From osteoarthritis treatments to future regenerative therapies for cartilage.

Abstract

Osteoarthritis (OA) is associated with cartilage degeneration and an accompanying inflammatory syndrome of the synovium in addition to alteration of the subchondral bone. The molecular and cellular events involved in OA have only partially been elucidated. This review provides a global view of the physiopathology of OA, as well as non-pharmacological and pharmacological treatments for the disorder. An update on surgical treatments and their indications is given with an orientation towards the management of OA and cartilage repair by cell-based regenerative therapies. These promising biological technologies will, potentially, play a major role in the treatment of cartilage-associated diseases.

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Drug Discovery Today?Volume 14,Numbers 19/20?October 2009 REVIEWS
Therapeutic strategies for the effective management of OA and cartilage defects.
From osteoarthritis treatments to future
regenerative therapies for cartilage
Johann Clouet1,2, Claire Vinatier1,3, Christophe Merceron1,
Marianne Pot-vaucel4, Yves Maugars4, Pierre Weiss1,
Gae ¨l Grimandi1,2and Je ´ro ˆme Guicheux1
1INSERM (Institut National de la Sante ´ et de la Recherche Me ´dicale), U791, Centre for Osteoarticular
and Dental Tissue Engineering, Group Physiopathology of Skeletal Tissues and Cartilage Engineering,
University of Nantes, France
2Pharmacy, University Hospital of Nantes, France
3GRAFTYS SAS, Aix en Provence, France
4Department of Rheumatology, University Hospital of Nantes, France
Osteoarthritis (OA) is associated with cartilage degeneration and an
accompanying inflammatory syndrome of the synovium in addition to
alteration of the subchondral bone. The molecular and cellular events
involved in OA have only partially been elucidated. This review provides a
global view of the physiopathology of OA, as well as non-pharmacological
and pharmacological treatments for the disorder. An update on surgical
treatments and their indications is given with an orientation towards the
management of OA and cartilage repair by cell-based regenerative
therapies. These promising biological technologies will, potentially, play a
major role in the treatment of cartilage-associated diseases.
Osteoarthritis (OA) is a public health concern particularly in modern society and is the leading
osteoarticular pathology of developed countries. In the United States, OA is the primary reason
for medical consultation in persons older than 60 years of age and affects at least 30% of this
subpopulation [1]. Population ageing will probably worsen the socio-economic impact of such
pathologies. The growing epidemic of obesity is also an exacerbating factor, with an indisputable
role in knee OA [2].
The current view is that OA is a complex syndrome that is, in fact, the ultimate outcome of
various factors affecting the joint [3]. Once established, OA is characterised by a decrease in
articular cartilage (AC) thickness, subchondral bone sclerosis (bone thickening), formation of
osteophytes (bone outgrowth on the joint margin) and modification of the synovial fluid
composition (Fig. 1). Several joints might be affected by OA but the sites most commonly
affected are knees, hips, fingers and the lumbar and cervical spine. Given that many questions,
particularlythose concerningthephysiopathology ofOA,remainunanswered,itisnotsurprising
that treatments, either pharmacological or surgical, only partially address the clinical issue.
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Johann Clouet was born in
Cha ˆteaubriant, France, on 26
November 1975. He
obtained his doctorate
degree in pharmacy in 2006
and his research master’s
degree in 2007 at the
University of Nantes,
(France). Presently he is
working in the department of physiopathology of
skeletal tissues and cartilage engineering in the centre
for osteoarticular and dental tissue engineering
(LIOAD-INSERM U791) at the University of Nantes
(France). His research work focuses predominantly
on the development of scaffolds and the use of stem
cells for cartilage tissue engineering.
Je ´ro ˆme Guicheux was
born in Le Mans (France) on
20 February 1970. He
obtained his PhD thesis in
1997 and his degree for
directing research in 2002.
Currently, he is working as a
research director/professor
at the national institute for
health and medical research
(INSERM). He is head of the department of
physiopathology of skeletal tissues and cartilage
engineering in the centre for osteoarticularand dental
tissue engineering (LIOAD-INSERM U791) at the
University of Nantes (France). His research focuses
on the differentiation process of osteoarticular cells
and the use of scaffolds and reparative cells for
cartilage tissue engineering.
Corresponding author: Guicheux, J. (jerome.guicheux@inserm.fr)
1359-6446/06/$ - see front matter ? 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2009.07.012
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For many years, various treatments likely to slow down the OA
degenerative process have been assessed in preclinical studies,
particularly theDisease-Modifying
(DMOADs). In parallel, advances in the field of cell therapy and
tissue engineering also deserve to be given major attention.
This review provides a global view of the physiopathology of
OA, as well as the non-pharmacological and pharmacological
treatments of this debilitating osteoarticular disease.
OsteoArthritisDrugs
The joint and the articular cartilage
A diarthrodial joint is a complex structure comprising various
connective tissues including AC, synovial membrane, subchon-
dral bone, ligaments and sometimes menisci. All of these struc-
tures contribute to joint function and performance. In particular,
ACpossessesachemicalcompositionthatenablestheexecutionof
repetitive loading cycles and a physical structure that allows for
essentially frictionless motion.
AC is a slick, white tissue that covers joint surfaces. AC is
composed of an extracellular matrix (ECM) produced by chon-
drocytes, and is characterised by the absence of blood vessels and
nerves. Being avascular, cartilage has a low oxygen tension, ran-
ging from 1 to 7%. Chondrocytes are developmentally adapted to
these hypoxic conditions by having an enhanced anaerobic gly-
colysis. Contrary to other mesenchymal tissues (liver, heart, brain,
kidney and so on) yet in common with bone, the properties of
cartilage are mainly related to its ECM rather than to its cells [4].
Nevertheless, articular chondrocytes play a central role in the
equilibrium between ECM synthesis (anabolism) and degradation
(catabolism).
AC is organised into four layers according to the type and
orientation of collagen fibres, the amount of proteoglycans (PG)
and water, as well as the shape and activity of chondrocytes
(Fig. 2):
- The outer surface area can be divided into two zones, is in
contact with the synovial fluid and provides an essentially
frictionless surface. The superficial zone is acellular and
contains types I, II and III collagen fibres and low amount of
PG. The deepest zone contains ellipsoidal chondrocytes which
synthesise lubricin and types I, II and III collagen fibres.
- The transitional area is made up of types II, VI, IX and XI
collagen fibres that intersect obliquely in a poorly organised
network. This network is less dense and hydrated than that of
the outer articular surface. The network of type VI collagen is
essentially concentrated around the chondrocytes in the
pericellular area [5]. The role of this type VI collagen is not
yetclear butcertain elements suggestthatit interactswith fibres
of type II collagen and create a mechanical interface between
the chondrocyte and the ECM [6]. The chondrocytes have a
round morphology.
- The deep area of the AC contains types II, IX and XI collagen
fibres directed perpendicular to the joint surface. Chondrocytes
form radial columns are aligned along the collagen fibres.
- The calcified area is in contact with the subchondral bone. In
this area, cartilage contains a limited number of hypertrophic
chondrocytes that synthesise type X collagen. Calcification
takes place on collagen fibres, which anchor cartilage to the
subchondral bone.
This histological organisation confers the cartilage to its biome-
chanical properties. The orientation of the collagen fibres
decreases shear and compression constraints respectively on the
surface and the deep area of the AC.
Physiopathology of osteoarthritis
The first physiopathological hypothesis concerning OA was pri-
marily mechanical, based on an age-associated degenerative pro-
cessofAC.Youngjointsmay,however,alsoexhibitsomeclinically
benign but erosive lesions of the cartilage, characterised by a slow
evolution. The frequency and precocity of these lesions contrast
with the slow degenerative process classically described during OA
development in elderly patients. This recent consideration makes
the physiopathology of OA more complex than a simplistic age-
dependent degenerative process of AC and can no longer be
regarded as a single disease. It should be seen as a group and
perhaps the term osteoarthritic diseases would be more suitable
[7]. OA is,therefore, today consideredto be adegenerative osteoar-
ticular disease with multiple affected targets including AC, syno-
vium and subchondral bone.
Articular cartilage impairments
During OA degenerative processes, major modifications of AC are
observed at the tissue, cellular and molecular levels.
Tissue and cellular levels
Compared with the slick appearance of healthy cartilage, osteoar-
thritic cartilage surface is rough [3]. The osteoarthritic chondro-
cyte is obviously activated and exhibits a capacity to divide into
clusters. Interestingly, it has also been reported that type IIA
REVIEWSDrug Discovery Today?Volume 14,Numbers 19/20?October 2009
FIGURE 1
X-ray radiographic observation of an osteoarthritic knee (standing
anterioposterior view). Characteristic features of advanced osteoarthritis of
the medial tibiofemoral joint are shown. Note the joint space narrowing (!)
and the formation of osteophytes (*). Femur (Fe); Tibia (T) and fibula (Fi).
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collagen, a splice variant of mature collagen type II mainly
expressed during embryologic chondrogenesis, was re-expressed
by adult articular chondrocytes in OA cartilage [8]. This data
support the hypothesis that OA chondrocytes reverse their phe-
notype towards a chondroprogenitor phenotype, thereby high-
lightingthe recapitulation ofembryonic genesattheadultstagein
the pathophysiology of OA [9]. The levels of PG and collagen
synthesis are largely increased, at least during the early stage of the
disease [10]. It is usually acknowledged that chondrocytes, at this
stage, attempt to counterbalance the upregulated catabolic pro-
cesses. This supraphysiological metabolism precedes the first
symptomatic evidence of OA. After these early compensating
mechanisms, caspase-mediated chondrocyte apoptosis increases
and could therefore contribute to the late mechanisms of cartilage
degeneration [11]. With respect to their role in OA, caspases are
considered the ultimate messengers of a multiple-step signalling
cascade with a variety of upstream activators, notably interleukin-
1 (IL-1) and nitric oxide. Inhibition of chondrocyte apoptosis
through the caspase signalling pathway could thus be a promising
therapeutic target for the management of OA [12].
Molecular level
The destruction of AC and the loss of its biomechanical properties
are largely related to the alteration of ECM, particularly the loss of
aggrecan. This process results from an imbalance between degra-
dation and synthesis of the matrix components, despite the com-
pensatory activity of chondrocytes (Fig. 3). This point highlights
the pivotal role of chondrocytes in the physiopathology of OA.
Among the cartilaginous anabolic factors, Insulin Growth Fac-
tor-1 (IGF-1), Transforming Growth Factor-beta (TGF-b), Bone
Morphogenetic Proteins (BMPs) and Fibroblast Growth Factors
(FGFs) have been extensively described. Interestingly, the level
of expression of these factors declines with ageing and advanced
OA [13].
An increase in catabolic enzymes responsible for ECM degrada-
tion has been reported during OA, predominantly matrix metal-
loproteinases (MMP-2, -7, -8, -9, -13, -14), A disintegrin and
metalloproteinase with thrombospondin repeats-1 (ADAMTS-1)
and aggrecanases 1 and 2 (ADAMTS-4 and -5 respectively). IL-1b
and Tumor Necrosis Factor (TNF) have been largely implicated in
the increased synthesis of catabolic enzymes by osteoarthritic
chondrocytes [14]. Of interest, it has also been reported that a
deficit in Tissue Inhibitors of Metalloproteinases (TIMPs) could
also play a pivotal role in the excessive ECM degradation [15].
Several lines of evidence also highlight the role of adipokines in
OA [16,17]. Adipokines (leptin, adiponectin and resistin) are pro-
teins produced by white adipose tissue. They are essential regula-
tors of immune and inflammatory responses. All three adipokines
have been detected in synovial fluid from OA-affected joints. Fat
tissue is, therefore, an active organ that greatly contributes to
inflammatory and degenerative processes during OA.
Recently, a role has also been suggested for Wnt/b-catenin and
Smad ubiquination-related factor 2 (Smurf2) in chondrocyte func-
tionand apoptosis [18,19]. Whether the controlof these signalling
pathways could lead to the development of new therapeutic
intervention strategies in OA deserves consideration.
Synovium and subchondral bone alterations
Whilst studies of OA mainly focus on the comprehension of
catabolic disorders described in cartilage, a pivotal role for syno-
vium and/or subchondral bone has been recently described.
Inflammation of the synovium (synovitis) has often been asso-
Drug Discovery Today?Volume 14,Numbers 19/20?October 2009 REVIEWS
FIGURE 2
Histological organisation of articular cartilage. Articular cartilage is organised in four zones according to the type and orientation of collagen fibres, amount of
proteoglycan and water as well as shape and activity of chondrocytes. A histological section of articular cartilage of the knee stained with Alcian Blue and
photographed under a light microscope is shown. +: Moderate cell density, ++: high cell density.
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ciated with advanced OA [20].Synovitis leadsto anoverexpression
of pro-inflammatory cytokines (IL-1b, TNF-a and -b) that in turn
contribute to the subsequent catabolic degenerative processes of
AC [21]. These cytokines also stimulate the production of nitric
oxide by upregulating the expression of iNOS (inducible Nitric
Oxide Synthase) and other pro-inflammatory cytokines, such as
IL-6, LIF (Leukemia Inhibitory Factor), IL-17, IL-18 and chemo-
kines [22].
The subchondral bone also exhibits noticeable alterations at an
early stage of OA with a decrease in osteoblast activity that induces
a thinning of the adjacent trabecular bone [3]. At later stages, an
excessive bone remodelling is observed in the areas where AC has
degraded, which unfortunately results in sclerosis and necrosis of
the subchondral bone. This excessive bone remodelling has been
suggested to increase the production of cytokines by osteoclasts
and could induce the loss or damage of cartilage [23,24]. In
addition, the leakage of synovial fluid towards the medullar spaces
of the subchondral bone affects the bone marrow mesenchymal
stem cells (MSCs), thereby contributing to the formation of osteo-
phytes and cartilage nodules. These deteriorations of the subchon-
dral bone are responsible for joint pain and are largely involved in
the progression of OA [25].
Viewed together, these recent advances in the understanding of
OA physiopathology clearly indicate that OA is a multi-target
disease that affects AC, synovium and subchondral bone. The
chronic evolution of OA could consequently be explained by
the existence of a vicious circle comprising these three structures.
Risk factors for osteoarthritis
AmongtheriskfactorsforOA,itisnecessarytodistinguishbetween
intrinsic risk factors (age, genetic polymorphisms, sex and hormo-
nal status) and extrinsic risk factors (cartilaginous defects, obesity,
microtraumatisms, joint misalignment, hyperlaxity and tabagism)
[26].Amongtheintrinsicriskfactors,itisclearthatageplaysamajor
role in OA. A large body of evidence indicates that the major
components of ECM, type II collagen and PGs undergo alterations
in content, compositionand structural organisationduring ageing.
There is also an accumulation of advanced glycation end-products,
which enhances collagen cross-linking and contributes to the
increaseincartilagestiffnessobservedwithageing[27].Theireffects
are mediated through their direct binding to a specific receptor
RAGE (Receptor of Advanced Glycation Endproducts) expressed by
chondrocytes. Genetic polymorphisms are also crucial to OA, par-
ticularly when they affect genes encoding proteins involved in
cartilagebiologyandECMstructure.Thus,polymorphismsofgenes
encodingtypeIXcollagen,IGF-1andvitamin Dreceptorhavebeen
correlatedwithanincreasedriskofOA[28].Amongtheextrinsicrisk
factors, cartilaginous defects and obesity are probably the most
significant ones. Owing to its poor capacity for spontaneous repair,
when AC is damaged, it hardly heals. The traumatic loss of cartila-
ginous tissue therefore greatly contributes to the subsequent devel-
opment of osteoarthritic lesions. The deleterious role for obesity in
OAisalsowellestablished[29]andaprevailinghypothesisisthatan
increased load on the joint surface because of a large body weight
leads to cartilage wear. The most significant link between OA and
obesityhasbeen reportedfortheknee joint(aBMIincreaseby1 kg/
m2above 27 accounts for an additional 15% increase in risk) [16].
Nevertheless, OA in non-load bearing joints such as metatarso-
phalangeal joints is also associated with obesity. These data suggest
that systemic factors, including adipokines, may be involved in the
high prevalence of OA among obese individuals [16,17].
More in-depth research is currently being conducted to evaluate
the real impact of polymorphisms, as well as other risk factors, and
could end up highlighting the multifactorial nature of OA. Such a
multifactorial nature is likely to complicate epidemiological ana-
lyses and thereby hamper the development of future treatments.
Treatments for osteoarthritis
The optimal management of OA patients requires a critical com-
bination of both non-pharmacological and pharmacological
therapies. Patients who cannot obtain adequate pain relief and
functional joint improvement should be considered for the
REVIEWSDrug Discovery Today?Volume 14,Numbers 19/20?October 2009
FIGURE 3
Imbalance between anabolic and catabolic factors in the physiopathology of osteoarthritis. This imbalance contributes to the alteration of the biomechanical
properties of articular cartilage related to the destruction of its ECM. IGF: Insulin-like Growth Factors, TGF-b: Transforming Growth Factor-b, BMPs: Bone
Morphogenetic Proteins, FGFs: Fibroblast Growth Factors, NO: Nitric Oxide, MMPs: Matrix Metalloproteinases, ADAMTS: A Disintegrin And Metalloproteinase with
ThromboSpondin repeats, IL-1b: Interleukin-1b, TNF: Tumor Necrosis Factor.
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ultimate OA treatment: the prosthetic replacement of the affected
joint.
Non-pharmacological therapies
Non-pharmacological therapies are currently still considered the
first intention treatment in OA by the American College of Rheu-
matology(ACR),EULARandOARSIguidelines[30–32].Thesenon-
pharmacological treatments are, however, mainly suitable for
patients suffering from knee and hip OA. Among the multitude
of non-pharmacological modalities, the most widely proposed
include weight reduction, education and self-management, refer-
ral to a physical therapist, aerobics, muscle strengthening, walking
aids, thermal modalities, transcutaneous electrical nerve stimula-
tion and acupuncture.
Pharmacological therapies
For many osteoarthritic patients, the non-pharmacological thera-
pies are not sufficient to produce sustained reduction in the pain
and restoration of joint function. Various pharmacological treat-
ments have, therefore, been developed including both the fast-
and slow-acting drug families. Some of these drugs are still in
development and could be promising for therapeutic interven-
tion, primarily in advanced OA.
The fast-acting drug family
The fast-acting drug family is mainly used for pain relief and
includes acetaminophen, Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), Cyclooxygenase-2 (Cox-2) inhibitors, glucocorticoids
and opioids.
Acetaminophen (otherwise known as paracetamol) signifi-
cantly reduces pain and increases the quality of life of osteoar-
thritic patients. The doses of acetaminophen (up to 4 g/day) can,
however, trigger adverse hepatic events in patients with hepatic
insufficiency [33]. Although OA does not involve systemic inflam-
mation, typical anti-inflammatory compounds such as NSAIDs
and Cox-2 inhibitors are largely used as analgesic treatments [34].
They exhibit some adverse effects, however, such as gastrointest-
inal, renal and cardiovascular toxicity [35]. Today, the association
of NSAIDs with gastrointestinal protectors, particularly the proton
pump inhibitors, leads to an improved gastrointestinal tolerance.
NSAIDs are therefore widely used with adapted doses and are
restricted to short-term treatments. For many years, intra-articular
injections of glucocorticoids have been successfully administered
to prevent pain [26]. They provide, however, only short-term
efficacy [36] and exhibit adverse metabolic events. Consequently,
the ACR recommended limiting intra-articular glucocorticoid
injections to every three or four months. Opioids are considered
in the treatment of OA as a final resort when pain is not controlled
or for patients with intolerance to other pharmacological treat-
ments [35]. They too, however, exhibit a wide range of adverse
effects such as gastrointestinal (nausea, vomiting and constipa-
tion), alteration in the cognitive function, dependence and
respiratory depression.
The slow-acting drug family
The slow-acting drug family is dedicated to the prevention of pain
as well as the slowing down of the cartilage destruction. Several
drugs are available, including glucosamine, chondroitin sulfate,
S-adenosylmethionine,avocado/soybeanunsaponifiablesandhya-
luronic acid (HA). Glucosamine and chondroitin sulfate belong to
the large family of dietary supplements. Glucosamine is a natural
precursor of GAGs that stimulates GAG production by chondro-
cytes, as well as the synthesis of collagen [37]. The glucosamine
found in dietary supplements is usually extracted from the shells of
prawns and other crustaceans, or made from maize starch. Positive
effects of the oral administration of synthetic glucosamine in OA
patients have been demonstrated by a significant reduction in the
rate of joint space narrowing [38]. Nevertheless, a direct effect of
glucosamine on the prevention of AC erosion has not yet been
demonstrated to date [39]. Chondroitin sulfate is one of the major
components of cartilaginous ECM. It can be extracted from carti-
lage of various origins (shark, cow, pig, fish and bird) by chemical
treatment. Oral administration of chondroitin sulfate has been
reported to decrease the activity of catabolic enzymes in osteoar-
thritic cartilage and to stimulate the synthesis of GAGs and col-
lagens[40]. TheGAIT(Glucosamine/chondroitin
Intervention Trial) did not, however, demonstrate any effect on
pain by comparison with the placebo, when chondroitin sulfate
was administered either alone or in association with glucosamine
[41]. S-adenosyl methionine (SAM) is a small non-protein metabo-
lite, namely a coenzyme, involved in methyl group transfers
between enzymes. Endogenous SAM has been described to exert
an antidepressant effect in humans. In vitro, SAM increases the
synthesis of GAGs in articular chondrocytes, which could suggest
thatitmaybeabletoaidinthe repairofdamagedcartilagethrough
this mechanism [42]. Oral administration of SAM induces a sig-
nificant decrease in pain and an improvement in joint function
comparable to that of NSAIDs. In the absence of long-term follow-
up, however, it remains difficult to rule out the possibility that the
effectivenessofSAMmayberelatedtoitsantidepressant effect [43].
The evidence for symptomatic efficacy of avocado/soybean unsa-
ponifiable in patients with OA hip or knee available is not clearly
established. However, of four studies three studies showed some
evidence of efficacy for relief of pain in OA hip and knee [32]. HA is
a polysaccharide ubiquitously found in ECMs. It can be extracted
from mammalian cartilaginous tissues or produced by bacterial
fermentation. The therapeutic concept of visco-supplementation
suggests that the intra-articular injections of HA can help restore
the viscoelastic and tribologic properties of the synovial fluid. In
addition, HA has been proposed as a chondroprotective com-
pound, since it is able to stimulate the production of TIMPs in
chondrocytes [44]. Intra-articular injection of HA decreases the
symptoms of OA with significant improvements in pain and func-
tional outcomes [45]. This effect appears from 2 to 5 weeks after
injection and can persist for up to 12 months. Visco-supplementa-
tion is not, however, indicated for patients with advanced OA, or
for patients with an articular misalignment [46]. The rare adverse
effects of intra-articular HA injection include pain and infection at
theinjectionsite,inflammatoryresponsesandhypersensitivitydue
to excipient components.
Arthritis
Future treatments
To address further the clinical outcome of OA prevention and
treatment, several new pharmacological compounds are under
intense investigation. On the one hand, novel analgesic and
anti-inflammatory drugs able to decrease pain but with reduced
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gastrointestinal and cardiac adverse events are in clinical study.
On the other hand, a new class of compounds has been developed,
the Disease-Modifying OsteoArthritis Drugs (DMOADs), which
may slow down the degenerative process of OA. Finally, the use
of growth factors that could have chondroprotective effects is also
being contemplated.
Analgesic and anti-inflammatory drugs
Numerous pharmaceutical companies are testing new drugs, espe-
cially COX/LOX inhibitors (Cyclooxygenase/Lipooxygenase) and
CINODs (Cyclooxygenase-inhibiting nitric oxide donors) [47,48].
The results of a phase III study with the naproxcinod (Nicox), the
first CINOD, showed an effective anti-inflammatory activity with
no detrimental effects on blood pressure and good gastrointestinal
tolerability and safety. Table 1 indicates the different drugs cur-
rently in development with an update on their clinical status.
Disease-Modifying OsteoArthritis Drugs (DMOADs)
These drugs aim at slowing down the inevitable OA-associated
cartilage degeneration by affecting various targets such as cata-
bolic enzymes or cytokine-activated signalling cascades [48,49].
Table 2 illustrates the different drugs currently in development.
Studies have been conducted to identify small molecular weight
compounds that selectively inhibit the catabolic activity of
enzymes from the MMP family . Several investigators have, how-
ever, reported some adverse events related to the musculoskeletal
system (prinomastat, marimastat, BMS-27591 and PG-116800)
with MMP inhibitors during the course of clinical trials in oncol-
ogy and cardiology [50]. Many anti-cytokines are also under
development. The anakinra (KINERET1, Amgen), an IL-1 receptor
antagonist, is indicated for the treatment of rheumatoid arthritis.
In OA, this anti-cytokine showed no significant effect on gonar-
throsis symptoms [51]. This antagonist also has some drawbacks,
primarily its high cost and the necessity of intra-articular injec-
tion. The interest of this type of anti-cytokine for the OA ther-
apeutic arsenal is, thus, still difficult to delineate. In parallel, some
studies are also being performed to decipher whether humanised
monoclonal antibodies (adalimumab HUMIRA1, Abbott and
infliximab REMICADE1, Schering Plough) that blunt the biologi-
cal activity of TNF-a may be of therapeutic interest in OA. These
monoclonal antibodies are well known to block the inflammatory
processes in rheumatoid arthritis, psoriatic arthritis, ankylosing
spondylitis and Crohn’s disease. In OA, only one study was per-
formed and unfortunately efficacy was not demonstrated [52].
Finally, great attention has also been paid to synthetic inhibitors
of various signalling pathways implicated in the physiopathology
of OA, such as MAP kinases [48,49]. With respect to the alteration
of the subchondral bone in OA [53], bone anti-resorptive agents
bisphosphonates calcitonin or licofelone have ultimately been
proposed, but with disappointing results [54–56]. In addition,
the pivotal role of RANKL (receptor activator of NF-kB ligand)
and osteoprotegerin in bone resorption could also be potential
targets and future clinical trials will hopefully be able to provide
answers to the efficiency of these treatments [57]. A potential
association of anti-resorptive compounds with specific chondro-
protective drugs could be of interest in OA and deserves further
consideration.
Growth factors
The administration of growth factors, such as basic-Fibroblast
Growth Factor (FGF), BMPs (particularly BMP-2 and -7) and
TGF-b, is also being considered as a potential therapeutic strategy.
The in vitro effects of growth factors on chondrocyte function
could make them useful for the prevention of cartilage degrada-
tion [58]. Among them, FGF-18 stimulates the repair of damaged
cartilage inprogressiveOA inrats[59].Nevertheless, thedirectand
repetitive injection of growth factors into the joints does not
appear feasible for the management of chronic diseases such as
OA. Much attention is therefore being paid to the development of
drug delivery systems enabling the sustained delivery of growth
factors.
Surgical treatments for osteoarthritis
Surgical treatments are generally considered the ultimate proce-
dure when drug therapy has failed to relieve pain and/or to restore
an adapted joint function. All these techniques are mainly dedi-
cated to highly degenerative and advanced OA. Three procedures
are currently used: osteotomy, arthrodesis and arthroplasty.
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TABLE 1
Analgesics and anti-inflammatory drugs in preclinical development
Targets DrugsClinical status in OA
Company
COX/LOX inhibitor
Licofelone Phase III beginning in 2008Merckle
CINODsa
Naproxcinod
SD-6010
Phase III (results in 2009)
Phase II–III (results in 2011)
Nicox
Pfizer
NSAIDs
IDEA-033Phase I Idea Therapeutics
Phospholipase inhibitor
EfipladibPhase I Wyeth
TRPV1b
ALGRX-4975 (Adlea) Injectable capsaicinPhase III (results in 2010)Adolor
Serotonin–norepinephrine reuptake
inhibitor
Zucapsaicin Phase IWinston laboratories
Bradykinin B2receptor antagonist
IcatibantPreclinical study stopped Aventis
Unknown
SFPP
MK-0686
Bicifadine
Phase I
Phase I
Phase I
Mitsubishi Pharmaceuticals
Merck
XLT Biopharmaceuticals
aCyclooxygenase-Inhibiting Nitric Oxide Donators.
bTransient receptor potential vanilloid subfamily 1 receptor agonist.
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Osteotomy
Osteotomy is indicated in OA patients with joint misalignment,
such as a valgus or varus knee. It is a surgical procedure that
involves the removal of bone. A wedge of bone located near the
damaged joint is removed to cause a realignment of the varus/
valgus deformity. This realignment reduces mechanical stress on
the affected compartment by redistributing load to healthy carti-
lage. The clinical outcome depends on the angulation of joint axis
correction [60]. This procedure remains, however, associated with
adverse events like haemorrhage, inflammatory reactions and
nerve damage.
Arthroplasty
Total joint replacement or arthroplasty is reserved for the most
severe and recalcitrant forms of OA or when other treatments have
failed. Several human joints are routinely replaced, such as the hip
and knee. Technology has advanced such that other joints can be
replaced, including the shoulder and wrist. Total and partial knee
replacements, which are now considered relatively routine sur-
gery, have a 95% success rate at 20 years and are associated with an
effective improvement in health-related quality of life [61]. There
are more than 300,000 total knee replacements in the United
States each year and a projection model predicted a 673% increase
in primary knee arthroplasty to a total of 3.48 million procedures
in 2030 [62]. Among all these surgeries, approximately 80% are
unilateral, meaning only one knee is replaced, and 20% are
bilateral. Recent advances in surgical technology have enabled
total knee replacements to be performed as a minimally invasive
surgical procedure, conducted under local anaesthesia that
requires only a small incision in the centre of the knee. Physical
therapy generally begins two days following surgery. Patients
generally rely on walking aids for the first few weeks and are back
to normal health in a few months. Nevertheless, the overall
complication rate of 5.5% includes infection that continues to
dominate the literature concerning complications after total knee
replacement. Deep vein thrombosis and poor wound healing have
also been described. Moreover, the revision rate after five or more
years is 2% [63].
Drug Discovery Today?Volume 14,Numbers 19/20?October 2009REVIEWS
TABLE 2
Update in Disease-Modifying OsteoArthritis Drugs (DMOADs)
TargetsDrugs Clinical status in OA
Company
MMPs
CPA-926
PD-0200347
VX-765
ONO-4817
CP-544439
S-3536
PG-530742
BAY12-9566
RO32-3555 (cipemastat)
RS-130-830
Doxycycline
Minocycline
Preclinical study Kureha
Pfizer
Vertex
Pfizer
Pfizer
Shionogri
Procter and Gamble
Bayer
Roche
Roche
–
–
Preclinical study stopped
Preclinical study
Preclinical study stopped
Unknown
Preclinical study stopped
Studies stopped
ADAMTS-5
ST109
ST154
UnknownBMSg
BMSg
Cathepsin K
SB-357114
SB-462795
GSKh
GSKh
ICEa
PralnacasanPreclinical study Sanofi-Aventis
p38 MAP-kinaseb
SB 242235 Preclinical studyGSKh
NF-kBc
NF-kB decoy oligonucleotide AnGes MG
iNOSd
N-iminoethyl-L-lysine–
iNOS activity
PD-0200347Pfizer
Caspase
Isatin sulfonamideGSKh
MEK-1/2e
PD 198306 Pfizer
PPARgf(agonist)
Pioglitazone Takeda
Bone resorption
Bisphosphonates (risedronate)
Calcitonin
Ranelate strontium
Phase III in progress
Phase III beginning in 2008
?
Procter and Gamble
Novartis
–
Anabolism
FGF-18Preclinical study–
aIL-1 converting enzyme (=caspase-1).
bMitogen Activated Protein.
cNuclear Factor-KappaB.
dInducible Nitric Oxide Synthase.
eMAP Erk Kinase.
fPeroxisome proliferator activated receptor gamma.
gBristol Myers Squibb.
hGlaxo Smith Kline.
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Arthrodesis
Arthrodesis, also known as artificial ankylosis or syndesis, is the
artificial induction of joint ossification between two bones.
Arthrodesis, however, is limited to a certain number of joints
within the body. Most arthrodesis surgery is performed in either
the wrist or hands, or the foot or ankle. Historically, knee and hip
arthrodesis was also performed as a pain-relieving procedure.
Given the great success achieved in hip and knee arthroplasty,
however,arthrodesisoftheselargejointshasfallenoutoffavouras
a primary procedure and is now only used as a last resort in some
cases of failed arthroplasties.
Regenerative therapies for articular cartilage defects
As previously described, cartilaginous defects constitute one of the
major extrinsic risk factors for OA. The incidence of cartilaginous
defects is estimated at 63% in the United States population of
31,516 arthroscopies [64]. Over the past 20 years, a great deal of
attention has, therefore, been paid to therapeutic procedures for
the early treatment of cartilaginous defects. Early treatments of
cartilaginous defects could indeed be crucial to slowing down the
chronic development of OA. Current procedures include washing,
shaving and debridement, stem cell stimulation-based procedures
(Pridie drilling and microfracture) and chondrogenic explant
grafts (allo and autografts) [65]. The major challenges in regen-
erative medicine for cartilage are the restoration of a biomecha-
nically competent ECM and the integration of this newly
synthesised matrix within the resident tissue. To address this
specific issue, Autologous Chondrocyte Implantation (ACI) was
developed and has paved the way for cell therapy and biomaterial-
assisted cartilage engineering.
Washing, shaving and debridement
Endoarticular washing consists of irrigating the joint with a phy-
siological salt solution. Although washing has shown beneficial
effects on pain, it remains an experimental approach. Elimination
of inflammatory waste by this technique could explain the analge-
sic effect [66]. Thus, some studies have shown a positive effect for
uptooneyear[67],whilstothersobservednodecreaseinpain[68].
Arthroscopic shaving consists in decreasing friction by removing
fibrillated cartilage with rapid shaving [69]. Today this method is
fairlycontroversialandisthereforeusedlessandless.Debridement
combines washing, meniscectomy, ablation of foreign bodies and
osteophytectomy. The long-term follow-up of patients under-
going such treatment has indicated that debridement leads to
an aggravation of OA [70].
Stem cell stimulation-based procedures
These procedures aim at improving the poor spontaneous repair of
cartilaginouslesionsbytakingadvantageofthepresenceofrepara-
tive stem cells in the subchondral bone marrow [71]. Two tech-
niques have been developed: Pridie drilling and microfracture.
Pridie drilling consists in perforating AC [72]. During this
procedure the cartilage and bone sustain a trauma with ensuing
therapeutic bleeding from the subchondral bone space. The ben-
efit of this procedure is related to the fact that the blood clot
triggers the spontaneous formation of a cartilage-like fibrous
tissue. This procedure is disadvantageous in that it is largely
invasive and has a longer recovery period and a higher probability
of complications. Moreover, this technique leads to the formation
ofafibro-cartilaginousmatrixthatremainstransitoryanddoesnot
possess the biomechanical properties of the native cartilage.
Whilst effective at preventing further bone damage, the newly
formed fibro-cartilaginous tissue is very poor at handling com-
pressive force and has a very limited load bearing capacity. As a
consequence, Pridie drilling is associated with excruciating
amounts of pain largely because of the loss of smooth articulation
and probably leading to bony crepitus. Microfracture is derived
from Pridie drilling and consists in creating multiple small per-
forationsinthecartilagedefects(4 mmindepth).Thesize-reduced
perforations can be performed via a mini-invasive procedure [60]
and have less of an impact on joint function [73]. Microfracture is
mainly indicated for the treatment of young patients and athletes
where it has been shown to be efficient [73]. Nevertheless, the
newly formed fibro-cartilaginous tissue is, as described above,
poorly competent from a mechanical point of view. Long-term
results of Pridie drilling and microfracture procedures need further
careful consideration.
Allo and autografts
The principle of cartilage grafting procedures is to fill cartilage
defects with healthy cartilage generally derived from human
cadavers (allografts) or from the patients themselves (autografts).
Allografts
Although allografts have been used for several decades to treat AC
defects, grafts derived from human cadavers induce immunologi-
cal reactions [74]. In addition, it has also been reported that
allografts lead to an increased risk of viral and NCTA (NonCon-
ventional Transmissible Agents) transmission.
Autografts
The first generation of osteochondral autografts consisted of har-
vesting a single and large patch of healthy osteochondral tissue
(single graft) [75]. Unfortunately this procedure has several major
drawbacks, such as a prominent morbidity of the donor site and an
unsuitable geometry of the collection specimen [76]. As a conse-
quence, a second generation of osteochondral autografts (multiple
grafts or mosaicplasty) has been developed and is still largely used
today.Thissecondgenerationofmultipleosteochondralautografts
wasfirstdevelopedbyHangodyetal.[77].Mosaicplastyisaone-step
procedure that consists of collecting several small cylindrical grafts
in a low-weight bearing area of the joint and transferring the
explants to the defect. Currently, mosaicplasty is restricted to sub-
jects under the age of 50 years who exhibit small lesions located at
the femoral condyles (lower than 4 cm2requiring fewer than 6
grafts), without mirror lesions and misalignment of the knee.
Despite the promising clinical results obtained [78], this technique
presents some major disadvantages, such as the difficulty to treat
large lesions (>4 cm2) and the instability of the graft. In addition,
thereissomeuncertaintyconcerningthelong-termoutcomeofthe
graft because of the discrepancy in the mechanical properties
between the donor and the recipient sites [60].
Despite their numerous disadvantages, microfracture and
mosaicplasty are largely considered the method of choice for
the treatment of cartilage defects and, therefore, occupy a strategic
place in orthopaedic surgical therapy.
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Cell-based surgical therapy: Autologous Chondrocyte
Implantation
Autologous Chondrocyte Implantation (ACI) is based on the
grafting of isolated cells with chondrogenic properties within
the cartilage defect. Brittberg et al. were the first to publish clinical
results in humans with this technique [79]. The technique consists
of three steps: cartilage collection, isolation and in vitro expansion
of chondrocytes in monolayer culture, and implantation of the
cultured chondrocytes in the lesion under a periosteal flap. Today,
this technique is largely used in the United States where the FDA
(Food and Drug Administration) delivered in 1997 the first agree-
ment for CARTICEL1(Genzyme Corporation, Cambridge, MA), a
commercial process for the production of autologous chondro-
cytes for transplantation. Today, in addition to CARTICEL1, sev-
eral new products are being developed and tested, such as
ChondroCelect1(Tigenix, Leuven, Belgium) or Hyalograft-C1
(Fidia Advanced Biopolymers, Abano Terme, Italy). CARTICEL1
is indicated for the repair of symptomatic cartilage defects in
femoral condyles (medial, lateral or trochlea), caused by acute
or repetitive traumatisms, in patients who have had an inadequate
response to a prior repair procedure (e.g. debridement, microfrac-
ture and mosaicplasty). In 2005, the French National Authority for
Health (HAS) evaluated the ACI technique [80]. Clinical studies
have shown an encouraging improvement in clinical signs of OA.
ACI-derived techniques, like the MACI technique (Matrix guided
Autologous Chondrocytes Implantation), have subsequently
undergone further developments. In the MACI, the periosteal flap
is replaced by a membrane composed of a mixture of type II and I
collagens stabilised on the defect by fibrin glue [81]. These cell-
based surgical therapies for cartilage defects have led to encoura-
ging results but also remain disappointing, particularly because
the recovery of articular chondrocytes leads to damage at the
donor collection site [60]. In addition, chondrocytes lose expres-
sion of the main chondrocytic markers during their in vitro expan-
sion in monolayer culture, and this process of dedifferentiation
leads to the formation of a fibrocartilage, biomechanically inferior
to the original hyaline cartilage [82]. Another limitation is related
to the use of a periosteal flap or a membrane to retain transplanted
cells within the defects, which is not totally impervious and
sometimes leads to hypertrophy [83] or uncontrolled calcification
[60]. To overcome these limits, much attention has been paid to
the development of three-dimensional scaffolds for the transfer
and maintenance of cells in the recipient site. In addition, the
increase in minimally invasive surgery has pushed researchers
towards the development of injectable cartilage tissue engineering
systems [84,85].
Drug Discovery Today?Volume 14,Numbers 19/20?October 2009 REVIEWS
FIGURE 4
Strategy for cartilage tissue engineering. Autologous reparative cells are isolated from cartilage or derived from bone marrow or adipose tissue. Cells are then
amplified and committed towards the chondrogenic lineage by exposure to various morphogenetic factors and finally seeded onto a scaffold. Hybrid constructs
can finally be implanted into the defect.
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Cartilage tissue engineering
Tissue engineering associates the principles and methods of engi-
neering and life sciences with the development of biological
substitutes that restore, maintain or improve tissue function
[86]. Tissue engineering involves seeding a biocompatible scaffold
with appropriate cells. The biomaterial scaffold can be loaded with
signalling molecules (morphogens) that promote cell differentia-
tion and maturation into the desired tissue. Two tissue engineer-
ing approaches have been developed. One consists of generating
functional tissue in vitro then implanting the construct into the
joint. In the other approach, the construct is cultured briefly,
implanted when still immature and allowed to mature in vivo
within its intended environment [87]. With respect to its biolo-
gical features and its poor capability for endogenous repair, much
attention has been paid to the development of tissue engineering
applied to the repair of cartilage [88]. The theoretical scheme of
cartilage tissue engineering is illustrated in Fig. 4 and involved a
scaffold, cells and morphogens.
Scaffolds
Many scaffolds have been investigated for cartilage tissue engi-
neering. They can be classified according to their nature (protein,
polysaccharide, synthetic or natural), their shape (massive, porous
massive, foams, viscous liquids and hydrogels) or their chemical
formulation. The ideal scaffolds must exhibit the following essen-
tial properties. They should be biocompatible to prevent inflam-
matory and immunologicalresponses,
dimensional environment favourable to the maintenance of a
differentiated chondrocyte phenotype. They should also be
permeable to allow for the diffusion of molecules and nutrients.
They should be adhesive to allow for the fixation of cells in the
lesion, and bioactive to enable homogeneous and controlled
release of growth factors. Finally, they should be injectable to
enable mini-invasive surgery, and biodegradable to enable long-
term integration into host tissues. The principal scaffolds used in
cartilage tissue engineering are cited in Table 3. Because of their
structure and properties, hydrogels are probably the most promis-
ing candidates, given the assumption that cartilage tissue engi-
neering may become successful not only in vitro or ex vivo [85] but
also in clinical situations. Hydrogels are composed of chains of
synthetic or natural absorbent macromolecules. Cross-linking
agents (glutaraldehyde, irradiation, pH or temperature) lead to
chemical modifications resulting in the formation of a reticulated
hydrogel [89]. The macromolecular network contains a high pro-
portion of water which reproduces the characteristics of the three-
dimensional environment of the cartilaginous ECM [90]. The
porosity of hydrogels can be adjusted by the modification of
the network density [84]. The fact that they can be injected is
another advantage of hydrogels, enabling minimally invasive
surgery [91], thereby reducing morbidity and the hospitalisation
period. These injectable scaffolds must also be able to increase in
volume, to acquire the desired shape once implanted. Preclinical
studies to evaluate the mechanical properties of hydrogels are
underway [85].
constituteathree-
Cells
Several sources of cells have been considered for cartilage tissue
engineering, including chondrocytes of various origins (articular,
nasal and costal) [92] and MSCs isolated from bone marrow,
periosteum, perichondrium or adipose tissue [93].
A recent study [94] compared different chondrocyte origins and
suggested that nasal chondrocytes could be the most appropriate
cell source for cartilage tissue engineering. Whether these data
obtained in a rabbit preclinical study can be extrapolated to
human remains to be demonstrated. The key limitations to the
use of chondrocytes, besides their origin, are their phenotypic
instability observed during the course of their expansion in mono-
layerculture.Thisphenotypicinstability,called‘dedifferentiation’
is characterised by a decreased expression of type II collagen,
increased expression of type I collagen and a shift of cellular
morphology from a rounded shape to the typical fusiform shape
of fibroblasts [82]. This process of dedifferentiation may, however,
be reversible when dedifferentiated chondrocytes are cultured in a
three-dimensional environment [95]. Considering their chondro-
genic potential, MSC could constitute an alternative source of
reparative cells for cartilage tissue engineering [87,96]. The term
‘mesenchymal stem cell’ originally refers to adult stem cells from
bone marrow (BMMSC). These BMMSC are characterised by an
extensive capacity to proliferate whilst retaining their multipo-
tentiality and ability to generate different connective tissue
lineages (osteoblasts, chondrocytes, adipocytes, cardiomyocytes
and so on) [97]. More recently, it has been demonstrated that MSC
can also be reproducibly isolated from human adipose tissue
(ATSC). Whereas the chondrogenic potential of ATSC is probably
not as effective as BMMSC [98], these cells have the ability to
differentiate along the chondrocyte lineage [99]. These ATSC have
the advantages that they can be harvested with a low morbidity of
REVIEWSDrug Discovery Today?Volume 14,Numbers 19/20?October 2009
TABLE 3
Scaffolds developed in cartilage tissue engineering
ScaffoldsHydrogel available
Proteic scaffolds
CollagenYes
Gelatin No
Fibrin Yes
Laminin (MATRIGELW)No
Polysaccharidic scaffolds
AgaroseYes
AlginateYes
Cellulose Yes
ChitosanYes
Hyaluronic acidYes
Artificial scaffolds
Carbon fibreNo
Calcium phosphateNo
DacronWa
No
Polybutyric acidNo
PolyestherurethaneNo
Polyethylmethacrylate Yes
Polyglycolic acid (PGLA) Yes
Polylactic acid (PLA)Yes
TeflonWb
No
aTerephtalate polyethylene.
bPolytetrafluoroethylene.
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the donor site. Moreover, once digested and adipocytes removed,
adipose tissue contains a high proportion of MSC (1–5%) com-
pared tobonemarrow (0.01–1%) [100].MSCare easilyamplifiedin
monolayer culture and can undergo a differentiation process
towards the chondrogenic lineage under appropriate conditions.
The optimal conditions to differentiate MSC towards chondro-
cytes still have to be clearly established. Many pivotal parameters
have been demonstrated to influence this process, such as growth
factors, tri-dimensional culture and oxygen tension. MSC also
have therapeutic potential as a result of their immunosuppressive
properties. It has been demonstrated that BMMSC and ATSC are
well tolerated and decrease the host response to the graft in the
context of allogenic transplantations [101].
Culture conditions and morphogens
Culture conditions and morphogens (growth factors, oxygen ten-
sion and mechanical constraints) are essential parameters to take
into account in the development of tissue engineering.
As previously described, three-dimensional culture enables pre-
servation of the differentiated phenotype of chondrocytes [102].
Moreover, dedifferentiated chondrocytes recover their phenotype
when they are placed in three-dimensional culture [95]. The
molecular mechanisms governing the processes of dedifferentia-
tion and re-differentiation are only partially understood, but a key
role for integrins has been proposed [103]. Bioreactors constitute
mechanically active and controllable culture systems. The ideal
bioreactor must provide the tissue with mechanical stimulation
similar to the in vivo conditions and increase ECM synthesis,
nutrition and oxygenation of the tissue [104]. Physiological load
exerted in the joint is essential to the development and the
regeneration of normal AC [105]. Mechanical stimuli impact
the behaviour of chondrocytes in vivo and in vitro [106]. Never-
theless, the consensus from in vitro mechanical loading experi-
ments is that static compression stimulates depletion of PG and
damage to the collagen network and decreases the synthesis of
cartilage matrix proteins, whereas dynamic compression increases
matrix synthetic activity [107]. The choice of the ideal parameters
of stimulation is still under evaluation. Among the morphogens,
growth factors are largely used to maintain chondrocytic pheno-
type or to differentiate MSC towards a chondrocytic phenotype.
Many growth factors are involved in chondrocyte maturation and
formation of cartilage [108]. These factors include the TGF-b
family (Transforming Growth Factors), BMPs (Bone Morphoge-
netic Protein), CDMP (Cartilage Derived Morphogenetic Protein),
FGFs (Fibroblast Growth Factors) and IGF-1 (Insulin-like Growth
Factor-1). Another morphogen that has been considered as a
potential tool for cartilage tissue engineering is hypoxia. Indeed,
AC is a non-vascular tissue and chondrocytes are, therefore,
immersed in a hypoxic environment (between 1 and 5% O2)
[109]. Hypoxia is involved in the differentiation of chondrocytes
[109] and MSC [110] through the HIF (Hypoxia Inducible Factor)
pathway [111]. It has also been suggested that hypoxia could be a
major factor for the prevention of chondrocyte terminal differ-
entiation and cartilage mineralisation [109].
Gene therapy
Whereas the majority of research is directed towards the develop-
ment of growthfactor delivery systems, gene therapythat usescells
for the in situ production of therapeutic proteins is considered with
interest [112]. In the context of cartilage tissue engineering, this
typeoftherapyaimsatstimulatingtheexpressionofgenesinvolved
in the processes of tissue regeneration. Genes coding for various
membersoftheTGFsuperfamily(TGF-b,BMPs),IGF-1,Soxfamily(-
5,-6,-9),FGF-3andSMADscouldbepotentialcandidates[113,114].
However, the clinical use of gene therapy is still in its infancy and
will require further in vitro and in vivo evaluation before becoming
part of the therapeutic arsenal in osteoarticular diseases.
Conclusion
The increasing knowledge regarding the pathogenesis of OA,
particularly the role of cytokines, growth factors and signalling
molecules, has provided new perspectives for cartilage repair and
treatment of OA. The huge number of aetiological factors means
that a multidisciplinary approach is necessary for the successful
management of this disease. Regenerative therapies for the articu-
lar surface alone may not necessarily lead to pain relief and
improvement of joint function, because other tissues including
bone, muscles, tendons,ligaments andthesynovial membrane are
also involved in the pathogenic processes. The expanding reper-
toire of potentially therapeutic options offers the possibility to
combine pharmacological treatments and tissue engineering
towards regenerative medicine and thus to improve OA treatment
andoptimisecartilagerepair.Aninevitablepre-requisiteforchoos-
ing the proper strategy and achieving the highest therapeutic
benefitis,however,theabilitytodefinethestageandpathogenetic
backgroundofthedisease,whichrequiresverysensitivediagnostic
methods. Prevention of OA will be a key issue in the quest to
decrease OA incidence in our ageing societies. The main challenge
in tissue engineering is to find a compromise between the benefits
to the patients, regulatory agencies, costs, coverage by health
insurance and the role of pharmaceutical companies.
Acknowledgements
This study was supported by grants from ‘Socie ´te ´ Franc ¸aise de
Rhumatologie’, ‘Fondation Arthritis Courtin’, ‘Fondation de
l’Avenir pour la Recherche Me ´dicale Applique ´e’, ‘Agence Nationale
delaRecherche’(ANR‘‘SCARTIFOLD’’,ANR‘‘CHONDROGRAFT’’),
‘Institut National de la Sante ´ et de la Recherche Me ´dicale’ and
University Hospital of Nantes. The authors also thank Servier
Medical Art for illustration.
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