Best Practice & Research Clinical Rheumatology
Vol. 22, No. 2, pp. 209–220, 2008
doi:10.1016/j.berh.2007.12.001
available online at http://www.sciencedirect.com
1
Joint homeostasis, restoration, and
remodeling in osteoarthritis
Rik J.U. Lories *
MD, PhD
Associate Professor
Laboratory for Skeletal Development and Joint Disorders, Division of Rheumatology,
Department of Musculoskeletal Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
Osteoarthritis is the major cause of joint failure. The outcome of the disease process is determined by complex interactions between cells and molecules steering homeostasis, destruction,
restoration, and remodeling. The articular cartilage has a limited restoration and repair capacity.
Genetic studies in humans and the development of mouse models have identified the role of
signaling pathways that are important for skeletal development in the postnatal biology and pathology of articular cartilage. These include bone morphogenetic protein, transforming growth
factor beta, fibroblast growth factor, wingless-type signaling, and their respective antagonists
such as noggin and frizzled related protein. The synovium is prone to inflammation and emerging
evidence suggests that innate and adaptive immune responses are important. Bone and cartilage
form a biomechanical unit; stiffer bones might impair cartilage homeostasis. The biology of
frizzled related protein provides a basis for the hypothesized inverse relationship between
osteoarthritis and osteoporosis.
Key words: bone morphogenetic protein; bone; cartilage; frizzled related protein; osteoarthritis; synovium; wingless-type (WNT).
INTRODUCTION
The impact and outcome of physiological and pathological processes in the joint and
bone are determined by molecular signaling pathways that regulate tissue homeostasis,
restoration, and remodeling.1 Homeostatic processes ensure the adaptive maintenance of tissue integrity and function. This can fail in case of strain or direct injury,
which result in tissue damage. Tissue responses to damage aim to restore function,
integrity, and homeostasis. Ideally, this is achieved by tissue restoration. However, in
many cases, damage instead leads to tissue remodeling with either the formation of
* Department of Rheumatology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Tel.: þ32 16 342542; Fax: þ32 16 342543.
E-mail address: [email protected]
1521-6942/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
210 R. J. U. Lories
a surrogate tissue (repair) or new tissue.1,2 The remodeling process does not result in
full restoration of integrity and homeostasis and might therefore fail in the long term,
with progressive loss of function as a consequence.
The osteoarthritic diseases are a group of disorders characterized by gradual failure
of the joints, leading to damage, pain, and disability.3 The primacy of cartilage damage
versus excessive stress in the bone–cartilage biomechanical unit as the driving mechanism for osteoarthritis (OA) is still debated.4,5 It is clear, however, that the healthy
joint requires a fine-tuned balance between molecular signals that regulate homeostasis, damage, restoration, and remodeling. This balance is determined at the level of the
individual cells, of the tissue architecture, and of the interactions between different
tissues in the joint organ, e.g. articular cartilage, synovium, and bone.
Different factors appear to impair maintenance of homeostasis in a joint that has
been damaged or strained. First, the articular cartilage is a very specialized tissue,
the function of which is critically dependent on its physicochemical properties. It is
rich in nonvascular, paucicellular extracellular matrix, which might explain its limited
potential for regeneration and repair. Second, adaptive responses in the bone with
which the articular cartilage is forming a biomechanical unit might strengthen the
bone component but thereby inappropriately impair cartilage homeostasis and function.5,6 Third, articular chondrocytes can produce a number of proinflammatory cytokines and tissue-destructive enzymes. Under physiological circumstances these might
play a role in normal tissue homeostasis and turnover. In situations of damage, they
could inappropriately enhance tissue destruction.
Increasing evidence supports the hypothesis that tissue restoration and remodeling
in different forms of arthritis are regulated by signaling pathways that are also involved
in the development of cartilage and bone.1 In particular, transforming growth factor
beta (TGFB), bone morphogenetic protein (BMP), wingless-type (WNT), and fibroblast growth factor (FGF) signaling have been studied in OA. Here, we focus on three
important questions and their potential clinical implications: (1) What is the role of
these signaling pathways in homeostasis, restoration, and remodeling of the articular
cartilage? (2) How do these pathways regulate and influence the interactions between
cartilage, bone, and synovium in the joint? (3) Are these pathways involved in new tissue formation in OA?
ACTIVATION OF SIGNALING PATHWAYS CRITICAL FOR JOINT
DEVELOPMENT IN POSTNATAL ARTICULAR CARTILAGE
In-vitro cell culture experiments, cartilage explant analysis, in-vivo genetic models
(Table 1), and gene transfer protocols, as well as genetic studies in humans, support
a role for the above-mentioned signaling pathways in the biology and pathology of articular cartilage. The wealth of data generated also highlights the complexity of the
processes involved. In addition, these signaling pathways might have a wide range of
effects in vivo, depending on factors such as target cell type and differentiation. For instance, different members of the TGFB superfamily, such as TGFBs, BMPs, and related
cartilage-derived morphogenetic proteins (CDMPs) have anabolic effects on chondrocytes (for recent review, see ref. 7). However, these molecules should be considered
as pleiotropic morphogens, growth factors, and cytokines with diverse effects on distinct cell types. Indeed, TGFB is not only a chondrogenic growth factor but also an
immune-regulating cytokine and a potent stimulus of fibrosis.8,9 BMPs were originally
identified as proteins that can induce a cascade of ectopic endochondral bone
Joint homeostasis, restoration, and remodeling is osteoarthritis 211
Table 1. Genetic models showing a role for developmental signaling pathways in OA.
Reference
Bone morphogenetic protein signaling
Tissue-specific BmprIa knockout mice
Nog haploinsufficient mice
21
22
Transforming growth factor beta signaling
TgfbrII dominant negative mice
Smad3 knockout mice
28
29
Wingless-type signaling
Frzb knockout mice
48
BmprIa, bone morphogenetic protein type Ia receptor; Frzb, frizzled related protein; Nog, noggin; Smad3,
Smad family member 3; TgfbrII, transforming growth factor beta type II receptor.
formation in vivo10,11 but are also critical during developmental patterning.12 The respective roles of the above-mentioned pathways in cartilage biology and OA is most
strongly supported by data from in vivo genetic mouse models using either loss or
gain of function approaches.
Bone morphogenetic proteins
CDMP1 was originally identified from a chondrogenic extract of articular cartilage.13 In
the mouse, its homolog growth and differentiation factor 5 (Gdf5) is expressed in the
joint interzone during development.13 A spontaneous mutation in this gene leads to
joint fusions in mice.14 Similar phenotypes are found in human chondrodysplasias
caused by mutations in the CDMP1 gene.15–17 Of specific interest, a genetic association
between OA and polymorphisms in the regulatory region of CDMP1 has recently been
described.18 The protein is present in normal human adult articular cartilage.19 Its expression is mostly restricted to the superficial cartilage in normal joints, whereas in
OA cartilage the expression domain extends into damaged areas.19 Recombinant
CDMP1 increases proteoglycan synthesis in adult articular cartilage explants that
have been partially matrix depleted by mild trypsin treatment.20 The in-vivo role of
Gdf5 in animal models of OA, however, remains to be studied.
The developmental expression of Gdf5 in the joint interzone was used to generate
a joint-specific Bmp-receptor (Bmpr) knockout mouse.21 Heterozygous BmprIaþ/
mice, engineered to express a Cre recombinase in the Gdf5 locus (Gdf5Cre/Cre;BmprIaþ/),
were crossed with mice that carry a floxed BmprIa allele (Gdf5þ/þ;BmprIaloxP/loxP). Expression of the Cre gene leads to cell-specific deletion of the floxed BmprIa gene. Therefore, the Gdf5þ/Cre;BmprIa/loxP conditional knockout mice have no BMPRIa in the
progeny of cells that expressed Gdf5 during development. These mice show some
mild developmental defects (short ears, soft-tissue syndactyly between digits 1 and 2,
and tarsal joint ankylosis), but more importantly they developed rapid cartilage loss after
birth.21 These data suggest that BMP signaling through BMPRIa is essential to maintain
cartilage homeostasis.
Our observations in noggin (Nog) haploinsufficient mice (Nogþ/LacZ) provide further
support for this hypothesis.22 NOG is a secreted antagonist of BMP signaling that
binds to different BMP ligands and is expressed in the articular cartilage.22 Nog
212 R. J. U. Lories
knockout mice are embryologically lethal whereas the haploinsufficient mice are viable
but with a þ50% reduction in Nog expression levels.22,23 Reduced NOG levels in
Nogþ/LacZ mice protect the articular cartilage in a mouse model of inflammatory joint
destruction. Reduction in NOG enhanced BMP signaling in the articular cartilage, as
demonstrated by immunohistochemistry for phosphorylated SMAD1/5, a downstream
mediator in the activated signaling cascade. By contrast, overexpression of NOG in
wild-type mice in this model increased cartilage damage, probably by reducing BMP
activity.22
These data from genetic mouse models of BMP signaling are further corroborated
by a number of in-vitro and in-vivo studies, in particular on BMP2 and BMP7 (for review, see ref. 7). In addition, proinflammatory cytokines such as interleukin-1 (IL1) upregulate BMP2 in chondrocytes and synoviocytes.24,25 Intra-articular injections of
BMP2 in the mouse knee have been used to assess the effect of this BMP on articular
cartilage in vivo. BMP2 stimulates proteoglycan synthesis in normal knees but cannot do
this in a model of destructive arthritis.26 Injection of BMP2 also triggers osteophyte
formation (see below).
These combined findings highlight the potential role of BMPs in the maintenance of
the chondrocyte phenotype and the integrity of the postnatal joint surface. Not surprisingly, BMPs have been suggested for tissue restoration or repair therapeutic approaches.27 The use of growth factors for tissue engineering approaches is beyond
the scope of this chapter, but the delicate in-vivo balance between BMPs, their antagonists, and their anabolic effects resulting in new tissue formation suggest that this
approach will require careful design and optimal control.27
Transforming growth factor beta
TGFBs – members of the same superfamily – can also play a role cartilage biology and
OA. Skeletal tissue-specific overexpression of a dominant negative TGFB type II receptor (TGFBRII), thereby effectively neutralizing TGFB signaling, leads to an OA-like phenotype with hypertrophy and terminal differentiation of chondrocytes.28 A similar
phenotype is seen in mice deficient in Smad3, a TGFB-associated intracellular signaling
molecule.29 Smad3/ mice develop an OA-like disease, characterized by progressive
loss of articular cartilage, surface fibrillation, formation of large osteophytes, upregulation of type X collagen, and decreased proteoglycan synthesis at the age of 6 months.
Intra-articular joint injections of TGFB1 have been used to study the in-vivo effects
of TGFBs on cartilage metabolism and potential interactions with IL1. Following
TGFB1 injection, proteoglycan synthesis rises steadily and the response is maintained
for 20 days. Stimulation of endogenous TGFB or BMP production and/or upregulation
of receptors are hypothesized as underlying mechanisms for this observation. Remarkably, TGFB1 counteracts the IL1-induced suppression of proteoglycan synthesis
whereas BMP2 does not.30–34 Of interest, the effects of TGFB on articular cartilage
appear age dependent.35
Wingless-like family
The WNT family consists of over 15 secreted glycoproteins with diverse functions in
development and postnatal life. WNT signaling is crucial for joint and bone development.36–38 As with CDMP1, the strongest evidence supporting a role for this pathway
in OA has come from human genetics. Polymorphisms in frizzled related protein
Joint homeostasis, restoration, and remodeling is osteoarthritis 213
(FRZB), a secreted antagonist of WNT signaling39–41, have been associated with OA.42–47
Like CDMP1, FRZB was originally identified from a chondrogenic extract of articular
cartilage and found to be expressed in developing skeletal elements.39 Our group has
developed Frzb/ mice.48 The mice do not show apparent developmental abnormalities
in the skeleton. However, in different models of cartilage damage, proteoglycan loss is
significantly enhanced as compared to wild-type mice. Cartilage damage is associated
with increased WNT signaling and matrix metalloproteinase-3 (Mmp3) expression. In
addition, FRZB can also directly inhibit MMP activity48,49, providing a second mechanism
for an increased incidence of OA in patients with FRZB polymorphisms.
The role of WNTs in postnatal cartilage biology is certainly complex. Our data in
the Frzb/ mice suggest that WNTs would contribute to cartilage damage and hence
OA development. However, Dell Accio et al also demonstrated that mechanical injury
to cartilage explants results in downregulation of Frzb and upregulation of WNT target
genes like axin2. Activation of WNT signaling also upregulates type II collagen and
aggrecan expression in their system.50
Fibroblast growth factors
FGFs and their receptors (FGFRs) play important roles in multiple biological processes, including mesoderm induction and patterning, cell growth and migration, organ
formation, chondrogenesis, and growth.51,52 Mechanical injury to cartilage explants results in activation of the extraceullar regulated kinase (ERK) mitogen-activated protein
kinase (MAPK) pathway. This is mediated by FGF2.53 A similar activation cascade was
identified in mechanically loaded articular cartilage.54 Interestingly, FGF2 is bound in
the pericellular chondrocyte matrix to perlecan, suggesting that the trapped growth
factor is acting as a ‘structural’ protein.55 However, as for WNTs, the effects of
FGFs in cartilage and OA are far from clear as FGF2 treatment of cartilage explants
results in enhanced expression of MMPs and of tissue inhibitors of MMP (TIMPs).53
Clinical implications
The biology of articular chondrocytes in health and disease should guide the development of therapeutic plans to treat or prevent OA. Pharmacological interventions in
a later stage of the disease, e.g. when symptoms are already present, might have
missed an important window of opportunity to revert the ongoing process of tissue
damage and loss of function. Hence, treatments with MMP inhibitors or growth factors
are not likely to cure the disease at this stage and at best limit further damage and
stimulate repair, not restoration. By contrast, prevention of disease could be an attractive alternative, albeit difficult to achieve. Early recognition of patients at risk might include evaluation of lifestyle risk factors, such as overweight and lack of exercise, as well
as genetic profiling. A number of polymorphisms have been identified and important
associations have been convincingly replicated in the last couple of years. The identification of high-risk patients might not only allow developing lifestyle measures but
could also lead to preventive treatments in an earlier disease stage. This would result
in a risk reduction approach not unlike current practice in the prevention and treatment of osteoporosis. However, toxicity of treatments with growth factors as well
as enzyme inhibitors might be important limiting factors, particularly in elderly patients
who require a long-term therapy. Better understanding of different types of OA, including their specific genetics, might not only help us to better identify subgroups of
214 R. J. U. Lories
patients but also to specifically develop local treatment strategies that would not bear
the disadvantages of systemic treatment.
TISSUE INTERACTIONS IN THE JOINT ORGAN
Collaboration between different tissues within the joint organ is necessary for normal
movement. These include articular cartilage, bone, synovium, ligaments, tendons, and
eventually menisci. Not surprisingly, all the tissues of the joint organ can play a role in
OA.
Inflammation in the synovium
Synovitis and joint effusions have gained increased attention in the last years as they
are associated with pain and swelling and therefore directly clinically relevant.56 A classic hypothesis suggests that the release of factors from cartilage and bone triggers nonspecific inflammation in the synovium. The articular cartilage is resistant to vessel
invasion and cellular infiltration. Therefore, any inflammatory reaction in the joint
will find its way into the tissue that is most prone to inflammation and that can potentially transform in a secondary lymphoid organ-like tissue: the synovium.57 Under
physiological circumstances, the synovium is a thin tissue that consists of a pseudoepitheloid lining layer with synovial fibroblasts, macrophages, and a loose connective tissue in the sublining zone. Different factors can stimulate angiogenesis and a massive
inflammatory cell infiltrate. Joint inflammation with specific tropism for the synovium
has recently been put forward in the context of the existence of a synovio-entheseal
complex in spondyloarthritis58, and this concept can easily be adapted to OA. From
this point of view, synovitis can be considered a common final pathway in a tissue
that is easily primed for innate immune responses triggered by cartilage damage.
However, synovitis in OA patients might be driven by specific antigens and also involve adaptive immunity. Recent work has demonstrated the existence of clonal B-cell
populations in OA synovium, pleading against the nonspecific nature of inflammation in
OA.59 Cytokines and tissue-destructive enzymes produced by the synovium can contribute to cartilage destruction. In addition, the synovium can be the source of growth
factors that play a role in joint remodeling (see below). However, recent MRI data suggest that synovitis and effusions contribute to joint symptoms rather than to cartilage
damage.56
The bone–cartilage biomechanical unit
Interactions between cartilage and bone are of particular interest from a biomechanical
point of view. An inverse clinical relationship between OA and osteoporosis has been
hypothesized but remains controversial.60 Our observations in Frzb/ mice provide
evidence that WNT signaling and its antagonists could present a molecular mechanism
for this relationship.48 In addition to increased cartilage damage in induced models,
Frzb/ mice also have increased cortical thickness, bone mineral density, and content
as compared to wild-type littermates.48 Although at first sight the differences appear
fairly limited, the increase in cortical thickness strongly affects the stress–strain relationship in the bone. Therefore, the long bones of Frzb/ mice are stiffer than those
of their wild-type littermates. Increased stiffness is likely to alter the load in the
Joint homeostasis, restoration, and remodeling is osteoarthritis 215
articular cartilage providing a third mechanism by which functional polymorphisms in
FRZB can play a role in OA.
Frzb/ mice do not show differences in trabecular or subchondral bone density.
Additional research is therefore required to identify factors that lead to increased subchondral bone thickness and thereby cause or accelerate OA. One potential candidate
is the FRZB-related secreted frizzled related protein 1 (sFRP1) gene.61 In line with current concepts on the role of subchondral bone in OA pathology, it seems likely that
local or systemic bone remodeling to strengthen the bone might have adverse effects
on the cartilage by disturbing the cartilage–bone biomechanical unit.
Clinical implications
The critical involvement of synovitis and joint effusion in pain in a number of OA patients supports the use of anti-inflammatory drugs for their management.56 As these
drugs have significant toxicities, their use should be limited to those patients in whom
they are undoubtedly beneficial. Better identification of patient subgroups is therefore
essential. The current evidence supporting a role for adaptive immunity in inflammatory changes in OA further strengthens the concept that different subgroups of patients should be distinguished. Theoretically at least, immune modulating or even
biologicals could be considered for a number of patients. Again, it is important to consider the potential toxicity. Biomarker development and analysis, as well as further
studies of synovium biology in OA patients, are likely to enhance our current knowledge and might have an important impact on therapeutic approaches in the years to
follow.
The role of FRZB in the balance between cartilage and bone sheds new light on the
important question of exercise needs in the prevention of OA. Frzb/ mice show increased periosteal new bone formation after cyclic loading in vivo.48 This will further
increase the stiffness of the long bones and compromise normal cartilage biology.
However, molecular evidence suggests that a certain amount of loading will stimulate
extracellular matrix synthesis and strengthen the cartilage. Nevertheless, excessive exercise, in particular in genetically predisposed individuals, could increase stiffness in the
bone–cartilage unit and contribute to the development of OA. Again, identification of
biomarkers and genotype analysis could be important means to individualize patient
profiles and define both nonpharmacological and pharmacological strategies.
TISSUE REMODELING: OSTEOPHYTE FORMATION
Osteophytes are a characteristic manifestation of remodeling in joints affected by OA.
New cartilage and bone formation appear to arise from the anatomical zone where the
synovium overlies the bone in a process that recapitulates endochondral bone formation during development and growth.2,62 In general, there is no convincing evidence
that osteophytes contribute to the signs and symptoms of the disease. Rather, they
might represent a stabilizing effort in an already damaged joint in order to deal with
load and strain. From this point of view, osteophytes would be considered (ectopic) repair efforts rather than remodeling contributing to pathology. This type of new tissue
formation in the joint might therefore be different from that seen in the spondyloarthritides, in which progression towards ankylosis typically results in loss of joint function.62
Not surprisingly, molecular signaling pathways such as BMPs and TGFBs also appear
to play a role in osteophyte formation. Different groups have studied the presence of
216 R. J. U. Lories
BMPs in human osteophytes.63,64 Three different types of bone formation in the growing
osteophyte are observed: endochondral and membranous from the periost, and from the
endosteum.63 Immunohistochemistry demonstrated BMP2 in both fibrous matrix and osteoblasts. BMP3 was found in osteoblasts and osteoclasts; BMP6 in osteocytes and osteoclasts; and BMP7 in hypertrophic chondrocytes, osteoblasts, and osteocytes. Nakase et al
demonstrated BMP2 in fibroblastic mesenchymal cells, fibrochondrocytes, chondrocytes,
and osteoblasts both at the mRNA and protein level.64 BMP and TGFB signaling in osteophyte formation have been studied more mechanistically in mouse models of OA. Injection
of recombinant BMP2 or TGFB into healthy murine knees stimulated osteophyte formation. Interestingly, osteophytes induced by BMP2 injection were found predominantly in
the regions where the growth plate met the joint space, whereas TGFB-induced osteophytes originated from the border between cartilage, bone and synovium.30,31
Synovial macrophages appear critical in this process as osteophyte formation induced by TGFB was reduced after depletion of macrophages. The number of BMP2and BMP4-positive cells in these experiments also decreased on deletion of the
macrophages.65 Osteophyte formation in papain-induced arthritis can be inhibited
by adenoviral overexpression of both BMP and TGFB antagonists. Again, expression
of BMP2 and BMP4 in this model was markedly increased in the synovium.66
Of clinical interest, one type of osteophyte in OA might be different in nature. Recent data obtained with MRI imaging suggest that OA of the interphalangeal joints is
closely associated with ligaments and their entheseal insertions.58 In these patients, inflammatory episodes can be very painful and often result in tissue damage with osteophyte formation. Sometimes, the radiographic changes in the joints can be difficult to
distinguish from those seen in patients with psoriatic arthritis and distal interphalangeal joint involvement. As joint destruction and remodeling in these joints are associated with loss of function, osteo- and enthesophyte formation can be considered
a potential therapeutic target. As indicated from a mouse model of ankylosis, inhibition
of BMP signaling might be useful for these patients.67
SUMMARY
Osteoarthritis is a leading cause of morbidity. Current therapeutic approaches are
largely insufficient to prevent initiation and progression of disease. OA is a disease
of the joint organ and involves articular cartilage, subchondral and cortical bone, synovium, ligaments, tendons, and their insertions. Genetic studies in humans have identified new molecules that are likely to play a role in the complex pathology of these
diseases. Genes identified, like CDMP1 and FRZB, are involved in signaling cascades
that are important during skeletal development. The use of genetic mouse models further corroborates their importance in OA. Most research questions have addressed
the role of signaling pathways in cartilage. However, accumulating evidence suggests
that tissue interactions, in particular between cartilage and bone, are critically involved
in OA. From this point of view, our observations in Frzb knockout mice demonstrate
that a single molecule might influence both cartilage and bone in OA development. In
addition, the biology of FRZB provides a molecular mechanism for the longstanding
hypothesis that OA and osteoporosis show an inverse clinical relationship. Major challenges for the clinical research community lie ahead. Molecules and signaling pathways
identified have a broad range of functions in the body and interference with these
pathways will require a specific, targeted approach. Therefore, local therapies might
become as important as systemic interventions.
Joint homeostasis, restoration, and remodeling is osteoarthritis 217
Practice points
The role of developmental signaling pathways in OA:
Genetic studies have identified specific polymorphisms associated with
OA. Identification of patients at risk may become increasingly important
to adjust preventive lifestyle and pharmacological strategies
The biology of growth factors is complex and specific targeted therapeutics need to be developed to prevent significant toxicity
Further progress in our understanding of OA must come from the combination of human genetics and animal models of the disease
Tissue interactions in the joint organ:
The synovium is the preferred localization of inflammation. Synovitis and
joint effusion contribute to pain and loss of function
Both innate and adaptive immune responses may be involved in OA-associated synovitis
The hypothesized inverse relationship between OA and osteoporosis is
supported by animal model data using Frzb knockout mice
Osteophyte formation:
Osteophytes in large joints and in the hand may be different in nature
Osteophytes in large joints can be considered as stabilizing repair efforts
Research agenda
Close interactions between human genetic research and the development of
new animal models of OA are required to further advance our understanding
of cartilage and joint biology. In particular, complex genetic models including
tissue-specific and/or inducible knockout animals need to be developed
The roles of cortical and subchondral bone, and their impact on the biomechanical properties of the articular cartilage, need to be further defined.
From a clinical research point of view, the impact of exercise on bone and cartilage needs to be carefully evaluated. In this context, genotype of patients involved might be important to understand outcomes
ACKNOWLEDGEMENTS
Rik Lories is the recipient of a postdoctoral fellowship from the Scientific Research
Foundation Flanders (FWO-Vlaanderen). His work is supported by FWO-Vlaanderen
and KU Leuven (GOA grant).
REFERENCES
1. Luyten FP, Lories RJ, Verschueren P et al. Contemporary concepts of inflammation, damage and repair
in rheumatic diseases. Best Practice & Research. Clinical Rheumatology 2006; 20: 829–848.
218 R. J. U. Lories
2. De Vlam K, Lories RJ & Luyten FP. Mechanisms of Pathologic New Bone Formation. Current Rheumatology Reports 2006; 8: 332–337.
3. Hunter DJ & Felson DT. Osteoarthritis. BMJ 2006; 332: 639–642.
4. Goldring MB. Update on the biology of the chondrocyte and new approaches to treating cartilage
diseases. Best Practice & Research. Clinical Rheumatology 2006; 20: 1003–1025.
5. Brandt KD, Radin EL, Dieppe PA et al. Yet more evidence that osteoarthritis is not a cartilage disease.
Annals of the Rheumatic Diseases 2006; 65: 1261–1264.
6. Lajeunesse D & Reboul P. Subchondral bone in osteoarthritis: a biologic link with articular cartilage
leading to abnormal remodeling. Current Opinion in Rheumatology 2003; 15: 628–633.
7. Lories RJ & Luyten FP. Bone Morphogenetic Protein signaling in joint homeostasis and disease. Cytokine
& Growth Factor Reviews 2005; 16: 287–298.
8. Li MO, Wan YY, Sanjabi S et al. Transforming growth factor-beta regulation of immune responses.
Annual Review of Immunology 2006; 24: 99–146.
9. Verrecchia F, Mauviel A & Farge D. Transforming growth factor-beta signaling through the Smad
proteins: role in systemic sclerosis. Autoimmunity Reviews 2006; 5: 563–569.
10. Urist MR. Bone: formation by autoinduction. Science 1965; 150: 893–899.
11. Wozney JM, Rosen V, Celeste AJ et al. Novel regulators of bone formation: molecular clones and
activities. Science 1988; 242: 1528–1534.
12. Mishina Y. Function of bone morphogenetic protein signaling during mouse development. Frontiers in
Bioscience 2003; 8: D855–D869.
13. Chang SC, Hoang B, Thomas JT et al. Cartilage-derived morphogenetic proteins. New members of the
transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development. The Journal of Biological Chemistry 1994; 269: 28227–28234.
14. Storm EE, Huynh TV, Copeland NG et al. Limb alterations in brachypodism mice due to mutations in
a new member of the TGF beta-superfamily. Nature 1994; 368: 639–643.
15. Thomas JT, Lin K, Nandedkar M et al. A human chondrodysplasia due to a mutation in a TGF-beta
superfamily member. Nature Genetics 1996; 12: 315–317.
16. Thomas JT, Kilpatrick MW, Lin K et al. Disruption of human limb morphogenesis by a dominant negative
mutation in CDMP1. Nature Genetics 1997; 17: 58–64.
17. Polinkovsky A, Robin NH, Thomas JT et al. Mutations in CDMP1 cause autosomal dominant brachydactyly type C. Nature Genetics 1997; 17: 18–19.
*18. Miyamoto Y, Mabuchi A, Shi D et al. A functional polymorphism in the 5 UTR of GDF5 is associated
with susceptibility to osteoarthritis. Nature Genetics 2007; 39: 529–533.
19. Erlacher L, Ng CK, Ullrich R et al. Presence of cartilage-derived morphogenetic proteins in articular cartilage and enhancement of matrix replacement in vitro. Arthritis & Rheumatism 1998; 41:
263–273.
20. Erlacher L, McCartney J, Piek E et al. Cartilage-derived morphogenetic proteins and osteogenic protein-1 differentially regulate osteogenesis. Journal of Bone and Mineral Research 1998; 13: 383–392.
*21. Rountree RB, Schoor M, Chen H et al. BMP Receptor Signaling Is Required for Postnatal Maintenance
of Articular Cartilage. PLoS Biology 2004; 2: e355.
*22. Lories RJ, Daans M, Matthys P et al. Noggin haploinsufficiency differentially affects tissue responses in
destructive and remodeling arthritis. Arthritis & Rheumatism 2006; 54: 1736–1746.
23. Tylzanowski P, Mebis L & Luyten FP. The Noggin null mouse phenotype is strain dependent and haploinsufficiency leads to skeletal defects. Developmental Dynamics 2006; 235: 1599–1607.
24. Fukui N, Zhu Y, Maloney WJ et al. Stimulation of BMP-2 expression by pro-inflammatory cytokines IL-1
and TNF-alpha in normal and osteoarthritic chondrocytes. The Journal of Bone and Joint Surgery. American
Volume 2003; 85A: 59–66.
25. Lories RJ, Derese I, Ceuppens JL et al. Bone morphogenetic proteins 2 and 6, expressed in arthritic
synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like
synoviocyte apoptosis. Arthritis & Rheumatism 2003; 48: 2807–2818.
26. van der Kraan PM, Vitters EL, van Beuningen HM et al. Role of nitric oxide in the inhibition of BMP-2mediated stimulation of proteoglycan synthesis in articular cartilage. Osteoarthritis Cartilage 2000; 8:
82–86.
*27. Luyten FP, Dell Accio F & De Bari C. Skeletal tissue engineering: opportunities and challenges. Best
Practice & Research. Clinical Rheumatology 2002.
Joint homeostasis, restoration, and remodeling is osteoarthritis 219
28. Serra R, Johnson M, Filvaroff EH et al. Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. The
Journal of Cell Biology 1997; 139: 541–552.
29. Yang X, Chen L, Xu X et al. TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. The Journal of Cell Biology 2001; 153:
35–46.
30. Glansbeek HL, van Beuningen HM, Vitters EL et al. Bone morphogenetic protein 2 stimulates articular
cartilage proteoglycan synthesis in vivo but does not counteract interleukin-1alpha effects on proteoglycan synthesis and content. Arthritis & Rheumatism 1997; 40: 1020–1028.
31. van Beuningen HM, Glansbeek HL, van der Kraan PM et al. Differential effects of local application of
BMP-2 or TGF-beta 1 on both articular cartilage composition and osteophyte formation. Osteoarthritis
Cartilage 1998; 6: 306–317.
32. Bakker AC, van de Loo FA, van Beuningen HM et al. Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthritis
Cartilage 2001; 9: 128–136.
33. Scharstuhl A, Glansbeek HL, van Beuningen HM et al. Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. Journal of Immunology
2002; 169: 507–514.
34. Scharstuhl A, Diepens R, Lensen J et al. Adenoviral overexpression of Smad-7 and Smad-6 differentially
regulates TGF-beta-mediated chondrocyte proliferation and proteoglycan synthesis. Osteoarthritis and
Cartilage 2003; 11: 773–782.
35. Scharstuhl A, van Beuningen HM, Vitters EL et al. Loss of transforming growth factor counteraction on
interleukin 1 mediated effects in cartilage of old mice. Annals of the Rheumatic Diseases 2002; 61:
1095–1098.
36. Hartmann C & Tabin CJ. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell 2001; 104: 341–351.
37. Tamamura Y, Otani T, Kanatani N et al. Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. The Journal of
Biological Chemistry 2005; 280: 19185–19195.
38. Hens JR, Wilson KM, Dann P et al. TOPGAL mice show that the canonical Wnt signaling pathway is
active during bone development and growth and is activated by mechanical loading in vitro. Journal
of Bone and Mineral Research 2005; 20: 1103–1113.
39. Hoang B, Moos Jr. M, Vukicevic S et al. Primary structure and tissue distribution of FRZB, a novel protein related to Drosophila frizzled, suggest a role in skeletal morphogenesis. The Journal of Biological
Chemistry 1996; 271: 26131–26137.
40. Lin K, Wang S, Julius MA et al. The cysteine-rich frizzled domain of Frzb-1 is required and sufficient for
modulation of Wnt signaling. Proceedings of the National Academy of Sciences of the United States of
America 1997; 94: 11196–11200.
41. Wang S, Krinks M, Lin K et al. Frzb, a secreted protein expressed in the Spemann organizer, binds and
inhibits Wnt-8. Cell 1997; 88: 757–766.
*42. Loughlin J, Dowling B, Chapman K et al. Functional variants within the secreted frizzled-related protein
3 gene are associated with hip osteoarthritis in females. Proceedings of the National Academy of Sciences of
the United States of America 2004; 101: 9757–9762.
43. Valdes AM, Loughlin J, Oene MV et al. Sex and ethnic differences in the association of ASPN, CALM1,
COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee. Arthritis &
Rheumatism 2007; 56: 137–146.
44. Min JL, Meulenbelt I, Riyazi N et al. Association of the Frizzled-related protein gene with symptomatic
osteoarthritis at multiple sites. Arthritis & Rheumatism 2005; 52: 1077–1080.
*45. Lane NE, Lian K, Nevitt MC et al. Frizzled-related protein variants are risk factors for hip osteoarthritis.
Arthritis & Rheumatism 2006; 54: 1246–1254.
46. Lories RJ, Boonen S, Peeters J et al. Evidence for a differential association of the Arg200Trp singlenucleotide polymorphism in FRZB with hip osteoarthritis and osteoporosis. Rheumatology (Oxford)
2006; 45: 113–114.
47. Rodriguez-Lopez J, Pombo-Suarez M, Liz M et al. Further evidence of the role of frizzled-related protein
gene polymorphisms in osteoarthritis. Annals of the Rheumatic Diseases 2007; 66: 1052–1055.
220 R. J. U. Lories
*48. Lories RJ, Peeters J, Bakker A et al. Deletion of frizzled related protein affects articular cartilage and
biomechanical properties of the long bones. Arthritis & Rheumatism 2007; 56: 4095–4103.
49. Zi X, Guo Y, Simoneau AR et al. Expression of Frzb/secreted Frizzled-related protein 3, a secreted Wnt
antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and
cellular invasiveness. Cancer Research 2005; 65: 9762–9770.
*50. Dell Accio F, De Bari C, El Tawil NM et al. Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury. Arthritis Research & Therapy 2006; 8: R139.
51. Chen L & Deng CX. Roles of FGF signaling in skeletal development and human genetic diseases.
Frontiers in Bioscience 2005; 10: 1961–1976.
52. Goldring MB, Tsuchimochi K & Ijiri K. The control of chondrogenesis. Journal of Cellular Biochemistry
2006; 97: 33–44.
53. Vincent T, Hermansson M, Bolton M et al. Basic FGF mediates an immediate response of articular cartilage to mechanical injury. Proceedings of the National Academy of Sciences of the United States of America
2002; 99: 8259–8264.
54. Vincent TL, Hermansson MA, Hansen UN et al. Basic fibroblast growth factor mediates transduction of
mechanical signals when articular cartilage is loaded. Arthritis & Rheumatism 2004; 50: 526–533.
*55. Vincent TL, McLean CJ, Full LE et al. FGF-2 is bound to perlecan in the pericellular matrix of articular
cartilage, where it acts as a chondrocyte mechanotransducer. Osteoarthritis Cartilage 2007; 15: 752–763.
56. Hill CL, Hunter DJ, Niu J et al. Synovitis detected on magnetic resonance imaging and its relation to
pain and cartilage loss in knee osteoarthritis. Annals of the Rheumatic Diseases 2007.
57. Simkin PA. The musculoskeletal system: A. Joints 1997; 11: 10–14.
58. McGonagle D, Lories RJ, Tan A et al. The concept of a synovio-entheseal complex and its implications
for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis & Rheumatism 2007; 56: 2482–2491.
*59. Da RR, Qin Y, Baeten D et al. B cell clonal expansion and somatic hypermutation of Ig variable heavy
chain genes in the synovial membrane of patients with osteoarthritis. Journal of immunology 2007; 178:
557–565.
60. Dequeker J, Aerssens J & Luyten FP. Osteoarthritis and osteoporosis: clinical and research evidence of
inverse relationship. Aging Clinical and Experimental Research 2003; 15: 426–439.
61. Bodine PV, Zhao W, Kharode YP et al. The Wnt antagonist secreted frizzled-related protein-1 is
a negative regulator of trabecular bone formation in adult mice. Molecular Endocrinology 2004; 18:
1222–1237.
62. Lories RJ & Luyten FP. Bone morphogenetic proteins in destructive and remodeling arthritis. Arthritis
Research & Therapy 2007; 9: 207.
63. Zoricic S, Maric I, Bobinac D et al. Expression of bone morphogenetic proteins and cartilage-derived
morphogenetic proteins during osteophyte formation in humans. Journal of Anatomy 2003; 202:
269–277.
64. Nakase T, Miyaji T, Tomita T et al. Localization of bone morphogenetic protein-2 in human osteoarthritic cartilage and osteophyte. Osteoarthritis Cartilage 2003; 11: 278–284.
65. van Lent PL, Blom AB, van der KP et al. Crucial role of synovial lining macrophages in the promotion of
transforming growth factor beta-mediated osteophyte formation. Arthritis & Rheumatism 2004; 50:
103–111.
66. Scharstuhl A, Vitters EL, van der Kraan PM et al. Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor beta/bone morphogenetic protein
inhibitors during experimental osteoarthritis. Arthritis & Rheumatism 2003; 48: 3442–3451.
67. Lories RJU, Derese I & Luyten FP. Modulation of Bone Morphogenetic Protein signaling inhibits the onset and progression of ankylosing enthesitis. The Journal of Clinical Investigation 2005; 115: 1571–1579.