et al. [59]
Sawamura et al. [60]
van Tits et al. [62]
Galis et al. [63]
de Munter et al. [51]
Nishimura et al. [67]
Kakinuma et al. [68]
Kanata et al. [69]
Akagi et al. [70]
Kishimoto et al. [71]
Gierman et al. [38]
Wei et al. [88]
Akasaki et al. [90]
Aktas et al. [91]
Clockaerts et al. [93];
Kadam et al. [94];
Valdes et al. [95]
Beattie et al. [96];
Riddle et al. [97]
Evidence
Species
Lowering cholesterol levels decreases cartilage damage during spontaneous OA
A cholesterol-rich diet increases spontaneous cartilage damage
OA patients have higher serum LDL levels than healthy controls
Mouse
Mouse
Human
High LDL levels result in increased synovial TGF-b signalling, S100A8/9
production and ectopic bone formation during experimental OA
In vitro fibroblast stimulation with oxLDL increases MMP-1 and MMP-2
production
In vitro endothelial cell stimulation with oxLDL increases leucocyte adhesion molecules and enhances secretion of CCL2
In vitro macrophage stimulation with oxLDL causes production of IL-6,
IL-8, CCL2, S100A8/9, MMP-1, MMP-3 and TGF-b
In vitro macrophage stimulation with oxLDL causes production of MMP-1
and MMP-3
In vitro macrophage stimulation with oxLDL causes production of S100A8/
9 and TGF-b
In vitro chondrocyte stimulation with oxLDL induces intracellular ROS
production
Ex vivo chondrocyte stimulation with oxLDL induces MMP-3 accumulation
and secretion
In vitro chondrocyte stimulation with oxLDL induces VEGF expression
In vitro chondrocyte stimulation with oxLDL induces CCL-2 production
In vitro chondrocyte stimulation with oxLDL induces Runx2 expression and
type X collagen production
Atorvastatin diminishes OA severity, ezetimibe (non-statin) does not
Simvastatin does not affect cartilage damage
Mevastatin reduces cartilage damage in experimental OA
Simvastatin diminishes inflammation in experimental knee OA
Statins are beneficial for OA patients
Mouse
Mouse
Mouse
Rabbit
Rat
Human
Statins do not affect disease outcome in OA patients
Human
Human
Human
Human
Rabbit
Mouse
Bovine
Human
Bovine
Human
Bovine
CCL: C-C motive ligand; LDL: low-density lipoprotein; oxLDL: oxidized low-density lipoprotein; ROS: reactive oxygen species;
Runx2: runt-related transcription factor 2.
stimulate lining macrophages to produce growth factors
such as TGF-b [51] (Fig. 1, mechanism D). These processes could then aggravate synovial inflammation, cartilage destruction and ectopic bone formation, eventually
increasing oxidative stress and resulting in a vicious cycle
of increased OA pathology.
Treatment
Much is still unknown about the exact role of oxLDL in
inflammatory OA; nevertheless, involvement of oxLDL
in OA pathology stands to reason. This creates new
opportunities for possible therapies. To date, no drug
has been consistently found to have modifying effects
on the structural progression of OA. While cytokine targeting has been shown to be an effective treatment in RA,
there is little evidence that this is also the case in OA.
Studies focusing on biologics in OA, such as anti-IL-1
[75–82] and anti-TNF [83, 84], show no convincing therapeutic effects. Hence, current therapies (predominantly
involving analgesics and NSAIDs) focus merely on symptomatic relief [85]. More insight into OA progression, and
20
the possible role of (ox)LDL, may provide new leads for
effective therapies.
Considering a role for LDL-cholesterol in the development of OA, the use of statins would be one of the most
obvious therapies. Statins lower cholesterol biosynthesis
and thus systemic levels of LDL. In mice, the statin atorvastatin (lowering cholesterol biosynthesis) could diminish
the severity of OA in cholesterol-induced joint pathology,
whereas the total-cholesterol-lowering non-statin ezetimibe (limited to inhibiting cholesterol uptake in the intestine) could not [38]. Given that it has been described that
statins, in addition to specifically lower serum LDL levels,
also reduce development of atherosclerosis by modulating oxLDL-mediated pathology [86, 87], the theory arises
that specifically LDL-cholesterol and LDL modifications
(such as oxLDL) play a role in OA pathology.
Interestingly, another study by the same group showed
no effect on cartilage destruction by the statin simvastatin
in the spontaneous OA model in SRT/Ort mice [88]. It is
important to mention, however, is that these specific STR/
Ort mice display abnormal lipidaemic symptoms that
could interfere with statin treatment [89]. Also, several
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Pathological role of LDL in OA
other in vivo animal studies show beneficial effects of statins on cartilage degradation in animal OA models [90, 91];
however, evidence of beneficial effects in human OA is
scarce [92]. A Dutch prospective population-based
cohort study [93] and two studies from the UK [94, 95]
show positive effects of statins, whereas two studies
from the USA do not show beneficial effects [96, 97].
The controversies regarding statin use as a treatment for
OA could be explained by the assumption that, besides
high LDL-cholesterol levels, specific oxidative triggers
also play a role in OA pathology; emphasizing that high
LDL levels alone are not enough to induce/aggravate OA
without oxidation.
Perhaps combining statin treatment with antioxidants
could result in decreased OA morbidity; however,
even in atherosclerosis, where oxLDL involvement is
apparent, a beneficial role for antioxidants has not been
proved [98, 99].
Specifically blocking the mechanism by which oxLDL
could lead to joint pathology might be a better option.
For example, locally blocking SRs, which are the main
receptors for oxLDL, could stop uptake of oxLDL by
synovial cells and prevent progression of OA. It would
be worthwhile to investigate the role of SR inhibition in
OA pathology.
Conclusion
In this viewpoint article, we discuss the increasing in vitro
and animal model-based evidence that LDL-cholesterol
plays a role in OA pathology. Specifically, oxidized LDL,
which has been shown to play an essential role during development of atherosclerosis, could be involved in processes
such as synovial inflammation, cartilage destruction and ectopic bone formation (Table 2). Lowering local levels of
oxLDL could be an effective treatment strategy in early OA.
In vivo studies focusing on the direct role of oxLDL during OA
and local blocking of oxLDL-mediated processes could give
more insight into the role of oxLDL and could provide new
leads for effective treatment of patients with OA.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.
Disclosure statement: The authors have declared no
conflicts of interest.
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