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2017
Osteoarthritis: toward a comprehensive understanding of Osteoarthritis: toward a comprehensive understanding of
pathological mechanism pathological mechanism
Di Chen
Rush University Medical Center
Jie Shen
Washington University School of Medicine in St. Louis
Weiwei Zhao
The University of Hong Kong
Tingyu Wang
Shanghai JiaoTong University School of Medicine
Lin Han
Drexel University
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Recommended Citation Recommended Citation
Chen, Di; Shen, Jie; Zhao, Weiwei; Wang, Tingyu; Han, Lin; Hamilton, John L.; and Im, Hee-Jeong,
,"Osteoarthritis: toward a comprehensive understanding of pathological mechanism." Bone Research. 5,. .
(2017).
https://digitalcommons.wustl.edu/open_access_pubs/5587
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OPEN
REVIEW ARTICLE
Osteoarthritis: toward a comprehensive understanding of
pathological mechanism
Di Chen
1
, Jie Shen
2
, Weiwei Zhao
1,3
, Tingyu Wang
4
, Lin Han
5
, John L Hamilton
1
and Hee-Jeong Im
1
Osteoarthritis (OA) is the most common degenerative joint disease and a major cause of pain and disability in
adult individuals. The etiology of OA includes joint injury, obesity, aging, and heredity. However, the
detailed molecular mechanisms of OA initiation and progression remain poorly understood and, currently,
there are no interventions available to restor e degraded cartilage or decelerate disease progression. The
diathrodial joint is a complicated organ and its function is to bear weight, perform physical activity and
exhibit a joint-specific range of motion during movement. During OA development, the entire joint organ is
affected, including articular cartilage, subchondral bone, synovial tissue and meniscus. A full understanding
of the pathological mechanism of OA development relies on the discovery of the interplaying mechanisms
among different OA symptoms, including articular cartilage degradation, osteophyte formation, subchondral
sclerosis and synovial hyperplasia, and the signaling pathway(s) controlling these pathological processes.
Bone Research (2017) 5, 16044; doi:10.1038/boneres.2016.44; published online: 17 January 2017
INTRODUCTION
Osteoarthritis (OA) is the most common degenerative joint
disease, affecting more than 25% of the population over 18
years-old. Pathological changes seen in OA joints include
progressive loss and destruction of articular cartilage,
thickening of the subchondral bone, formation of osteo-
phytes, variable degrees of inflammation of the synovium,
degeneration of ligaments and menisci of the knee and
hypertrophy of the joint capsule.
1
The etiology of OA is
multi-factorial and includes joint injury, obesity, aging, and
heredity.
1–5
Because the molecular mechanisms involved
in OA initiation and progression remain poorly understood,
there are no current interventions to restore degraded
cartilage or decelerate disease progression. Studies using
genetic mouse models suggest that growth factors,
including transforming growth factor-β (TGF-β), Wnt3a and
Indian hedgehog, and signaling molecules, such as
Smad3, β-catenin and HIF-2α,
6–10
are involved in OA
development. One feature common to several OA animal
models is the upregulation of Runx2.
7–8,11–13
Runx2 is a key
transcription factor directly regulating the transcription of
genes encoding matrix degradation enzymes in articular
chond rocytes.
14–17
In this review article, we will discuss the
etiology of OA, the available mouse models for OA
research and current techniques used in OA studies. In
addition, we will also summarize the recent progress on
elucidating the molecular mechanisms of OA pain. Our
goal is to provide readers a comprehensive coverage on
OA research approaches and the most up-to-date
progress on understanding the molecular mechanism of
OA development.
ETIOLOGY
OA is the most prevalent joint disease associated with pain
and disability. It has been forecast that 25% of the adult
population, or more than 50 million people in the US, will be
affected by this disease by the year 2020 and that OA will
be a major cause of morbidity and physical limitation
among individuals over the age of 40.
18–19
Major clinical
symptoms include chronic pain, joint instability, stiffness and
1
Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA;
2
Department of Orthopaedic Surgery, Washington University, St
Louis, MO, USA;
3
Department of Orthopaedics & Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
4
Department of Pharmacy, Shanghai Ninth People ’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China and
5
School of
Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA
Correspondence: Di Chen (di_chen@rush.edu)
Received: 4 August 2016; Revised: 2 September 2016; Accepted: 8 September 2016
Citation: Bone Research (2017) 5, 16044; doi:10.1038/boneres.2016.44
www.nature.com/boneres
radiographic joint space narrowing.
20
Although OA primar-
ily affects the elderly, sports-related traumatic injuries at all
ages can lead to post-traumatic OA. Currently, apart from
pain management and end stage surgical intervention,
there are no effective therapeutic treatments for OA. Thus,
there is an unmet clinical need for studies of the etiology
and alternative treatments for OA. In recent years, studies
using the surgically induced destabilization of the medial
meniscus (DMM) model and tissue or cells from human
patients demonstrated that genetic, mechanical, and
environmental factors are associated with the develop-
ment of OA. At the cellular and molecular level, OA is
characterized by the alteration of the healthy homeostatic
state toward a catabolic state.
Aging
One of the most common risk factors for OA is age. A
majority of people over the age of 65 were diagnosed with
radiographic changes in one or more joints.
21–25
In addition
to cartilage, aging affects other joint tissues, including
synovium, subchondral bone and muscle, which is thought
to contribute to changes in joint loading. Studies using
articular chondrocytes and other cells suggest that aging
cells show elevated oxidative stress that promotes cell
senescence and alters mitochondrial function.
26–29
In a
rare form of OA, Kashin-Back disease, disease progression
was associated with mitochondrial dysfunction and cell
death.
30
Another hallmark of aging chondrocytes is
reduced repair response, partially due to alteration of the
receptor expression pattern. In chondrocytes from aged
and OA cartilage, the ratio of TGF-β receptor ALK1 to ALK5
was increased, leading to down-regulation of the TGF-β
pathway and shift from matrix synthesis activity to cata-
bolic matrix metalloproteinase (MMP) expression.
31–32
Recent studies also indicate that methylation of the entire
genomic DNA displayed a different signature pattern in
aging cells.
33–34
Genome-wide sequencing of OA patients
also confirmed that this epigenetic alteration occurred in
OA chondrocytes,
35–37
partially due to changes in expres-
sion of Dnmts (methylation) and Tets (de-methylation)
enzymes.
38–40
Obesity
In recent years, obesity has become a worldwide epi-
demic characterized by an increased body composition
of adipose tissue. The association between obesity and OA
has long been recognized.
41–42
Patients with obesity
develop OA earlier and have more severe symptoms,
higher risk for infection and more technical difficulties for
total joint replacement surgery. In addition to increased
biomechanical loading on the knee joint, obesity is thought
to contribute to low-grade systemic inflammation through
secretion of adipose tissue-derived cytokines, called
adipokines.
43–45
Specifically, levels of pro-inflammatory
cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor
necrosis factor alpha (TNF-α) were elevated
46–50
in high-fat
diet-induced mouse obesity models
51–54
and in obese
patients.
55–57
These inflammatory factors may trigger the
nuclear factor-κB(NF-κB) signaling pathway to stimulate an
articular chondrocyte catabolic process and lead to
extracellular matrix (ECM) degradation through the upre-
gulation of MMPs.
58–60
Sport injury
Knee injury is the major cause of OA in young adults,
increasing the risk for OA more than four times. Recent
clinical reports showed that 41%–51% of participants with
previous knee injuries have radiographic signs of knee OA
in later years.
61
Cartilage tissue tear, joint dislocation and
ligament strains and tears are the most common injuries
seen clinically that may lead to OA. Trauma-related sport
injuries can cause bone, cartilage, ligament, and meniscus
damage, all of which can negatively affect joint
stabilization.
62–66
Signs of inflammation observed in both
patients with traumatic knee OA and in mouse injury
models include increased cytokine and chemokine pro-
duction, synovial tissue expansion, inflammatory cell infiltra-
tion, and NF-κB pathway activation.
67
Inflammation
It has been established that the chronic low-grade
inflammation found in OA contributes to disease develop-
ment and progression. During OA progression, the entire
synovial joint, including cartilage, subchondral bone, and
synovium, are involved in the inflammation process.
68
In
aging and diabetic patients, conventional inflammatory
factors, such as IL-1β and TNF-α,aswellaschemokines,
were reported to contribute to the systemic inflammation
that leads to activation of NF-κB signaling in both synovial
cells and chondrocytes. Innate inflammatory signals were
also involved in OA pathogenesis, including damage
associated molecular patterns (DAMPs), alarmins (S100A8
and S100A9) and complement.
69–71
DAMPs and alarmins
were reported to be abundant in OA joints, signaling
through either toll-like receptors (TLR) or the canonical
NF-κB pathway to modulate the expression of MMPs and a
disintegrin and metalloprotease with thrombospondin motif
(ADAMTS) in chondrocytes.
72–76
Complement can be
activated in OA chondrocytes and synovial cells by
DAMPs, ECM fragments and dead-cell debris.
77–78
Recent
studies further clarified that systemic inflammation can re-
program chondrocytes through inflammatory mediators
toward hypertrophic differentiation and catabolic
responses through the NF-κBpathway,
9–10,79
the ZIP8/Zn
+
/
Bone Research (2017) 16044
Osteoarthritis
D Chen et al
2
MTF1 axis,
80
and autophagy mechanisms.
81–85
Indeed, the
recent Kyoto Encyclopedia of Genes and Genomes
(KEGG) pathway analyses of OA and control samples
provide evidence that inflammation signals contribute to
OA pathogenesis through cytokine-induced mitogen-acti-
vated protein (MAP) kinases, NF-κB activation, and oxida-
tive phosphorylation.
86
Genetic predisposition
An inherited predisposition to OA has been known for
many years from family-based studies.
87–89
Although the
genetics of OA are complex, the genetic contribution to
OA is highly significant. Over the past decade, the roles of
genes and signaling pathways in OA pathogenesis have
been demonstrated by ex vivo studies using tissues derived
from OA patients and in vivo studies using surgically
induced OA animal models and genetic mouse models.
For example, alterations in TGF-β,Wnt/β-catenin, Indian
Hedgehog (Ihh), Notch and fibroblast growth factor (FGF)
pathways have been shown to contribute to OA
development and progression by primarily inducing cata-
bolic responses in chondrocytes.
8,90–95
Such responses
converge on Hif2α, Runx2, and inflammatory mediators
that lead to cartilage ECM degradation through the
increased expression of MMPs and ADAMTS
activity.
80,96–99
Recent studies of genome-wide association
screens (GWAS) that have been performed on large
numbers of OA and control populations throughout the
world have confirmed over 80 gene mutations or single-
nucleotide polymorphisms (SNPs) involved in OA patho-
genesis. Some of the genes are important structural and
ECM-related factors (Col2a1, Col9a1,andCol11a1), and
critical signaling molecules in the Wnt (Sfrp3), bone
morphogenetic protein (BMP) (Gdf5), and TGF-β (Smad3)
signaling pathways; most of these genes have been
previously implicated in OA or articular cartilage and joint
maintenance by studies using mouse models of induced
genetic alteration- or surgically induced OA.
100–106
A
recent arcOGEN Consortium genome-wide screen
study
107
identified new SNPs in several genes, including
GNL3, ASTN2, and CHST11. These findings need to be
verified by further studies.
MOUSE MODELS FOR OA RESEARCH
DMM model
DMM was developed 10 years ago and is a well
established surgical OA model in mice and rats. It is widely
used to study OA initiation and progression in combination
with transgenic mouse models and aging and obesity
models. DMM surgery was performed by transection of the
medial meniscotibial ligament (MMTL).
26–27
Briefly, following
the initial incision, the joint capsule on the medial side was
incised using scissors to expose either the intercondylar
region or the MMTL, which anchors the medial meniscus
(MM) to the tibial plateau. The MMTL was visualized under a
dissection microscope and the MMTL was cut using micro-
surgical scissors, releasing the ligament from the tibia
plateau thus destabilizing the medial meniscus. Closure of
the joint capsule and skin was with a continuous 8–0
tapered Vicryl suture. As a control for DMM studies, sham
surgery was performed by only exposing the medial side of
knee joint capsule. Because of the medial displacement of
the meniscus tissue, greater stress occurred on the posterior
femur and central tibia, especially on the medial side.
108
Histology demonstrated the severity of OA lesions at
4-weeks post-surgery with fibrillation of the cartilage
surface. Cartilage destruction and subchondral bone
sclerosis developed 8 weeks post-surgery and osteophyte
formation was seen 12-weeks post- surgery.
98,109–111
Aging model
As a degenerative disease, OA always occurs in
elderly populations; thus, aging is a major risk factor for
the most common form in humans, spontaneous OA.
Several laboratory animals develop spontaneous
OA, which approximates the stages of human OA
progression. These animal models are valuable tools for
studying natural OA pathogenesis.
112–113
The most com-
monly used inbred strain of laboratory mouse is C57/BL6;
these mice usually develop knee OA at about 17 months
of age.
112
The STR/ort mouse is one strain that easily
develops spontaneous OA. It requires 12–20 weeks for
STR/ort mice to develop articular cartilage
destruction.
114–116
This may be partially due to their heavier
body weight compared with other mouse strains. Given
the background genetic consistency, although aging OA
models have many advantages, it normally requires at
least one year for mice to model the disease. Therefore,
surgically induced OA models
107,117
and genetic mouse
models are preferred in recent decades for their relatively
fast induction for use as aging models for the study of OA
lesions.
In addition to the mouse, the Dunkin Hartley guinea
pig provides an aging model widely used to study OA
development.
118
The Dunkin Hartley guinea pig can
develop a spontaneous, age-related OA phenotype
within 3 months. The severity of OA lesions increases with
age, and moderate to severe OA is observable in
18-month-old animals. Histological analysis demonstrated
that the spontaneous OA progression in Dunkin Hartley
guinea pig resembles that of humans. Thus, the Dunkin
Hartley guinea pig is a useful animal to study the
pathogenesis and evaluation of potential treatments for
human OA.
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