Buckwalter, J.

Martin, J.

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C12 Abstracts from Invited Speakers
tions regarding surgical RCT’s in a lively format that will draw
examples several recently published or ongoing surgical trials.
Results: The randomized controlled trial (RCT) is the time-
honored scientiﬁc approach for assessing the efﬁcacy of inter-
ventions. Trial methodology has developed largely to conform to
the needs of pharmacologic studies. When RCTs are performed
in other settings, such as to assess the efﬁcacy of a surgical
intervention, investigators must confront difﬁcult methodological
questions. Some of these are unique to the non-pharmacological
setting and others are more challenging in this setting. For ex-
ample: what is an appropriate control in a trial of a surgical
intervention? Is sham surgery ethically defensible? To what ex-
tent can blinding can be achieved in the absence of a sham?
How does the research team ensure and assess compliance
with surgical or non surgical intervention? What are the scien-
tiﬁc consequences of cross-overs (from nonoperative therapy to
surgery, and vice versa) ? How can cross-overs be minimized
in the design of trials and accounted for in the trial analysis?
How should the investigator account for the effects of correlation
among patients of the same surgeon and the same hospital in
the design and analysis of trials?
Conclusions: This workshop will be of particular interest to
persons interested in non-pharmacological trials in OA, including
trials of surgery.
MOLECULAR BIOMARKERS OF OSTEOARTHRITIS:
CURRENT CANDIDATES AND FUTURE PROSPECTS
C.R. Flannery
Wyeth Research, Cambridge, MA
The ongoing challenge of identifying valid molecular biomarkers
to monitor osteoarthritis (OA) has involved translating basic stud-
ies of joint tissue metabolism into reliable biochemical assays of
accessible body ﬂuid samples (i.e. synovial ﬂuid, serum, plasma,
urine) [1]. Predominantly, the aim of such assays is to survey the
turnover/release of macromolecules which may originate from
affected articular tissues (such as cartilage), and correlate these
levels with the degree of disease activity.
Practicable assays have been reported (and in many cases are
commercially available) for, among others, aggrecan degradation
products and substituents (i.e. glycosaminoglycans), type II col-
lagen fragments, cartilage oligomeric matrix protein (COMP) and
hyaluronan (HA). In addition, procedures to assay the neosynthe-
sis of aggrecan and collagens are described, and offer additional
measurements for combining multiple biomarker parameters in
attempts to enhance diagnostic accuracy [2-4].
Attention has also been directed toward the catabolism of small
leucine-rich proteoglycans (SLRPs) and the ability to quantify
relevant SLRP fragments in biomarker assays [5]. Other logical
candidates to assess may include the cartilage boundary glyco-
protein lubricin/PRG4 [6], and a variety of other proteinaceous
components which, for example, are differentially abundant in
normal and osteoarthritic human cartilage extracts [7].
While inherent variation among individuals poses signiﬁcant hur-
dles, the utility of using appropriate molecular biomarkers as
surrogate measures of OA offers promise for longitudinal as-
sessments, and in the evaluation of potential responses to ther-
apeutic, interventional treatments [8].
References
[1] Lohmander LS. Markers of altered metabolism in osteoarthri-
tis. J Rheumatol 2004;31(Suppl 70):28-35.
[2] Sumer EU, Schaller S, Sondergaard BC, Tanko LB, Qvist P.
Application of biomarkers in the clinical development of new
drugs for chondroprotection in destructive joint diseases: a
review. Biomarkers 2006;11:485-506.
[3] Birmingham JD, Vilim V, Kraus VB. Collagen biomarkers for
arthritis applications. Biomark Insights 2006;2:61-76.
[4] Charni-Ben Tabassi N, Garnero P. Monitoring cartilage
turnover. Curr Rheumatol Rep 2007;9:16-24.
[5] Flannery CR. Usurped SLRPs: novel arthritis biomarkers
exposed by catabolism of small leucine-rich proteoglycans?
Arthritis Res Ther 2006;8:106.
[6] Young AA, McLennan S, Smith MM, Smith SM, Cake MA,
Read RA, Melrose J, Sonnabend DH, Flannery CR, Little
CB. Proteoglycan 4 downregulation in a sheep meniscectomy
model of early osteoarthritis. Arthritis Res Ther 2006;8:R41.
[7] Wu J, Liu W, Bemis A, Wang E, Qiu, Y, Morris EA, Flannery
CR, Yang Z. Comparative proteomic characterization of ar-
ticular cartilage tissue from normal donors and patients with
osteoarthritis. Arthritis Rheum 2007;in press.
[8] Bauer DC, Hunter DJ, Abramson SB, Attur M, Corr M, Felson
D, Heinegard D, Jordan JM, Kepler TB, Lane NE, Saxne T,
Tyree B, Kraus VB. Classiﬁcation of osteoarthritis biomarkers:
a proposed approach. Osteoarthritis Cartilage 2006;14:723-
7.
BIOLOGY & BIOMECHANICS OF AGING JOINTS –
ROLES IN OSTEOARTHRITIS
J. Buckwalter, J. Martin
University of Iowa, Iowa City, IA
Purpose: A number of factors increase the risk of osteoarthritis
including genetic predisposition, body mass, and developmental
disorders including joint dysplasias. However, in all populations,
age and excessive articular surface contact stress are asso-
ciated with substantial increases in the probability of the joint
degeneration that leads to the clinical syndrome of osteoarthritis.
With increasing age, articular cartilage loses tensile stiffness and
strength, frequently develops superﬁcial ﬁbrillation and alteration
of matrix macromolecules including proteoglycans and collagens.
We have been investigating the causes of these biological and
biomechanical age related changes in articular cartilage.
Methods: To examine the age related changes in human chon-
drocytes we have harvested articular cartilage samples from
humans ranging in age from newborns to the elderly. We have
studied the function of the chondrocytes in culture and in their
native matrix and tested their responses to mechanical stimuli
and antioxidants.
Results: We have found that with increasing age human chon-
drocytes show decreased synthetic activity, decreased prolifer-
ative activity, altered proteoglycan synthesis and a decline in
the response to anabolic growth factors. In addition, we have
found that with increasing age chondrocytes show a decline
in cartilage speciﬁc gene expression including aggrecan gene
expression and in their ability to form a cartilaginous matrix in
culture. In human chondrocytes these changes are associated
with a decrease in telomere length. Recent studies indicate that
loss of telomere length is a marker of impaired chondrocyte
function that is caused at least in part by cumulative oxidative
damage. We have also explored the role of chondrocyte ox-
idative damage in the development of osteoarthritis in young
adults and in particular the osteoarthritis that develops follow-
ing joint injuries (post-traumatic osteoarthritis) and in association
with joint dysplasia. In both of these conditions the articular sur-
face is exposed to increased contact stress. A study of human
articular cartilage in vitro shows that increased contact stress
and in particular shear stress increases the release the oxygen
free radicals. This increase in oxygen free radicals is associated
with chondrocyte death and apoptosis and use of antioxidants
blocks a substantial fraction of this deleterious effect. In addition,
we have found that pre-conditioning chondrocytes with oxidants
appears to stimulate antioxidant defenses and protects the cells
from mechanical stress induced apoptosis and death. Protect-
ing human chondrocytes from oxidative damage and providing
them with telomerase as a DNA repair mechanism substantially
Osteoarthritis and Cartilage Vol. 15, Supplement C C13
increases the number of chondrocyte population doublings in
vitro.
Conclusions: Taken together these observations indicate that
both aging and excessive articular surface contact stress may
cause oxidative damage to chondrocytes, and that strategies that
involve treating age related osteoarthritis in its earliest stages
and joint injuries may be beneﬁcial if they minimize deleterious
mechanical stresses and prevent propagation of chondrocyte
oxidative damage.
BIOMECHANICS AND MECHANOBIOLOGY OF
OSTEOARTHRITIS: THE YEAR IN REVIEW
F. Guilak
Duke University Medical Center, Durham, NC
Purpose: Biomechanical factors play a critical role in the onset
and progression of osteoarthritis, yet the mechanisms by which
biomechanical and molecular factors interact to control cartilage
physiology and pathology are not fully understood. Here we will
review recent studies focusing on osteoarthritis and cartilage that
have provided new insights on the role of biomechanics in OA.
Methods: In the past year, a number of exciting new studies
have revealed new details on the role of biomechanical factors in
the development, growth, remodeling, degeneration, and regen-
eration of joint tissues. Recent studies have focused at a variety
of different scales and topics, including:
• Micro- and nano-mechanics of extracellular matrix molecules
• Cartilage cell and tissue mechanical properties
• Mechanobiology of cartilage and other joint tissues
• Interactions of biomechanics and inﬂammation in obesity
• The role of biomechanics in tissue engineering and cartilage
regeneration
Results: These studies provide further evidence of the important
role that biomechanical factors play in the function of the synovial
joint, and in particular, how mechanical factors inﬂuence cell
biology and vice versa.
Conclusions: An improved understanding of these mechanisms
will hopefully lead to improved physical and pharmacologic ther-
apies for osteoarthritis.
CLINICAL AND MOLECULAR GENETICS – THE YEAR IN
REVIEW
J. Loughlin
University of Oxford, Oxford, United Kingdom
Purpose: The past year has been another highly productive one
in the ﬁeld of clinical and molecular genetics. New loci have
been reported, and older loci have either been replicated or
despatched from any further interest, in the objective style that
makes genetic linkage and association analysis such powerful
tools.
One of the most exciting new genes is GDF5, which codes for
growth and differentiation factor 5 (also known as cartilage-
derived morphogenetic protein 1). This signalling molecule,
which is a member of the TGF-β superfamily, is active during
joint formation and in mature tissues, implying both a design
and maintain function. A common polymorphism in a regulatory
element of the gene demonstrated a highly compelling associa-
tion in Asian populations and this was soon replicated in large
European cohorts. Subsequent meta-analysis on over 10,000
individuals has conﬁrmed the global relevance of this gene to OA
susceptibility whilst in-vitro and in-vivo functional studies have re-
vealed that the associated polymorphism reduces the expression
of GDF5 in chondrocytes. GDF5 joins the growing band of sig-
nalling or signalling-related genes that harbour polymorphisms
that confer susceptibility for OA. This is an exciting development
as these pathways are amenable to intervention.
Running alongside the new discoveries are the rumblings of
the agnostic genome-wide association scans. There are highly
progressed plans afoot for scans in North America, Europe and
Asia on large case-control cohorts. Very soon the OA research
community will be in the enviable position of understanding the
molecular genetic architecture of OA with quite high precision.
These are exciting times indeed.
CARTILAGE EXTRACELLULAR MATRIX IN HEALTH AND
DISEASE
D. Heinegård
Lund University, Lund, Sweden
The cartilage extracellular matrix is progressively broken down
and destroyed in joint disease leading to loss of tissue and
joint function. There is accumulating evidence for degradation of
cartilage extracellular matrix molecules at speciﬁc sites, following
the original observations of one unique speciﬁc cleavage site by
collagenases of triple helical collagen II and a total of ﬁve unique
sites in aggrecan by aggrecanases. In these cases the normal
and pathological turnover is accomplished by the same enzymes
and the same sites are cleaved. New information on degradation
of other matrix constituents indicates that there are processes
involving enzymes that appear more unique to a pathological
process and leading to unique cleavage sites. Antibodies raised
to the new terminals produced in the substrate proteins offer
opportunities to development of assays with a much higher
speciﬁcity for the pathological process. Such assays can be
used to depict sequence of events in the destruction process.
To understand the repair process that invariably is associated
with breakdown, information needs to be gained about assembly
of the constituent building blocks into larger structural assemblies
such as the collagen ﬁbrillar networks. There is accumulating
information on the role of various cartilage matrix constituents
in the regulation of the assembly of e.g. the collagen network.
Such molecules include speciﬁc subsets of chondroitin sulfate,
COMP and the leucine rich proteins, where there are examples
of both accelerators and inhibitors. Dysregulation of any of these
constituents is likely to hamper the process of tissue repair.
A key element is how cells react to events of the matrix. This
is partly governed by mechanical load and by alterations in
matrix constituents able to bind to receptors at the cell surface.
New information is becoming available on interactions with a
variety of cell surface receptors including integrins, cell surface
proteoglycans and a number of others for speciﬁc molecules.
Such interactions will be involved in modulating cellular activities
relevant to the integrity of the matrix.
Degradation of matrix constituent will produce fragments of vari-
ous macromolecules. Some of the fragment will be able to bind
to and affect other players such as systems of factors and cells.
One classical example is the ﬁbronectin fragments that activate
e.g. catabolic and inﬂammatory responses. It is now becoming
apparent that also degradation of collagen will yield similarly ac-
tive fragments. Inﬂammation is an almost invariable component
of all joint diseases. New data are indicating that components
in the cartilage may bind and regulate various players in the in-
ﬂammatory system including macrophages and the complement
system. This may yield activation of inﬂammation that in turn
effect the cartilage to further breakdown in a vicious circle.
ADVANCES IN CLINICAL TRIAL DESIGN FOR
OSTEOARTHRITIS
R.D. Altman
UCLA, Agua Dulce, CA
Instruments that measure change in osteoarthritis (OA) are not
as sensitive as desired. In addition, the placebo response con-


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