RHEUMATOLOGY
Rheumatology 2011;50:v13–v18
doi:10.1093/rheumatology/ker395
Pathogenesis of skeletal and connective tissue
involvement in the mucopolysaccharidoses:
glycosaminoglycan storage is merely the instigator
Lorne A. Clarke1
Abstract
The mucopolysaccharidoses (MPSs) are a series of rare genetic disorders in which progressive bone and
joint disease represents a key source of morbidity for patients. The recent introduction of enzyme replacement therapy for many of the MPSs has led to a need for increased physician awareness of these
rare conditions in order to ensure that treatment is initiated at a time that leads to optimal benefit for
patients. In addition, the current experiences of the clinical responsiveness of patient’s symptoms to
enzyme replacement approaches have also fuelled an interest in the development of alternative and
adjunctive therapeutic approaches directed particularly to the rheumatological aspects of disease.
Understanding the underlying pathogenesis of the MPSs is a key element for advancements in both of
these areas. This review highlights the current knowledge underlying the pathophysiology of disease
symptoms in the MPSs and underscores the importance and role of pathogenic cascades.
Key words: Lysosomal storage disease, Mucopolysaccharidosis, Enzyme replacement therapy, Glycosaminoglycans,
Dysostosis multiplex, Signal transduction, Inflammation, Apoptosis, Proteoglycans, Arthropathy.
Introduction
The mucopolysaccharidoses (MPSs) are a complex group
of progressive storage disorders that ultimately affect
most organ systems [1, 2]. A key component of disease
morbidity relates to progressive involvement of bone and
connective tissue, leading to significant health impact.
Although the primary defect in glycosaminoglycan (GAG)
metabolism for each of the MPSs is well characterized,
the precise mechanisms underlying the disease symptoms, and in particular the symptoms that most significantly impact patients, are poorly understood [3].
Recent advances highlight an emerging concept that primary GAG storage leads to perturbation of cellular, tissue
and organ homeostasis mediated through alterations of
complex multifarious pathways, and that these secondary
effects are important effectors of disease symptoms and
progression (reviewed in [3]). In addition, once initiated,
these secondary events may not be easily reversible by
direct enzyme replacement strategies [4]. This concept
1
Child and Family Research Institute, Department of Medical Genetics,
University of British Columbia, Vancouver, BC, Canada.
Submitted 1 July 2011; revised version accepted 6 October 2011.
Correspondence to: Lorne A. Clarke, Children’s and Women’s Health
Center of British Columbia, 4500 Oak Street Rm C234, Vancouver, BC,
V6H-3N1 Canada. E-mail: [email protected]
underscores the critical importance of commencement
of therapy early in the course of disease and highlights a
need for additional and supplementary therapeutic strategies in the MPSs. Here we review the pathogenesis of the
MPSs with an emphasis on rheumatological aspects of
disease. An appreciation of the underlying pathogenesis
of the connective tissue and skeletal involvement in these
disorders provides insight into factors affecting the natural
history of MPS disease, the optimal timing and impact of
therapeutic intervention, as well as the identification of
potential alternative therapeutic targets.
Novel concepts of disease mediators in
the MPSs—the role and place of GAGs
Historically the pathogenesis of the MPSs has been considered as a simple storage phenomenon which assumed
that GAGs are an inert storage material and this storage
was the sole and direct mediator of disease symptoms. A
key observation that questions this view comes from various MPS animal model studies which demonstrate that
although disease symptoms in the MPSs are progressive,
most organs and tissues do not show progressive GAG
storage [5, 6]. This simple observation therefore challenges the primary storage or inert GAG-centric perspective of disease mediators and indicates that it is more
! The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Lorne A. Clarke
accurate to consider the specific MPS disease symptoms
or signs and then unravel the various complex homeostatic alterations that underlie the symptoms. This perspective
presumes that a causal link to the defect in GAG degradation can be made, although recent evidence suggests
that for some disease features the link may be complex
and not necessarily linear or first degree in nature, but
may be best conceptualized as a complex pathogenic
cascade [7–13]. For many lysosomal storage diseases
this concept of a pathogenic cascade has been clearly
illustrated [14, 15]. In the case of the MPSs, one must
consider the fact that GAGs are biologically active molecules both as free GAGs and when complexed with proteins forming proteoglycans. As such, GAGs are involved
in many critical cellular and tissue pathways, including
signal transduction (via their ability to modulate the function of cell surface receptors), sequestration of extracellular humoral factors and modulation of the cross talk
between cells [3]. Thus there are numerous potential
mechanisms underlying specific MPS disease symptoms
as indicated in Table 1. The complexity of the mechanisms underlying the progressive features of MPS disease
underpins the potential limitations and roles of therapeutic
approaches.
Primary arthropathy in the MPSs
Each of the MPSs has progressive joint involvement, but
there are significant differences in the specific joint symptomatology and rate of progression of the joint disease in
the individual disorders. The joint symptomatology in each
of the MPSs results from both primary effects of the disease on articular cartilage and the surrounding connective
tissue structures as well as primary bone disease. For
TABLE 1 Potential mediators of disease symptoms in the
MPSs
Direct storage of GAG in the extracellular matrix
Direct intralysosomal/endosomal GAG storage
Secondary effects of GAG storage in the extracellular
matrix
Alteration of signal transduction pathways
Direct cell surface receptor activation
Cell surface receptor function: ligand–receptor
interactions
Cell surface receptor maintenance
Modulation of humoral factor availability
Cytokines, inflammatory mediators
Secondary effects of intralysosomal GAG storage
Alteration of the endosomal network
Affecting intracellular targeting pathways
Affecting endocytosis
Affecting autophagy
Alteration of other lysosomal degradative pathways
General physiological effects of impaired GAG recycling
Energy imbalance: increased need for synthesis of
monosaccharides
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illustrative purposes, the underlying pathogenesis of the
articular disease and bone disease will be considered
separately, although overlapping mechanisms are clearly
at play. The joint disease in the MPSs is characterized as
progressive joint disease in the absence of significant clinical signs of inflammation [16–17]. MPS I, II, VI and VII
patients show progressive joint stiffness involving all
joints, with formation of joint contractures and eventual
destructive joint disease [18, 19]. The resulting progressive loss of hand dexterity, spinal alignment, joint pain and
joint mobility represents a significant source of morbidity
for patients. MPS III patients have less severe but similar
joint involvement. MPS IV patients also have progressive
joint involvement, but in contrast they have joint hyperextensibility, joint hypermobility and severe skeletal dysplasia [1, 16, 20].
Studies of articular chondrocytes and synovial tissues
from various MPS animal models, where dermatan sulphate is stored, reveals an age-dependant increase in articular chondrocyte apoptosis with associated increased
nitric oxide and inflammatory cytokine release [21]. This
enhanced apoptosis in MPS appears to be specific for
articular chondrocytes. Dermatan sulphate, by virtue of
its structural similarity to lipopolysaccharide (LPS), has
been proposed and demonstrated to be a direct mediator
of this process by activation of the LPS signal pathway
with evidence of elevated expression of LPS binding
protein (LBP), Toll-like receptor 4 (TLR4), CD14 and the
chemokine receptor CXCR4, all of which are essential
elements of the LPS signal transduction pathway
[9, 13, 22]. This LPS activation leads to activation of
TNF-a, IL-1b and macrophage inflammatory protein
(MIP)-1a with evidence of increased TNF-a and IL-1b in
SF samples. In addition the collagenase MMP-13 has
been noted to be overexpressed in MPS synoviocytes,
as is RANK ligand (receptor activator of nuclear factorkB), ceramide and sphingosine-1-phosphate [9]. Thus a
complex cascade leading to chondrocyte apoptosis, synovial hyperplasia and inflammatory joint destruction
mediated directly by MPS synoviocytes as well as via
cytokine and chemokine recruitment of macrophages
appears to underlie the progressive arthropathy in MPS
I, II, III, VI and VII. Therefore, despite the lack of clinical
evidence of joint inflammation, activation of inflammatory
pathways represents a significant component of joint disease in these MPSs.
Limited research has been directed towards the elucidation of the mechanisms underlying the joint disease in
MPS IV, where the primary storage material is keratan
sulphate. Unfortunately, clinically relevant animal models
for MPS IV are not available for study. Biochemical and
histological characterization of articular cartilage in two
individuals with MPS IVA revealed evidence of wider collagen fibre diameter with decreased lysyl hydroxylation
and total amount of pyridinolines, in addition to an altered
arrangement of proteoglycans in the extracellular matrix
surrounding articular chondrocytes [23]. A report of two
siblings with MPS IVA, where femoral condyle biopsies
were studied, revealed that in addition to detection of
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Pathogenesis of mucopolysaccharidoses
keratan sulphate there were significant increases in type I
collagen at both the protein and mRNA level as well as
decreases of type II collagen and the proteoglycan aggrecan at both the protein and mRNA level [24]. These studies serve to illustrate that in MPS IVA there also appear
to be perturbations in protein components of articular cartilage, but the underlying mechanisms and how the observations relate to the primary defect in keratan sulphate
degradation remain unknown.
Primary bone disease in the MPSs
Each of the MPSs is associated with primary skeletal dysplasia that is referred to by the descriptive term dysostosis
multiplex [1]. Unfortunately, this term is relatively poorly
defined and does not lend itself to objective severity assessment. The main clinical manifestations of skeletal
dysplasia in the MPSs are short stature, which can be
particularly severe in MPS IV and VI, and progressive skeletal deformation, leading to spinal misalignment, long
bone deformation, macrocephaly, hip dysplasia, chest deformity and facial dysmorphism. Osteopenia is described
in MPS VI and VII.
Studies of growth plate and bone tissues from various
MPS animal models reveal primary morphogenic abnormalities in the developing growth plate as well as the structure of cortical bone. In young MPS I and VII mice, as well
as MPS VI rat and cat models, there is evidence of disordered growth plate chondrocyte organization and trabecular architecture [8, 9, 22, 25, 26]. Studies by Wilson
et al. [27] using the MPS I murine model have demonstrated a defect in endochondral ossification, which is
secondary to osteoclast dysfunction. The primary mediator of the ossification defect appears to be the inhibition
of the collagenase activity of cathepsin K by the local
accumulation of heparan and dermatan sulphate.
Paradoxically, cathepsin K protein levels appear to be
up-regulated in the subgrowth plate area of MPS I mice,
but its ability to cleave type II collagen is inhibited by the
accumulation of GAGs. A primary defect in osteoclast
function has also been demonstrated in murine MPS VII
[9, 28]. Studies of the MPS VII murine growth plate show
significant accumulation of chondroitin-4-sulphate and reduction in the number of cells in the proliferative zone,
likely due to reduced chondrocyte proliferation rather
than increased apoptosis [8]. mRNA expression studies
of the growth plate show a marked decrease in expression of IL-6 family members, including leukaemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin 1 and
cardiotrophin-like cytokine factor 1, with more modest reductions in the cytokines IFN-g and IL-1b, proteins
involved in the TNF-a pathway and various negative regulators of signal transducer and activator of transcription
(STAT). Increases were noted in the proteases cathepsin
S and MMP-3 and reduced levels of tyrosinephosphorylated STAT3. Taken as a whole, these data
suggest that the bone shortening in MPS VII results from
the primary accumulation of chondroitin-4-sulphate and is
mediated through alteration of key components of the
Janus
kinase/STAT
(JAK/STAT)
signalling
and
www.rheumatology.oxfordjournals.org
transduction pathways. As chondroitin-4-sulphate does
not accumulate in the other MPSs, the mechanisms responsible for growth plate dysfunction and bone shortening in the other MPSs are largely unknown, but the
comprehensive studies in MPS VII indicate the complexity
of the homeostatic alterations that potentially underlie the
growth plate dysfunction in MPS.
Pathogenic insights from studies of
other organ systems
Cardiac
The cardiac manifestations of the MPSs consist of progressive valvular thickening leading to valvular incompetence as well as primary myocardial involvement; the
former is universal, whereas the latter is uncommon
[29–32]. Studies in MPS I mice, dogs and humans reveal
an abnormality in cardiac and aortic vessel elastogenesis,
which is likely secondary to both decreased elastic fibre
assembly or synthesis as well as augmented elastic fibre
fragmentation [7, 12, 29]. Decreased elastin synthesis and
elastin fibre assembly has been demonstrated in vitro in
MPS I and is hypothesized to be caused by accumulation
of dermatan sulphate, which ultimately leads to deficiency
of elastin binding protein, a key chaperone for elastin sorting and elastin fibre assembly [33]. A defect in elastin assembly in vivo has not been reported. Studies in the MPS I
murine model reveal that increased elastin fragmentation
is likely caused by increased expression of two elastindegrading proteins, MMP-12 and cathepsin S [7]. In addition, key transcriptional regulators of MMP, STAT1 and
STAT3 showed evidence of activation in tissues of affected
animals; these latter results show similarity to the activation of the STAT pathway in chondrocytes. The direct mediators responsible for activation of the STAT pathway in
the aorta are not known, but may relate to the abnormal
biomechanical properties of the vessel wall.
CNS
MPS III, MPS VII and a portion of MPS I and II patients
have progressive CNS disease manifesting as neurodegeneration [1]. Analysis of murine models of MPS IIIB
and MPS I reveal a central role of inflammation in which
activation of microglia and astrocytes are noted,
with increased CNS expression of CD38, lysozyme M,
cathepsins S and Z, cytochrome b558, DAP12 and complement factors C1q and C4 [34]. Accumulation of gangliosides (GM2 and GM3) as well as cholesterol, ubiquitin,
mitochondrial ATPase subunit c and aggregates of paired
helical filament P-tau has also been demonstrated in various MPS models [35–37]. These studies highlight the
complex secondary metabolic alterations that underlie
CNS disease in the MPSs (reviewed in [38]).
Conclusion
Rheumatological symptoms and disease complications
represent a significant contribution to disease burden for
MPS patients. The elucidation of the complex
v15
Lorne A. Clarke
pathophysiological processes that underlie these symptoms in the MPSs underscore discussions related to
therapeutic approaches in these conditions (Fig. 1). The
complex pathological cascade underlying the progressive
joint and bone involvement in the MPSs would imply that
initiation of treatment early in the course of disease would
afford the best outcome and have the greatest chance to
significantly impact quality of life. Conversely, delayed
diagnosis and late initiation of treatment would likely
lead to the patient entering a stage of disease where the
bone and joint pathology is unlikely to be reversed and
may in fact continue to progress despite treatment.
Therefore, methods need to be developed to diagnose
MPS patients early in the course of disease by increasing
awareness among physicians and consideration of either
newborn or early targeted population screening.
Therapy for the MPSs is reviewed elsewhere in this
supplement [39]. Experience with haematopoietic stem
cell transplantation (HSCT) in severely affected MPS patients indicates that bone and joint disease is minimally
impacted, even when HSCT is initiated early in the course
of disease [40–42]. Long-term experience with enzyme
replacement therapy (ERT) and specifically long-term
ERT started very early in the course of disease for patients with attenuated disease is limited. Two recent reports of sibling pairs with MPS I and MPS VI illustrate the
potential for significant alteration of bone and joint disease in attenuated patients when treatment is initiated
early in the course of disease. In the case of MPS I, experience with 5 years of laronidase (rhIDUA) treatment in a
sibling pair with one sibling beginning treatment at
5 months of age and the other at 5 years of age reveals
minimal joint and bone disease in the younger sibling as
compared with the older sibling at the same age [43]. In
the case of MPS VI, the comparison of siblings receiving
N-acetylgalactosamine-4-sulphatase (rhASB) beginning
at 8 weeks and 3.6 years of age, respectively, and followed for 3.6 years revealed evidence of stabilization of
severe scoliosis in the older sibling and prevention of
scoliosis, hand contractures and facial dysmorphism in
the younger sibling [44]. On the other hand, corneal
clouding continued to progress, as did radiological evidence of dysostosis.
A key factor highlighted by these cases is the uncertainty of the appropriate dose of recombinant enzyme that
is required to prevent disease, as clinical trials have utilized patients with pre-existing and advanced disease. It is
possible that higher doses or more frequent dosing of ERT
is required to impact skeletal and joint disease in the
MPSs, particularly during periods of rapid growth.
The identification of the complex pathogenic cascade
underlying the pathogenesis of the MPSs and, in particular, the identification of the TLR4 and STAT signal pathways, as well as inflammation and altered collagenase
activity of cathepsin K, as key elements in the pathogenesis of the rheumatological aspects of the MPSs should
lead to potential additional therapeutic approaches for
these disorders. It is likely that therapeutics targeted to
these key pathways will augment enzyme replacement
strategies.
FIG. 1 Mechanisms of bone and joint disease in the MPSs.
v16
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Pathogenesis of mucopolysaccharidoses
Rheumatology key messages
Defective GAG degradation in the MPSs leads to a
complex cascade of pathophysiological events.
. Secondary consequences of GAG storage can be
irreversible; early intervention may improve
long-term outcome.
. The complex pathophysiology of the MPSs may necessitate targeting and combining treatments for
optimal outcome.
.
Acknowledgements
L.A.C. holds an investigatorship through the Child and
Family Research Institute and acknowledges research
support provided from the Canadian MPS Society. The
opinions and conclusions set forth herein are those of
the authors and do not necessarily represent the views
of Genzyme, BioMarin or Shire.
Supplement: This paper forms part of the supplement entitled ‘Rheumatologic Aspects of the
Mucopolysaccharidoses’. This supplement was supported by joint educational funding from Genzyme,
BioMarin Pharmaceutical and Shire Human Genetic
Therapies.
Disclosure statement: L.A.C. has received honoraria and
travel expenses from Genzyme Corporation and Shire for
invited lectures.
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