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Mediators of structural remodeling in peripheral spondylarthritis.

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ARTHRITIS & RHEUMATISM
Vol. 60, No. 12, December 2009, pp 3534–3545
DOI 10.1002/art.27251
© 2009, American College of Rheumatology
REVIEW
Mediators of Structural Remodeling in
Peripheral Spondylarthritis
Bernard Vandooren,1 Nataliya Yeremenko,2 Troy Noordenbos,2 Johannes Bras,2
Paul P. Tak,2 and Dominique Baeten2
Introduction
RA cannot be fully explained by differential synovial
expression of mediators of tissue destruction. In contrast, increasing evidence suggests that the distinct type
of remodeling may relate to bone and cartilage anabolism rather than to degradation as such, reflecting sustained activity of tissue repair responses in SpA. In
contrast with bone and cartilage degradation, these
tissue repair responses have not yet been shown to be
influenced by TNF blockade.
Integration of experimental models and translational data as well as prospective imaging and biomarker
studies are now needed to determine how to block
ankylosis in SpA. This may also lead to new strategies for
promoting tissue repair in destructive diseases such as
RA.
The inflamed peripheral joint is relatively protected from erosive damage in nonpsoriatic spondylarthritis (SpA) as compared with rheumatoid arthritis
(RA), with psoriatic arthritis (PsA) showing a mixed
pattern of destruction and remodeling. The cellular and
molecular mechanisms of cartilage and bone destruction
have been extensively studied in experimental models
and in human RA. In contrast, the mechanisms and role
of new tissue formation are only starting to emerge from
studies in animal models, and translation to the arthritis
in humans remains challenging.
Here, we review the recent insights into the
mechanisms of structural remodeling in peripheral SpA.
The inflammatory milieu in the joints of patients with
SpA and the joints of patients with RA appears to be
clearly different, with a relative overexpression of the
proinflammatory cytokines tumor necrosis factor ␣
(TNF␣) and interleukin-1␤ (IL-1␤) in the latter. Even if
these cytokines can drive destructive mechanisms, the
differences in structural remodeling between SpA and
Structural remodeling in inflammatory arthritis
Destruction of connective tissues is a key feature
of inflammatory arthritis in humans, since it determines
in large part the long-term functionality of the joint and,
thus, the quality of life of the patients. Joint destruction
has been investigated in depth in RA, where it is
characterized by osteoporosis of paraarticular bone,
progressive loss of articular cartilage, and the development of lytic bone lesions at the synovium–bone interface. This pronounced cartilage and bone degradation
and damage is not associated with clear signs of new
bone formation or repair and can be halted by TNF
antagonists, even when this treatment fails to completely
halt the inflammatory component of the disease (1).
It is of major interest, however, that other types
of chronic joint inflammation lead to completely different patterns of joint remodeling. The prototypical example is spondylarthritis, which, besides modest cartilage
and bone degradation, mainly shows signs of extensive
new endochondral bone formation. This process affects
not only the sacroiliac joints and the spine, leading to
This publication reflects only the authors’ views. The European Community is not liable for any use that may be made of the
information herein.
Supported by The Netherlands Organization for Scientific
Research (NWO), the Dutch Arthritis Association, and the European
Commission Sixth Framework Programme (project AutoCure). Dr.
Vandooren’s work was supported by a Research Fellowship from the
Fund for Scientific Research, Flanders (FWO Vlaanderen).
1
Bernard Vandooren, MD, PhD: Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands, and Ghent
University Hospital, Ghent, Belgium; 2Nataliya Yeremenko, PhD,
Troy Noordenbos, Johannes Bras, MD, Paul P. Tak, MD, PhD,
Dominique Baeten, MD, PhD: Academic Medical Center, University
of Amsterdam, Amsterdam, The Netherlands.
Address correspondence and reprint requests to Dominique
Baeten, MD, PhD, Department of Clinical Immunology and Rheumatology, F4-105, Academic Medical Center, University of Amsterdam,
Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: D.L.
Baeten@amc.uva.nl.
Submitted for publication February 1, 2009; accepted in
revised form August 31, 2009.
3534
MEDIATORS OF STRUCTURAL REMODELING IN PERIPHERAL SpA
3535
regulated in different arthritic conditions. Since the Holy
Grail of treatment is to maintain and/or restore the
structural balance in the different types of arthritis, the
challenge is now to identify the cellular and molecular
mechanisms that underlie these differences.
Mediators of bone remodeling
Figure 1. Characteristics of peripheral joint remodeling in spondylarthritis (SpA). Shown are radiographs and drawings of a normal distal
interphalangeal joint (top) and an ankylosed joint of a patient with
psoriatic SpA (bottom).
axial ankylosis, but also the peripheral joints (Figure 1).
Although TNF blockade also strongly suppresses signs
and symptoms in SpA, clinical trials have thus far failed
to show any inhibitory effects on new bone formation
and ankylosis (2,3). In terms of joint remodeling, PsA is
a distinct subset of SpA: it shares the features of new
bone formation, but in contrast to nonpsoriatic SpA,
erosive disease is fairly common in PsA and can be even
much more aggressive than in RA. Again, TNF blockade
appears to block erosive disease (4–6), but there is no
evidence that it affects new bone formation and ankylosis.
These remarkable clinical differences teach us 3
important lessons about pathogenesis. First, whereas it is
clear that osteoclast-mediated bone erosions are crucial
in RA, nonpsoriatic and psoriatic SpA emphasize that
the structural outcome is not determined by destruction
alone, but rather, by the more complex balance between
destruction and repair. Second, TNF blockade has a
marked effect on the progression of erosions but has not
yet been demonstrated to influence new bone formation
in established SpA, suggesting that the mechanisms of
destruction versus repair may be either uncoupled or
differentially regulated. And third, the fact that ankylosis results from endochondral bone formation in SpA
raises the question concerning the extent to which not
only bone, but also cartilage, metabolism is differentially
The cellular and molecular mechanisms of bone
and cartilage remodeling have been extensively studied
and described in vitro as well as in different experimental models. Although it is beyond the scope of this review
to give an extensive discussion of the biology of bone and
cartilage, a number of these pathways provide essential
information for our understanding of structural damage
in human inflammatory arthritis.
Bone remodeling is a coupled process involving
bone formation and resorption. This process is regulated
by local and systemic factors that drive osteoblast and
osteoclast differentiation and function. Osteoblasts differentiate from mesenchymal precursors and deposit
bone matrix constituents, such as type I collagen and
osteocalcin. Although the regulation of osteoblast differentiation and function is a complex process, a number
of factors appear to be of pivotal importance (Figure 2).
For example, the osteoblast-specific transcription factor
runt-related transcription factor 2 (RUNX-2) integrates
the actions of different anabolic factors, such as transforming growth factor ␤ (TGF␤) and insulin-like growth
factor 1 (IGF-1), and hormones on osteoblasts and
thereby controls the transcription of osteocalcin and
other osteoblast-specific genes (7). This pathway is
further influenced by WNT signaling: upon binding to
Frizzled receptors, WNT indirectly inhibits the phosphorylation of ␤-catenin by glycogen synthase kinase 3␤
(GSK-3␤). Since nonphosphorylated ␤-catenin is less
susceptible to ubiquitin-mediated degradation, this leads
to accumulation of ␤-catenin, nuclear ingress, and ultimately, the transcription of factors involved in osteoblast
differentiation and activation. Accordingly, mutations in
members of the WNT family, ablation of the WNT
coreceptors low-density lipoprotein receptor–related
protein 5 (LRP-5) or LRP-6, or use of WNT inhibitors,
such as sclerostin or the Dkk family members, reduce
osteoblastogenesis and bone formation (8).
Apart from synthesizing bone matrix, osteoblasts
also regulate the differentiation and activity of osteoclasts (Figure 3). Osteoclasts are multinuclear cells of
hematopoietic origin that are specialized in resorbing
bone (9). Early osteoclast precursor cells in the bone
marrow express the c-Fms receptor and proliferate
3536
VANDOOREN ET AL
Figure 2. Schematic representation of the steps in the differentiation of mesenchymal stem cells toward
either chondrocytes or osteocytes. The boxes indicate the main differentiation factors for each step. The
main matrix products and transcription factors are indicated in the cells. BMP ⫽ bone morphogenetic
protein; TGF␤ ⫽ transforming growth factor ␤; Coll-II ⫽ type II collagen; MIA ⫽ melanoma inhibitory
activity; IGF-1 ⫽ insulin-like growth factor 1; FGF ⫽ fibroblast growth factor; RUNX-2 ⫽ runt-related
transcription factor 2; PTH ⫽ parathyroid hormone; 1,25(OH) 2 D 3 ⫽ 1,25-dihydroxyvitamin D3; BSP ⫽ bone sialoprotein.
under the influence of macrophage colony-stimulating
factor (M-CSF). Later on, they also start to express
c-Fos and RANK. Binding of RANKL, which is expressed by osteoblasts, is absolutely required for the full
maturation and activity of osteoclasts. This binding can
be regulated by osteoprotegerin (OPG), the decoy receptor for RANKL. In pathologic conditions, proinflammatory mediators can profoundly alter the balance
between bone resorption by osteoclasts and new bone
formation by osteoblasts. This has been best studied for
TNF, which on the one hand, directly (10,11) and
indirectly (through up-regulation of M-CSF and
RANKL expression by stromal cells) (12,13) promotes
osteoclast formation and activation and, on the other
hand, suppresses WNT signaling by up-regulating inhibitors such as Dkk-1 (14). The relevance of TNF for the
bone phenotype in vivo has been demonstrated both
experimentally in the TNF-transgenic mouse model
(15,16) and clinically in RA patients treated with TNF
blockers (17).
Mediators of cartilage remodeling
Articular cartilage is built up by 4 different layers
of chondrocytes that have different gene expression
profiles. The superficial layer consists of 2 or 3 flattened
cell layers, which express lubricin as well as type II
collagen, aggrecan core protein, tenascin, and SOX9.
The intermediate zone expresses no lubricin, but higher
levels of cartilage intermediate-layer protein. Chondrocytes in the radial zone express markers of chondrocyte
hypertrophy, such as type X collagen and alkaline phosphatase. In the mineralized cartilage, the cells start to
express osteoblast factors, such as RUNX-2 and osterix.
Chondrogenesis is crucially dependent on the transcription factor SOX9, because no cartilage is formed in the
absence of SOX9 (18) and SOX9 directly regulates the
expression of cartilage-specific genes, such as type II
collagen (19). The expression and activity function of
SOX9 is promoted by anabolic cytokines, such as TGF␤
(20), and impaired by proinflammatory cytokines, such
as IL-1␤ (21).
A clear distinction should be made here between
articular cartilage and growth plate and/or developmental cartilage. Although the same transcription factors
govern the behavior of these cells, the articular chondrocyte is a stable cell type that is regulated by a very
strict balance of signaling pathways under physiologic
conditions. In contrast, the biologic status of the devel-
MEDIATORS OF STRUCTURAL REMODELING IN PERIPHERAL SpA
3537
Figure 3. Mediators of osteoclast development from blood-borne myeloid precursors. Monocytes
enter the inflamed synovial tissue from a blood vessel and differentiate into osteoclasts under the
influence of mediators produced by resident cells. M-CSF ⫽ macrophage colony-stimulating factor;
TNF␣ ⫽ tumor necrosis factor ␣.
opmental chondrocyte is influenced by changing signals,
leading to hypertrophy and, eventually, apoptosis of
these cells. This occurs typically in endochondral ossification, a complex and finely tuned process involving
different steps. The first step is the condensation of
mesenchymal stem cells, which differentiate into chondrocytes. Subsequently, these cells proliferate, deposit
typical cartilage matrix, become hypertrophic, and release factors that promote the calcification of the matrix.
This triggers osteoclasts to resorb and invade the calcified matrix, paving the path for in-growing blood vessels.
Subsequently, poorly differentiated mesenchymal cells
that were initially located at the periphery of the process
attach to the excavated calcified matrix and differentiate
into osteoblasts. These osteoblasts finally secrete bone
matrix that replaces the calcified cartilage matrix.
In pathologic conditions, both processes (the
stable metabolism of articular chondrocytes and the new
tissue formation by developmental chondrocytes) could
be disturbed. Whereas the latter is an emerging field of
particular interest in tissue remodeling in SpA (see
below), the modulation of cartilage metabolism by inflammatory conditions has already been extensively
studied in different arthritic conditions (Figure 4). Prototypically, high levels of IL-1␤ will strongly suppress
cartilage anabolism and, thus, the production of normal
matrix constituents (11,22). Moreover, IL-1␤ and other
inflammatory mediators induce the production of a
series of enzymes that cleave cartilage extracellular
matrix constituents, such as type II collagen and aggrecan. These matrix-degrading enzymes, including cathepsins, aggrecanases, and matrix metalloproteinases
(MMPs), are produced by chondrocytes themselves or
by neighboring stromal cells (23,24), with the fibroblastlike synoviocyte (FLS) as prototype.
More recently, it was demonstrated that the
ability of FLS to degrade cartilage is also dependent on
the expression of cadherin 11, a molecule that mediates
homophilic adhesion between FLS and is critical for the
maintenance of the normal synovial microarchitecture
(25). Upon induction of arthritis, cadherin 11–deficient
mice are protected from cartilage loss but not bone
erosions (26), indicating a specific role of this molecule
in cartilage damage (Figure 4). Kiener et al (27) recently
demonstrated the abundant expression of cadherin 11 at
the cartilage–pannus junction and the crucial role of
cadherin 11 expression on FLS for in vitro invasive
behavior in the Matrigel invasion assay. These data
indicate that that this adhesion molecule is important
not only for cell–cell adhesion between FLS, but also for
the adherence (and subsequent invasion) of FLS to
cartilage. Taken together, the suppression of new matrix
3538
VANDOOREN ET AL
Figure 4. Mediators of cartilage degradation in chronic arthritis. Cartilage matrix is
degraded by mediators that are released from the inflamed synovium, as well as by synovial
fluid neutrophils (top). Pannus tissue extends over the cartilage surface and degrades the
matrix by producing proteolytic enzymes (bottom). MMP ⫽ matrix metalloproteinase;
IL-1 ⫽ interleukin-1; Coll-II ⫽ type II collagen; MIA ⫽ melanoma inhibitory activity.
formation by IL-1␤ and the degradation of existing
matrix by proteases contribute to the loss of articular
cartilage.
Inflammatory milieu in peripheral spondylarthritis
As mentioned above, proinflammatory cytokines,
such as TNF␣ and IL-1␤, play a crucial role in driving
bone and cartilage damage. Therefore, the differential
structural phenotype in RA, nonpsoriatic SpA, and PsA
may relate to differences in the type or degree of local
inflammation in these diseases. Indeed, there are clear
differences in the synovial histopathology between SpA
and RA synovitis, indicating that, despite similar levels
of overall inflammation, the type of inflammation is
different in the two diseases (28–34). Of particular
interest in the context of structural damage, however, is
that PsA resembles nonpsoriatic SpA rather than RA
(35). In both diseases, the synovial lining layer can
MEDIATORS OF STRUCTURAL REMODELING IN PERIPHERAL SpA
become hyperplastic and form a macroscopic and microscopic pannus that adheres to cartilage (28,32). The
difference between the two diseases appears to be
quantitative, since the degree of intimal lining layer
hyperplasia is slightly higher in RA than in SpA. At the
cellular level, an intriguing finding of most, but not all,
studies is the preferential infiltration by macrophages
expressing the alternative activation marker CD163 in
SpA (30,36,37). This specific macrophage subset appeared to correlate well with global disease activity as
well as with the response to treatment in SpA (38,39).
The subclassification of macrophages according
to the expression of phenotype markers such as CD163
refers to the increasing evidence that macrophages are
not a homogenous population but can be divided into
specific, although overlapping, subsets according to their
polarization requirements, phenotype, and function
(40). Of importance in the context of structural damage,
classically activated macrophages (M1) are the main
source of proinflammatory cytokines, such as TNF␣ and
IL-1␤, whereas alternatively activated macrophages
(M2) expressing CD163 have been implicated in immune regulation, phagocytosis, and tissue remodeling.
This also has functional implications for synovitis, since
synovial fluid levels of M1-derived cytokines, such as
IL-1␤ and TNF␣, are indeed significantly lower in SpA
than in RA synovitis despite a similar overall degree of
tissue inflammation (41). These data are consistent with
an earlier observation on TNF described by Cañete et al
(42). Consistent with the histopathologic findings, we
have also shown that the M1-derived cytokine profile in
PsA had a greater resemblance to that in SpA than to
that in RA (41).
Bone damage in peripheral spondylarthritis
The question raised by these studies is whether
the different inflammatory milieus, especially the lower
levels of TNF␣ and IL-1␤ in SpA, affect the presence
and activity of key mediators of bone and cartilage
remodeling. Since bone destruction is mediated exclusively by osteoclasts, several studies have compared the
potential of peripheral blood–derived myeloid cells to
differentiate into osteoclasts in different types of inflammatory arthritis.
When incubated in vitro with M-CSF and
RANKL, RA peripheral blood–derived cells were more
prone to differentiate to osteoclasts than were SpA
peripheral blood–derived cells (43). Using a different in
vitro assay without the addition of exogenous factors
(called spontaneous osteoclastogenesis), peripheral
3539
blood cells from patients with PsA showed increased
osteoclastogenic potential as compared with those from
healthy controls (44,45). Although the relevance of these
assays for in vivo bone destruction remains unclear, the
increased ex vivo osteoclastogenic potential appears to
be related to the inflammatory milieu, since it was
reversed by in vivo treatment with TNF blockers (43,44).
We recently reassessed the mechanisms of spontaneous osteoclastogenesis in order to explore whether
the different bone phenotypes of SpA, PsA, and RA
patients was related to either intrinsic differences in
myeloid cells or differences in T cell activation (46). T
cell depletion abrogated spontaneous osteoclastogenesis
in fresh peripheral blood mononuclear cells, but these
cells were completely redundant in the enhanced osteoclastogenesis observed in cryopreserved cells. Under
these conditions, osteoclastogenesis resulted from a
direct activation of CD14-positive osteoclast precursors
without clear differences between SpA, PsA, and RA
patients, indicating that there is no obvious intrinsic
difference in the osteoclastogenic potential of peripheral
blood monocytes between the different pathologic conditions.
These data raised questions about the translational relevance of the in vitro osteoclast differentiation
assays and emphasized the importance of in situ analysis
at the site of bone destruction. Because the RANK/
RANKL pathway is critical for bone remodeling under
both physiologic and inflammatory conditions, we also
compared the expression of these molecules in the
synovium of SpA and RA patients. We found no differences in the expression of RANK, RANKL, or the decoy
receptor OPG between RA, SpA, and PsA patients (47).
The partial discrepancy of these findings with those of
previous studies suggesting higher OPG levels in SpA
synovium is related to the poor specificity of the antibodies used in previous studies (48–50). Although the
differences in structural remodeling between RA and
SpA cannot be explained by differences in the synovial
expression of RANK, RANKL, or OPG, an important
caveat may be that the investigated synovium was obtained from a site away from the synovium–bone junction. Consequently, the expression of these factors in the
proximity of the bone or within the bone itself remains
to be investigated.
Cartilage damage in peripheral spondylarthritis
Our knowledge of articular cartilage damage in
peripheral SpA is still very limited. Results of imaging
studies suggest that cartilage integrity is better preserved
3540
in peripheral SpA than in RA (51), but this has not yet
been unequivocally confirmed by analysis of cartilage
degradation biomarkers in synovial fluid or by histopathologic assessments (52).
As indicated in our previous study, synovial fluid
levels of IL-1␤ and TNF were significantly lower in SpA
than RA (41). Since these proinflammatory cytokines
can directly stimulate synovial fibroblasts to develop an
aggressive phenotype, we investigated the expression of
cadherin 11 as a key factor for cartilage degradation by
FLS (53). Synovial cadherin 11 expression was significantly correlated with the degree of tissue inflammation
and was decreased upon in vivo treatment with glucocorticoids or upon TNF blockade. Accordingly, cadherin 11
expression by FLS was up-regulated by TNF␣ in vitro.
Although these data indicate that cadherin 11 upregulation may form an important link between TNFdriven synovial inflammation and cartilage degradation,
we did not find differences in cadherin 11 expression
between RA and SpA.
Another group of important mediators of cartilage destruction produced by activated FLS are the
MMPs. Performing a systematic analysis of the synovial
expression of MMP-1, MMP-3, and MMP-9 as well as
their endogenous inhibitors tissue inhibitor of metalloproteinases 1 (TIMP-1) and TIMP-2, we found no
differences between SpA and RA synovitis (54). Similar
to cadherin 11, synovial MMP expression was downregulated by TNF blockade in vivo (54,55). Of interest,
MMP-3 appeared to be the most sensitive marker of
treatment response and reflected peripheral joint disease rather than axial disease in SpA. Although this
concept has been confirmed by several studies (56,57), it
remains unclear if MMP-3 expression directly drives
structural damage or if it is merely an epiphenomenon of
the ongoing inflammatory process. Prospective studies
correlating cadherin 11 and MMP expression with levels
of biomarkers and with the results of imaging of cartilage damage are warranted in order to address these
issues.
Bone repair in peripheral spondylarthritis
Whereas most studies have focused on bone and
cartilage destruction, the typical ankylosis observed in
SpA emphasizes that bone and cartilage repair is at least
as important for the structural outcome of inflammatory
arthritis. Histologic studies have indicated that the ankylosis mainly results from chondroid metaplasia and
subsequent endochondral bone formation (58). This
suggests that the developmental chondrocytes discussed
VANDOOREN ET AL
above may play a crucial role in new tissue formation in
SpA, but the underlying molecular mechanisms and
triggers of this process remain elusive.
The study of new bone formation in SpA has
recently been revived by molecular studies in animal
models. Lories et al (59) investigated the role of bone
morphogenetic proteins (BMPs) in the structural remodeling of the joint in aging male DBA/1 mice. These
mice spontaneously develop arthritis and enthesitis of
the paw and ankle joints and, in contrast to TNF␣transgenic mice, also develop reactive endochondral
bone formation that leads to bony ankylosis. BMP-2 and
BMP-6 were demonstrated to play an important role in
this process. Of interest, a clear up-regulation of the
expression of BMPs 2 and 6, together with an activation
of the Smad signaling pathway, was also observed in SpA
synovium, but this was not different from that in RA
(60).
Another molecular pathway of major interest, the
Wingless/WNT signaling pathway, was investigated by
Diarra et al (14) in human TNF–transgenic mice. Deletion of the WNT inhibitor Dkk-1 not only reduced bone
erosions, but more importantly, it allowed new bone
formation despite ongoing inflammation. In contrast to
the previous model, the new bone formation may be
directly mediated here by osteoblasts rather than by
developmental chondrocytes and endochondral bone
formation. Also in humans, Dkk-1 is produced by FLS in
response to TNF␣ in vitro and is expressed in the
inflamed RA synovium, and it may therefore contribute
to the suppression of bone repair in the RA joint.
Although serum levels of Dkk-1 were reported to be
decreased in SpA as compared with RA, the interpretation of these data is complicated by the differences in
disease activity between both groups as well as the
predominant axial disease in the SpA cohort (14).
Therefore, the relevance of the Dkk-1/WNT pathway for
new bone formation in human SpA remains to be
assessed.
Both experimental models discussed here point
toward an intriguing relationship between inflammation
and new bone formation. In the ankylosing enthesitis
model, new bone formation could not be blocked by
TNF inhibition (61). In TNF-transgenic mice, inflammation and inhibition of new bone formation could be
completely uncoupled by targeting Dkk (14). In human
SpA, there is now increasing evidence that TNF blockade is very effective in controlling inflammation, but it
does not appear to have a major impact on the progression of axial ankylosis in established SpA (2,3). These
data need to be confirmed in longer-term studies as well
MEDIATORS OF STRUCTURAL REMODELING IN PERIPHERAL SpA
as in studies of patients with early disease. Moreover, the
extent to which TNF blockade affects new bone formation (either its inhibition or its promotion) in peripheral
SpA remains to be investigated.
The enthesis and new bone formation in peripheral
SpA
The experimental studies by Lories et al (59–61)
mentioned above are not only relevant to the molecular
mechanisms of new bone formation in SpA-like disease,
but they also emphasize the importance of the anatomic
context of such responses. This aspect was originally
described by McGonagle and colleagues in an important
magnetic resonance imaging study: focal inflammation
in affected knee joints was more frequently observed at
perientheseal sites in SpA than in RA (62), which led
them to propose the novel hypothesis that SpA is a
primary entheseal pathologic condition (63). Despite the
obvious interest of this novel conceptual framework, the
independent followup studies performed to confirm
these findings yielded contradictory results (64–69). In
particular, the findings of these imaging studies called
into question the specificity of this finding for SpA, since
enthesitis was also commonly observed in other types of
joint inflammation, including RA. Whether the enthesitis is primary in SpA and secondary in other types of
joint inflammation remains to be determined in prospective, longitudinal studies of patients with early, untreated disease. In addition, the exact histologic substrate of these imaging abnormalities at the enthesis
remains to be better defined, since the 2 studies on this
topic yielded conflicting results (70,71).
In the context of the present review, the main
question is whether the new bone formation seen in SpA
originates at this particular site of inflammation. It is
well known that bony spurs can develop in the normal
enthesis of healthy humans (72). This process of endochondral ossification affects the fibrocartilage of the
enthesis, without the need for preceding microtears or
any inflammatory reaction (73). Patients with early SpA
have the same type of small spurs in the distal part of the
enthesis as normal control subjects, but they display
bone erosions at the proximal insertion (74). Moreover,
large spurs, which are not observed in normal controls,
are found at the distal part of the enthesis in longstanding SpA. These data indicate that, indeed, new bone
formation can occur at the entheseal site but that this
process is topographically and temporally uncoupled
from bone erosions. This finding is consistent with
experimental data showing that inhibition of osteoclasts
3541
does not prevent ankylosis in the DBA/1 mouse model
of enthesitis (75).
Cartilage repair in peripheral spondylarthritis
As mentioned above, there are few indications
that articular cartilage may be better preserved in SpA
than in RA. It is tempting to speculate that triggers of
chondroid hyperplasia and resulting endochondral bone
formation that play a role in ankylosis in SpA may not
only affect developmental chondrocytes, for example, at
the enthesis, but may also modulate the anabolic/
catabolic balance of articular chondrocytes.
Different studies assessed cartilage metabolism
in SpA by measuring serum biomarkers of cartilage. Kim
et al (76) reported that serum levels of the 846 epitope
and C-propeptide of type II collagen (CPII), both of
which are considered to be anabolic markers, but not
C2C, a serum biomarker of type II collagen degradation,
were elevated in patients with ankylosing spondylitis as
compared with healthy controls. This skewing toward
cartilage anabolism in SpA contrasted with the catabolic
pattern in RA, but the use of serum biomarkers unfortunately does not allow the differentiation between
articular and developmental chondrocytes.
In an attempt to study the articular chondrocyte
more directly by measuring synovial fluid melanoma
inhibitory activity (MIA) as a biomarker of cartilage
anabolism, we found that chondrocyte anabolism was
more activated in the joints of SpA patients than in the
joints of RA patients despite similar levels of anabolic
growth factors IGF-1 and TGF␤3 (77). The fact that
IGF-1 levels correlated strongly with MIA levels in SpA
patients, but not RA patients, suggests that IGF-1 plays
an important role in driving cartilage anabolism in SpA.
These findings fit with the concept that the high levels of
proinflammatory cytokines found in RA as compared
with SpA may desensitize RA cartilage to the anabolic
effects of IGF-1 (78).
Even if cartilage anabolism is better preserved in
SpA than in RA, the levels of cartilage anabolism
biomarkers are further up-regulated by TNF blockade in
SpA. Infliximab therapy up-regulates MIA levels, and
etanercept treatment leads to a significant increase in
serum levels of CPII and the 846 epitope (77,79,80).
Overall, these biomarker data suggest that articular
cartilage anabolism is promoted by TNF blockade. This
may partly explain why restoration of the articular
cartilage thickness is observed after TNF blockade in
some SpA patients. Whether these processes also affect
the developmental chondrocyte and thereby contribute
3542
to cartilage metaplasia, endochondral bone formation,
and, eventually, pathologic ankylosis is not yet known.
Functional implications
The translational expression and biomarker studies described here have their obvious limitations, and a
number of important issues remain to be addressed.
First, expression studies do not allow us to directly
address the functional implications of these molecular
pathways. Whereas transgenic and knockout models
have turned out to provide useful biologic information,
the major challenge is to link this functional information
to a clinically relevant model of SpA. Analysis of these
pathways and interactions in the previously described
ankylosing enthesitis and TNF-transgenic models as well
as in the HLA–B27–transgenic rat model is therefore of
prime importance (14,59,81,82).
Second, translational expression studies in SpA
have been conducted in patients with peripheral disease,
since clinically relevant material can be obtained from
inflamed knee and ankle joints. It is only recently that
similar studies have been initiated for axial disease. Over
the last couple of years, Appel and colleagues (83,84)
have described a number of important features of bone,
cartilage, and synovium in patients with axial SpA. The
extent to which the mechanisms of bone and cartilage
remodeling are similar or different in axial versus peripheral disease remains to be determined.
Third, cross-sectional and short-term longitudinal studies are not able to define the exact order of
events in the structural remodeling that occurs in SpA.
Therefore, the question remains open whether progressive ankylosis depends on initial inflammatory damage
of bone and cartilage or whether the processes of
destruction and new tissue formation are completely
uncoupled (75,85).
Future directions
Our classic approach to complex biologic questions consists of careful histologic and immunopathologic analyses, functional experiments in vitro and in
experimental models, identification of novel targets, and
finally, development and testing of specific drugs in
patients with the disease. The limited access to clinically
relevant human tissue samples, the paucity of appropriate experimental models, and the requirement that
long-term longitudinal studies be performed are all
major hurdles for our classic approach to overcome in
deciphering the exact cellular and molecular mecha-
VANDOOREN ET AL
nisms of tissue remodeling in SpA. The development
and validation of reliable biomarkers that reflect specific
aspects of the pathophysiology of tissue remodeling may
circumvent some of these hurdles, but such markers are
not yet available.
An alternative and innovative approach is, however, now available with the increasing number of targeted biologic and small-molecule therapies. These
drugs, which have usually been developed and tested for
efficacy and safety in other pathologic conditions, indeed allow us to probe specific cellular and molecular
pathophysiologic mechanisms in vivo in our patients.
This reverse approach, using a targeted therapy as a
“human knock-down model” in which to delineate a
clinically relevant pathway, rather than to identify molecular mechanisms in order to develop new therapies,
may be particularly efficient for deciphering tissue remodeling in SpA. This should include early and aggressive intervention with existing inflammation-directed
biologic agents (anticytokine antibodies, costimulation
blockade, cell depletion) as well as the evaluation of
therapies designed to specifically target connective tissue in other fields of medicine in order to clarify the
extent to which inflammation and tissue remodeling are
coupled or uncoupled in SpA.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Baeten had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Vandooren, Yeremenko, Noordenbos,
Bras, Tak, Baeten.
Acquisition of data. Vandooren.
Analysis and interpretation of data. Vandooren, Yeremenko, Noordenbos, Bras, Tak, Baeten.
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