Bone 51 (2012) 249–257

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Bone
journal homepage: www.elsevier.com/locate/bone

Review

The role of synovitis in osteoarthritis pathogenesis☆

Carla R. Scanzello a,⁎, Steven R. Goldring b
a
Section of Rheumatology, Rush University Medical Center, Chicago, IL, USA
b
Hospital for Special Surgery and Weill Cornell Medical College, New York, NY, USA

a r t i c l e i n f o a b s t r a c t

Article history: Research into the pathophysiology of osteoarthritis (OA) has focused on cartilage and peri-articular bone, but
Received 25 October 2011 there is increasing recognition that OA affects all of the joint tissues, including the synovium (SM). Under
Revised 10 February 2012 normal physiological conditions the synovial lining consists of a thin layer of cells with phenotypic features
Accepted 11 February 2012
of macrophages and fibroblasts. These cells and the underlying vascularized connective tissue stroma form
Available online 22 February 2012
a complex structure that is an important source of synovial fluid (SF) components that are essential for normal
Keywords:
cartilage and joint function. The histological changes observed in the SM in OA generally include features indic-
Osteoarthritis ative of an inflammatory “synovitis”; specifically they encompass a range of abnormalities, such as synovial lining
Synovitis hyperplasia, infiltration of macrophages and lymphocytes, neoangiogenesis and fibrosis. The pattern of synovial
Toll-like receptors reaction varies with disease duration and associated metabolic and structural changes in other joint tissues. Im-
Complement aging modalities including magnetic resonance (MRI) and ultrasound (US) have proved useful in detecting and
Cytokines quantifying synovial abnormalities, but individual studies have varied in their methods of evaluation. Despite
Inflammation these differences, most studies have concluded that the presence of synovitis in OA is associated with
more severe pain and joint dysfunction. In addition, synovitis may be predictive of faster rates of cartilage
loss in certain patient populations. Recent studies have provided insights into the pathogenic mechanisms
underlying the development of synovitis in OA. Available evidence suggests that the inflammatory process
involves engagement of Toll-like receptors and activation of the complement cascade by degradation prod-
ucts of extracellular matrices of cartilage and other joint tissues. The ensuing synovial reaction can lead to
synthesis and release of a wide variety of cytokines and chemokines. Some of these inflammatory mediators
are detected in joint tissues and SF in OA and have catabolic effects on chondrocytes. These inflammatory
mediators represent potential targets for therapeutic interventions designed to reduce both symptoms
and structural joint damage in OA.
This article is part of a Special Issue entitled “Osteoarthritis”.
© 2012 Elsevier Inc. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Functions of the synovial membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Variability of synovial changes in OA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Synovial histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Synovial imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Anatomic variation in synovitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Clinical impact of synovial inflammation (synovitis) in OA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Disease progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Disease stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Pathways that may promote synovitis in OA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Toll-like receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Complement activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Soluble inflammatory mediators (chemokines and cytokines) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

☆ Disclosures: SRG has received research funding from Boehringer Ingelheim, and is a consultant for Bone Therapeutics and Fidia Pharmaceutical. CRS is a consultant for Cinkate,
Corp. Rush University and Hospital for Special Surgery have filed a patent application for biomarkers in Osteoarthritis on behalf of CRS and SRG.
⁎ Corresponding author at: Rush University Medical Center, 1611 W Harrison Street, Suite 510, Chicago, IL 60612, USA. Fax + 1 312 563 2267.
E-mail address: [email protected] (C.R. Scanzello).

8756-3282/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.bone.2012.02.012
250 C.R. Scanzello, S.R. Goldring / Bone 51 (2012) 249–257

IL-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
TNF-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Common-gamma chain cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

Introduction articular cartilage. Under normal conditions, high molecular weight

molecules like lubricin and HA are not readily permeable, while
Osteoarthritis (OA) is the most prevalent arthritic disease and a small molecules like growth factors and cytokines readily diffuse
leading cause of disability. It affects approximately 34% of the United through the SM. This allows for the retention of high molecular
States population over age 65 [60]. This common joint malady is char- weight (MW) lubricating molecules within the joint, while prevent-
acterized by marked alterations in the composition, structure and ing high MW plasma proteins from entering and becoming deposited
function of the articular cartilage. Research has focused on the impact on the articular surface or altering the viscosity and composition of
of abnormal joint biomechanics on articular cartilage integrity and the SF. When synovial alterations such as inflammation and hyperpla-
chondrocyte pathobiology, and this focus has led to important in- sia occur, the permeability of the membrane is altered. This change in
sights into complex biochemical and biomechanical influences on permeability likely contributes to the decreased concentrations of HA
chondrocyte behavior. However, recent evidence supports a newer and lubricin observed in SF in articular disease. Increases in HA are
perspective — that the clinical syndrome of “OA” affects not only artic- observed peripherally in the serum [35] in the setting of arthritis,
ular cartilage, but also the integrity of multiple joint tissues. Pathologic and serum HA concentrations have been used as a marker of synovitis
cellular and structural changes in synovium, bone, ligaments, support- [70].
ing musculature and fibrocartilagenous structures such as the meniscus The clinical syndromes of synovial chondromatosis and osteo-
are observed in OA, and what has emerged is an appreciation that OA is chondromatosis suggest the existence of synovial resident cell popu-
a “whole joint” disease. As adult articular cartilage is avascular and lations that can differentiate along osteochondral cell lineages [22].
aneural, pathologic changes to non-cartilagenous joint tissues are of Indeed, recent evidence points to a role for the SM as a “niche” that
particular interest in understanding the source of pain generation in is a rich source of mesenchymal stem cells with multipotency, able
OA. This review will focus on the impact of synovial inflammation (sy- to differentiate into multiple mature cell lineages including cartilage,
novitis) in OA. We will discuss recent developments in our understand- bone, muscle and adipose tissue [29,112]. In this way the SM can partic-
ing of (I) the role of the SM in health and joint homeostasis, (II) the ipate in the regeneration and repair of injured or disrupted connective
variability of synovitis in OA, (III) the clinical impact of synovitis on tissue components of the joint [32]. The role of the SM in repairing de-
OA-related symptoms and disease progression, and (IV) pathways pro- fects in joint tissues suffered as the result of injury or disease warrants
moting synovitis relevant to OA. further investigation.

Variability of synovial changes in OA

Functions of the synovial membrane

Any discussion of the impact of synovitis on the natural history of

The cellular elements of the SM are a major source of synovial
OA must first begin with a description of the variability of SM changes
fluid (SF) components; these components contribute to the unique
and the numerous methods of detecting and quantifying synovitis.
functional properties of articular surfaces and modulate chondrocyte
Synovitis can be defined histologically by the pattern of synovial
activity. Two important molecules produced by synovial lining cells,
changes [57]; grossly by the visual appearance of the synovial lining
lubricin and hyaluronic acid (HA), help to protect and maintain the
in patients undergoing surgical procedures [3]; or by the use of
integrity of articular cartilage surfaces in diarthrodial joints [44]. To-
non-invasive imaging techniques including Magnetic Resonance Im-
gether, these two molecules reduce friction by providing boundary lu-
aging (MRI) and Ultrasound (US). Although an argument can be
brication at the articular surface. In addition, lubricin reduces
made that the “gold standard” method of detection of OA is synovial
pathologic deposition of proteins at the articular surface [82]. In the set-
histology [93], this requires an invasive biopsy that may not be appli-
ting of OA or after joint injury, the concentration and average molecular
cable or acceptable to all patients. In fact, each of the approaches for
weight of HA, and the concentration of lubricin in SF are altered
characterizing SM changes, including histology and imaging, have
[5,25,101], which adversely affects cartilage integrity. During OA pro-
provided important insights into the nature and variability of synovitis
gression, the synovial membrane is also a source of proinflammatory
in the setting of OA.
and catabolic products, including metalloproteinases and aggrecanases,
which contribute to articular matrix degradation. Therefore, alterations
in the SM can result in decreased concentrations of cartilage-protecting Synovial histology
factors, and increased production of factors that contribute to the degra-
dation of the articular matrix. Despite a long history of categorizing OA as a non-inflammatory
Articular cartilage has no intrinsic vasculature or lymphatic sup- form of arthritis, pathologic studies of SM specimens dating back to
ply, and therefore it relies on adjacent tissues (subchondral bone the 1980s described synovial inflammatory infiltrates of mononuclear
and SM) to provide nutrients that are essential for maintaining the cells, which in some cases were indistinguishable from infiltration ob-
health of the chondrocyte and articular cartilage [13]. It also relies served in rheumatoid arthritis (RA) [36,61,81]. It was assumed that sy-
on these adjacent tissues including the SM for removal of products novitis in OA occurred primarily in association with fragments of
of chondrocytic metabolism and articular matrix turnover. The SM cartilage and bone (detritus), observed within the SM. The majority of
acts as a semipermeable membrane controlling molecular traffic these early studies utilized tissue specimens from patients undergoing
into and out of the joint space, maintaining the composition of SF, total knee or hip arthroplasty, and so for many years it was unclear
which is essential for preserving the normal physiologic state of whether synovitis occurred at earlier stages of the disease. In 2002,
 C.R. Scanzello, S.R. Goldring / Bone 51 (2012) 249–257 251

Oehler and colleagues [73] performed a pathologic survey of synovial Synovial imaging
changes observed in OA including patients with earlier-stage disease
undergoing arthroscopic procedures. These investigators identified Although in some joints moderate to large synovial effusions can
four patterns of OA-associated “synoviopathy” including (i) hyperplas- be identified with routine X-ray techniques, in most cases, detection
tic, (ii) fibrotic, (iii) detritus-rich, and (vi) inflammatory. Capsular fibro- of the anatomically limited synovitis that is characteristic of OA re-
sis characterized the fibrotic pattern, and macromolecular cartilage and quires advanced imaging techniques such as MRI and US. There are
bone debris defined the detritus-rich pattern. Both of these patterns multiple MRI-based “whole-organ” grading systems that score specif-
were most often observed in patients with late-stage disease. Synovial ic anatomic features in the joint, including semi-quantitative charac-
lining and villous hyperplasia were the most common findings, often terization of the magnitude of synovial change [45,78]. The most
seen in the context of the other patterns, but when observed in isolation commonly used methods define synovitis according to the extent of
constituted the hyperplastic pattern characteristic of early OA SM spec- synovial cavity distension or total synovial volume. These systems
imens. The inflammatory pattern was observed equally in both early have been mostly applied to non-contrast imaging, but more recent
and late OA, was not dependent on the presence of detritus, and was studies have incorporated the use of contrast-enhanced MR imaging
characterized by lymphocyte and plasma cell infiltration diffusely or techniques to distinguish synovial thickening from effusion [31,39].
in perivascular aggregates. Increased synovial vascularity described by For example, in a recent study by Roemer et al. [85], the authors used
others [110] was not specifically discussed, but the authors nicely illus- both contrast-enhanced and non-enhanced images to examine a
trated that patterns of synovial change in OA are diverse, and may vary group of subjects with knee OA, and noted that synovitis was present
with the stage of disease. Fig. 1 shows representative photomicrographs in over 95% of the knee joints with an effusion, but also in 70% of
depicting synovial histopathologic changes observed in OA patients. knee joints in patients without an effusion. These findings suggest
Often, semi-quantitative synovial grading schemas combine common that in many cases synovial thickening may be independent of effu-
aspects of these patterns into a summed “synovitis” score. Using a sion, and may perhaps be a more reliable indicator of intra-
three-component summed score, Krenn and colleagues determined articular pathology than the presence of joint effusion. Ultrasound
that on average the synovitis of OA is low-grade in comparison to the has also been utilized to define the presence of synovitis in OA pa-
high-grade synovitis of RA, but still distinguishable from normal SM tients, and at least one report indicates that contrast-enhanced US
[56,77,97]. These specific histopathologic patterns of synovitis have may be as sensitive as contrast-enhanced MRI in detecting synovitis
not yet provided strong links to clinical disease patterns or specific dis- [99]. Whether synovitis defined by imaging approaches corresponds
ease mechanisms. However, the presence of inflammatory synovial in- to specific histologic features has been addressed by at least three
filtrates has been associated with worse knee symptom scores groups. In 1995, Fernandez-Madrid et al. demonstrated that areas
measured by patient administered questionnaires [87], and the specific of synovitis observed on MR images in patients with knee OA corre-
cellular nature of inflammatory infiltrates may differ between primary sponded to a low-grade chronic synovitis histologically [30]. Loeuille
OA and OA secondary to conditions such as hemachromatosis [42]. and colleagues noted that areas of synovial thickening identified on
These studies point to the possibility that more in depth assessment MR images [65] correlated well with individual histologic changes,
of synovial histopathology may provide insights into disease variability including inflammatory cell infiltration and lining hyperplasia.
or targetable mechanisms in the future. Most recently, Liu et al. [64] showed a similar correlation between

Fig. 1. Representative synovial histopathology observed in osteoarthritis. Paraffin-embedded, formalin fixed thin sections of synovial membrane from patients with OA undergoing
total joint arthroplasty. Hematoxylin and Eosin (panels a and b, 20 ×) or immunohistochemical stains with specific monoclonal antibodies against a macrophage marker (panels c
and d, anti-CD68,10X and 40 ×), a T-lymphocyte marker (panel e, anti-CD3, 40 ×), or a B-lymphocyte marker (panel f, anti-CD20, 40 ×). Panel a depicts normal appearing synovial
membrane with a thin lining layer and loose connective tissue subintimal layer. The section in panel b demonstrates synovial lining hyperplasia (arrow), villous hyperplasia (ar-
rowhead), fibrosis (star) and perivascular mononuclear cell infiltrates (double-headed arrow) which are histopathologic features often observed in OA. Panels c and d depict the
two typical distributions of CD68 + cells in OA SM: (c) concentrated in the synovial lining layer and (d) scattered throughout the subintimal layer and the perivascular infiltrates.
Panel e and f demonstrate that the majority of cells within the perivascular infiltrates express markers of (e) T and (f) B lymphocytes. (Immunostaining courtesy of Frank Pessler,
MD PhD, Section of Rheumatology/Immunology, Klinik und Poliklinik für Kinder- und Jugendmedizin, Dresden, Germany. Photomicrographs generously provided by Edward
DiCarlo, MD, Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York NY.).
252 C.R. Scanzello, S.R. Goldring / Bone 51 (2012) 249–257

histologic features of inflammation and synovial thickening on MRI. synovitis, Ishijima et al. [46] also demonstrated a relationship between
These studies demonstrate the ability of current imaging techniques synovitis and pain. We [87] contributed further evidence of an associa-
to non-invasively detect synovial inflammation, and provide further ev- tion between synovitis (defined histologically) and knee symptoms
idence that synovitis is an important contributor to OA pathobiology. measured by the Lysholm score (which measures pain, swelling, limp,
locking, instability, and functional disability on a single scale) in pa-
Anatomic variation in synovitis tients with early knee OA undergoing arthroscopic meniscectomy. Sy-
novitis has not only been related to knee pain, but also to knee joint
The above sections describe two approaches, histology and imaging, function using objective outcome measures of walking and stair-
utilized to identify synovitis in patients with OA. These approaches, as climbing times [100]. One recent study of patients with end-stage
well as direct arthroscopic visualization, have documented anatomic knee OA undergoing joint replacement did not support a relation-
variability in the location of the synovitis in the knee joint, which is ship between synovitis [64] and pain simply measured by a VAS.
most commonly studied. Early studies suggested that inflammation is The reasons for this are unclear, but may be due to differences in pa-
more focal in OA than the widespread synovitis seen in RA, with syno- tient populations studied, or differences in symptom assessments.
vium abutting cartilage lesions [36] or perimeniscal areas [3] preferen- We speculate that at advanced stages of knee OA where denuded
tially involved. A relationship between symptoms and synovitis bony surfaces are abutting each other, pain and symptoms may
localized to the infrapatellar and suprapatellar areas has been demon- have multiple origins related to extensive structural alterations. De-
strated [43]. In a recent study specifically addressing anatomic variation, spite some disagreement in the literature, the majority of available
synovitis detected by MRI was most commonly observed posterior to the studies provide compelling evidence that synovial inflammation is a ra-
posterior cruciate ligament (PCL) and in the suprapatellar region [85]. tionale target for therapeutic intervention to control joint symptoms in
Our own studies have focused on synovitis defined histologically in pa- OA. Future work should help define specific patient populations for
tients without radiographic evidence of OA undergoing surgery for whom targeting synovitis may have the greatest benefit.
meniscal tears [87]. Although radiographically normal, the majority of
these patients have cartilage abnormalities noted intraoperatively con- Disease progression
sistent with early stage OA. We examined the prevalence of synovial in-
flammation in these patients in three locations within the knee: In 2005, Ayral and colleagues published a study demonstrating a
suprapatellar pouch, medial gutter and lateral gutters. Of these locations, relationship between synovitis and progression of cartilage erosion
synovitis was most commonly detected in the suprapatellar pouch. [3]. This was a secondary analysis of 422 patients enrolled in a clinical
There does not appear to be a single preferential location in which syno- trial with medial compartment knee OA who had been followed lon-
vitis develops in the setting of all knee injuries and osteoarthritis, and the gitudinally for over one-year. Synovitis and cartilage integrity was
reasons for anatomic variation are unclear. Potential contributory factors documented by the visual appearance of the synovial membrane
include (i) biomechanical forces, (ii) local cartilage or other soft tissue in- and cartilage surfaces during baseline arthroscopy. Progression of car-
juries at specific locations, and (iii) differences in cellular or matrix com- tilage degeneration was determined by arthroscopic inspection one
position at these anatomic sites that may be more conducive to the year after the original procedure. Approximately 50% of the patients
development of synovial inflammation. had synovial inflammation by their criteria, and this was associated
with more severe baseline chondropathy. In addition, progression of
Clinical impact of synovial inflammation (synovitis) in OA cartilage pathology was statistically more advanced at one year in pa-
tients with synovial inflammation: 31.5% of patients with synovitis
Many decades of research have demonstrated the clinical signifi- progressed compared to 12.9% of those without synovitis. Although
cance of synovitis in the setting of RA. These studies led to the devel- an MRI based study in 2007 of patients with established OA [43] failed
opment of therapies (i.e. the anti-TNF agents) that improved the to corroborate these findings, a more recent study of 514 patients
clinical course and outcomes for patients with RA. It is only in the with knee pain but without radiographic knee OA demonstrated
past decade, though, that research efforts have been directed at un- that effusion and synovitis were associated with subsequent develop-
derstanding how the low-grade synovitis of OA relates to disease ment of cartilage loss at 30 months (adjusted OR = 2.7, 1.4–5.1,
manifestations. These efforts have provided substantial evidence p = 0.002) [84]. Using US, Conaghan and colleagues also found evi-
that synovitis is associated with greater symptoms such as pain and dence that synovial effusion was a predictor of progression to joint re-
degree of joint dysfunction, and may promote more rapid cartilage placement in a 3 year prospective study [21]. Although the majority
degeneration (Fig. 2). of published studies support a relationship between synovitis and
progression of joint damage, reasons for some disparate results are
Symptoms

Despite different approaches employed for detection and charac-

terization of synovitis (e.g. imaging or histologic assessment), pub-
lished studies provide evidence of a correlation between synovial
inflammation and symptoms such as pain, in patients with knee OA.
Torres L. et al. [107] investigated the relationship between knee
pain and specific joint pathology detected by MRI in patients with
knee OA. They noted that synovitis or effusion, as well as meniscal
tears and bone marrow lesions, were among findings that best corre-
lated with knee pain measured on a visual analog scale (VAS). Others
[43] specifically examined the relationship between pain and synovitis Fig. 2. The impact of synovitis on disease manifestations in OA. There is a substantial
on MRI and noted that changes in pain scores over time varied with body of evidence from multiple sources demonstrating a relationship between the
changes in synovitis, strengthening the notion of a causal relationship. presence of synovitis and symptoms such as pain, swelling, and joint dysfunction in
A similar association between pain and synovitis was reported more re- knee OA patients. Evidence from a smaller number of arthroscopic and imaging studies
suggests that the presence of synovitis may be associated with faster rates of cartilage
cently [4] using contrast enhanced MRI. In that study, higher grades of erosion in OA. Although not yet demonstrated in patients, additional studies of animal
synovitis conferred a 9-fold greater risk (95% confidence interval 3.2– models suggest that synovial macrophages, increased in synovitis, may be involved in
26.3) of having painful knee OA. Using serum HA as a marker of osteophyte formation in OA.
 C.R. Scanzello, S.R. Goldring / Bone 51 (2012) 249–257 253

likely related to differences in patient populations, methods of defin- damage-associated molecular patterns (DAMPS), rather than by mi-
ing synovitis, and anatomical areas assessed. In addition, molecular crobial ligands. The disruption of matrix homeostasis that occurs in
cross-talk between cartilage, synovium and other joint tissues could an osteoarthritic joint resembles a chronic injury [88].
influence the impact of synovitis on structural joint changes, and There are ten TLRs (TLR-1 through 10) that are functional in
this cross-talk very likely varies with the underlying cause of OA, humans. TLRs are constitutively expressed by a variety of cells in-
stage of disease and extent of chondropathy. cluding macrophages, but can be induced or up-regulated on other
cells types [47]. TLRs 1–7 and 9 have been detected in SM in both
Disease stage OA and RA, and in vitro synovial fibroblasts respond to many micro-
bial TLR agonists [16,58,74,75,104]. TLR activation in the SM is an
Despite differences in methods for detecting and defining synovi- important stimulus for NFκB activation and subsequent production
tis, there is general agreement that the prevalence and severity of sy- of chemokines (e.g. IL-8 and CCL5) and cytokines (e.g. IL-1, IL-6 and
novitis increases with advancing stage of OA defined by extent of TNF), which recruit and activate macrophages, granulocytes and
cartilage lesions and radiographic changes. We showed that suprapa- lymphocytes [2], but chondrocytes also can serve as targets for
tellar synovial inflammatory infiltrates were more prevalent (75% vs. TLR activation. Stimulating ligands have been identified for TLR1–
43%) and of higher histologic grade in patients with advanced knee 9 [103], and include microbial and endogenous host products. Re-
OA than in a cohort of patients undergoing arthroscopic meniscectomy cent evidence has suggested that a number of endogenous products
with no radiographic OA [87]. Further support for a relationship be- produced by matrix disruption or cellular stress can also bind and
tween stage of knee OA and synovial changes is provided by the recent activate TLRs, even in the absence of obvious microbial infection.
publication of Krasnokutsky et al. [55]. The authors assessed synovitis Many putative TLR ligands are modified in form or distribution, or
using 3 T contrast-enhanced MRI in a group of 58 patients with knee increased in concentration in joint fluids or tissues in the setting
OA. Fixed-flexion radiographs were used to determine joint-space of joint injury and OA. These include matrix components such as
width, narrowing and disease stage by the Kellgren–Lawrence (KL) tenascin C [72,19], fibronectin isoforms [17,59], small molecular
score. They showed that infrapatellar synovitis was present in 38% of weight species of hyaluronic acid [6,91,105,106] and biglycan
patients with KL stage 2–3 disease, compared with 83% of patients [9,23,80,90]. Recently, certain plasma proteins increased in OA SF
with KL stage 4 disease. Measurements of joint space narrowing and were demonstrated to activate macrophages in vitro via TLR-4 [98]. In
width were consistent with their findings with KL score. Therefore, a murine model of autoimmune arthritis [1], TLR-4 deficiency resulted
although synovitis is present early in disease and even at pre- in reduced disease severity reflected by less synovial cellular influx, car-
radiographic stages, the proportion of patients with synovitis ap- tilage damage and bone erosion. On the other hand, TLR-2 knock-out
pears to increase with advancing structural deterioration. Whether mice developed more severe disease, suggesting a protective role in
any impact of synovitis on structural disease or symptoms will be this particular model. The regulatory processes involved in TLR
the same at all stages remains to be determined. activation are complex, and their role in promoting synovitis in OA is
not fully established. However, targeting TLRs and the ligands and path-
Pathways that may promote synovitis in OA ways that trigger their activation need to be explored as potential ther-
apeutic approaches in OA.
There are multiple pathways and mediators that can directly influ- In addition to the development of synovitis, TLR activation has im-
ence the development and persistence of synovitis. Although histori- plications for cartilage degeneration in OA. Enzymes involved in articu-
cally this work has focused on RA, recent work suggests that some of lar matrix turnover and degradation include matrix metalloproteinases
these inflammatory pathways may be relevant to synovitis in both RA (MMPs) and aggrecanases, which may be produced by both chondro-
and OA. The available evidence has largely pointed to a role for innate cytes and synovial cell populations. In cartilage, TLR-2 and -4 are up-
immunity in OA [88]. Innate immunity is the first level of immune regulated specifically in lesional areas in patients with OA [52]. A
system activation in response to inflammatory challenges. Recent more recent study demonstrated that TLR2 and TLR4 signals are impor-
data suggests that matrix fragments and products released during tant in mediating catabolic responses and in increasing MMP-3 and
cellular stress can activate the innate immune response via pattern- MMP-13 production in murine cartilage explants [63]. A recent genetic
recognition receptors known as Toll-like receptors (Fig. 3). The ensu- study in a Chinese population identified a TLR-9 polymorphism that is
ing cellular response culminates in activation of specific transcription associated with the presence of radiographic knee OA [102]. This report
factors, with nuclear-factor κB (NF-κB) playing a prominent role. This did not reveal an association with common TLR-2 or -4 polymorphisms,
transcription factor leads to production of multiple potent proinflam- and how TLR-9 is linked to increased risk of OA is not yet clear. Taken
matory mediators including cytokines and chemokines that can cause together, though, these results implicate numerous members of the
local tissue damage. Many matrix metalloproteinases implicated in TLR family of pattern recognition receptors in inflammation, cartilage
OA-related cartilage damage are dependent on the activity of NF-κB responses, and disease susceptibility in OA. A potential mechanism for
as well [68,38]. Additional effector responses of innate immunity in- activation of TLRs is depicted in Fig. 3.
clude activation of macrophages and the complement cascade. The
role of activated synovial macrophages in promoting catabolic mediator Complement activation
production [8,10] and osteophytosis [109] in OA animal models is well
documented. Evidence for activation of the complement cascade has The complement cascade is one of the major effector mechanisms
been provided more recently and will be reviewed (Fig. 3). of immune system activation. The three main pathways of comple-
ment activation (the classical, alternative and lectin pathways) are
Toll-like receptors important in both innate (alternative and lectin pathways) as well
as adaptive immune responses (the classical pathway, triggered by
Activation of the innate response often begins with stimulation of antibody/immune complexes), and have been extensively reviewed
pattern-recognition receptors, classically in the setting of infectious elsewhere [27]. Soluble complement mediators such as C3a, C3b and
insult by microbial ligands [47]. However, activation of the same C5a are produced by serial proteolytic activation of this cascade, and
pattern-recognition receptors involved in the response to pathogens these mediators promote inflammation and phagocytosis. The terminal
occurs during cellular stress and extracellular matrix damage in the complement protein complex, the membrane attack complex (MAC),
setting of sterile tissue injury [79]. Under these circumstances, can directly lyse target cells through pore formation when deposited
pattern-recognition receptors can be activated by endogenous on cellular membranes. Activation of the complement cascade is
254 C.R. Scanzello, S.R. Goldring / Bone 51 (2012) 249–257

Fig. 3. A model of Toll-like Receptor (a) and complement activation (b) in the joint leading to synovitis and potentiation of cartilage erosion in OA. Joint tissue injury, either acute
traumatic injury to joint tissues, or chronic cartilage damage occurring throughout the course of OA, can lead to the elaboration of both matrix molecules and complement com-
ponents that are released into the synovial fluid. Some matrix molecules may act as TLR agonists while others can activate the complement cascade. TLR activation is depicted
on the left (a). Certain matrix components increased in OA and injury can interact with TLRs on resident and infiltrating cells of the synovium. In addition, TLR expression on chon-
drocytes is increased in lesional areas of cartilage. Binding of these ligands to TLRs leads to the generation of inflammatory cytokines and chemokines, which can promote cellular
infiltration, the hallmark of synovitis. This molecular and cellular inflammation can then potentiate cartilage erosion via production of enzymatic mediators of matrix degradation.
Complement activation in the joint is depicted on the right (b). Synovial inflammation can lead to leakage of plasma complement proteins into the joint, but chondrocytes and the
SM itself also may be a source of complement components. Articular matrix components distinct from those activating TLRs have been demonstrated to bind complement compo-
nents, leading to activation of the complement cascade and generation of active complement proteins. These proteins also can bind to receptors or deposit on cells of the synovium
leading to increased cytokine production, and increased synovial inflammation.

essential for effective clearance of many pathogens, but when comple- Soluble inflammatory mediators (chemokines and cytokines)
ment activity is improperly regulated it can lead to extensive tissue
damage. As early as 1988, complement deposition in synovial mem- Activation of pattern-recognition receptors and the complement
branes of some patients with meniscal tears and cartilage degeneration cascade results in transcriptional activation of genes involved in the de-
was noted [15]. Increased synovial complement component deposition velopment of inflammation, most notably genes for soluble mediators
in the setting of acute flare-ups of symptomatic OA has been demon- such as cytokines and chemokines. These mediators may be produced
strated [54]. Blood or serum leaking into the joint under circumstances by a variety of cell types, including macrophages, chondrocytes and sy-
of injury likely provides a source of complement proteins in many pa- novial fibroblasts [51]. A broad spectrum of cytokines and chemokines
tients, but chondrocytes and synovial macrophages may also actively are detectable in joint tissues and fluids, and may prove useful as
produce complement components and inhibitors [12]. Using proteomic markers of the synovial inflammatory response. These same mediators
approaches, complement components and immunoglobulins have may also play a role in development of joint inflammation and cartilage
been identified in synovial fluids from OA patients [34] and in vesicles re- matrix destruction typical of OA. Some specific examples will be dis-
leased from osteoarthritic cartilage in vitro [86]. Several investigators cussed below.
have demonstrated that molecular components of the articular extracel-
lular matrix may affect complement cascade activity. Fibromodulin [95], IL-1
cartilage oligomeric matrix protein (COMP) [40], and osteoadherin [96]
have been shown to activate the complement cascade, either the classi- Since the identification of IL-1 as a synovial factor that is able to in-
cal or alternative pathways. In contrast, other matrix components can act duce cartilage destruction in vitro [26], much progress has been made
as complement inhibitors, such as the NC4 domain of Collagen IX [50]. regarding this cytokine's role in driving catabolic responses in chon-
Exactly how complement deposition occurs in synovium and cartilage drocytes. IL-1β signaling suppresses aggrecan [83] and collagen syn-
in the setting of OA, and the role of the complement cascade in OA path- thesis [37] in chondrocytes, and also can up-regulate the proteolytic
ogenesis remains to be determined. In recent collaborative studies, mice enzymes ADAMTS-4 [108] and MMP-13 [71]. However, IL-1β is not
with impaired ability to generate the MAC were partially protected from consistently elevated in the synovial fluid of OA patients [53,92] and
the development of OA, providing direct evidence for a role of the com- the endogenous IL-1 receptor antagonist, which blocks IL-1 activity,
plement system in OA pathogenesis [111]. The potential pathway to is produced by synoviocytes at higher levels in OA than in RA [33]. At-
complement activation in the OA joint is depicted in Fig. 3. tempts to block IL-1 activity therapeutically in patients have been
 C.R. Scanzello, S.R. Goldring / Bone 51 (2012) 249–257 255

associated with only minimal symptom-reducing efficacy at best in response to its ligand, CCL19 [14], suggesting a role in synovial angio-
[18,20]. However, it is possible that IL-1 activity is important in specific genesis. Other chemokines, specifically MCP-1 and MIP-1β, have been
clinical settings in OA. Production of active IL-1 requires activation of associated with knee pain in patients undergoing arthroscopic proce-
the NALP3 inflammasome; activation of the inflammasome by uric dures [24]. An important role for MIP-1γ produced by T helper cells in
acid crystals has been implicated in flares of gouty arthritis [69]. Other the synovium was demonstrated in a murine model of OA induced by
crystals, including basic calcium phosphate [76] and hydroxyapatite ligament transection [94]. Similar to the cytokines discussed above, che-
[48] have recently been shown to activate inflammasome-mediated mokines can induce matrix metalloproteinase (MMP)-3 and proteogly-
IL-1 production. Both hydroxyapatite and basic calcium phosphate crys- can loss from articular cartilage [11]. Furthermore, many chemokines
tal deposition occurs in patients with OA. Therefore, it is possible that may directly affect osteoclast-mediated remodeling of peri-articular
IL-1 is important in patients with OA and evidence of crystalline bone. In summary, chemokines represent a class of soluble inflammato-
deposition. ry mediators that have pleiotropic effects on multiple joint tissues, and
may contribute to inflammation and clinical symptoms in patients with
TNF-α OA. Further studies are needed to investigate the utility of targeting spe-
cific chemokines for symptom control or disease modification in OA.
TNF-α is readily detectable in SF in patients with OA [92]. Like
IL-1, TNF can activate chondrocyte-mediated catabolic protease pro- Conclusion
duction [51]. The well-established clinical efficacy of TNF inhibition in
the setting of RA, and the availability of blocking agents, led to trials of There is increasing evidence that synovial inflammation plays a
a TNF-inhibitor in an open-label pilot study to treat pain and inflamma- critical role in the symptoms and structural progression of OA. Impor-
tion in twelve patients with erosive hand OA [67]. Like the IL-1 trials, tantly, synovitis has been shown to correlate with symptom severity,
this trial did not demonstrate significant efficacy, but improvement in rate of cartilage degeneration and osteophytosis (Fig. 2). The synovial
pain and physical function scores was reported for some individuals. It response in OA is complex and variable with regard to histologic pat-
remains to be seen whether different patient subsets will respond to tern (Fig. 1), and in part this complexity can be attributed to changing
targeted therapies blocking the actions of TNF. patterns as disease evolves and progresses. Although structural joint
damage in OA is a constant feature, the clinical syndrome of OA is
Common-gamma chain cytokines quite variable, with differences in affected joint patterns, risk factors,
rates of progression, and severity of symptoms. Further efforts to under-
The perivascular inflammatory cell infiltrates observed in the OA stand the cellular and molecular variability of OA-associated synovitis
synovium are largely composed of lymphocyte populations [7]. may provide insights into the clinical heterogeneity of the disease.
Based on this observation, our group investigated the expression and Pathways and soluble mediators that can promote or sustain syno-
activity of cytokines involved in lymphocyte biology in OA synovium. vitis also are quite diverse. In this review we highlighted two poten-
We focused our efforts on the common-γ chain family of cytokines (in- tial innate inflammatory mechanisms that may lead to development
cluding IL-2, IL-15, and IL-21) which are involved in recruitment, sur- of synovitis in OA, the TLR pathway and the complement cascade
vival and activity of lymphocytes [89]. IL-15 was consistently (Fig. 3). Furthermore, we highlighted the roles of cytokines and che-
detectable and elevated in patients with early stage OA, compared mokines that play a role in the initiation and perpetuation of synovitis
with end-stage OA patients undergoing total knee arthroplasty. In rheu- and OA symptoms. These pathways and mediators also may impact car-
matoid synovial fibroblasts, TLR-2 and -4 stimulation were shown to in- tilage matrix homeostasis and peri-articular bone remodeling. In addi-
duce IL-15 production in vitro [49]. Both synoviocytes [89] and tion, the products associated with synovial inflammation may serve as
chondrocytes (Scanzello, unpublished results) from OA patients ex- surrogate markers of disease activity or responses to therapeutic inter-
press the specific IL-15 receptor, suggesting there may be multiple cel- ventions. Further understanding of mechanisms promoting synovial in-
lular targets of IL-15. Serum IL-15 detected using a proteomic approach flammation in OA may lead to identification of novel therapeutic targets
was associated with the presence and progression of radiographic OA for controlling symptoms and slowing structural progression in this dis-
[62]. Studies by Long et al. showed that IL-7, another common-γ chain abling joint disease.
cytokine which activates lymphocytes, is produced by chondrocytes
[66]. This same study demonstrated that chondrocytes also express Acknowledgments
the IL-7 receptor and respond to IL-7 stimulation with increased pro-
duction of matrix metalloproteinases and proteoglycan release. Further This study was supported by 1K08 AR057859-02, Mentored Clinical
investigation into the importance of this cytokine family in disease Scientist Career Development Award, from the National Institute of Ar-
models is necessary to determine whether they play a central role in thritis, Musculoskeletal and Skin Diseases (CRS).
progressive joint degeneration in OA.
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