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Abstract:
Osteoarthritis is the most common joint disorder
considered as the cumulative result of mechanical and
biological events that induce an imbalance between the
degradation and synthesis within articular joint
tissues. The diagnosis of OA mainly based on physical
examination and radiographs which provide semi quantitative
assessment of disease state. Biomarkers are sensitive to
minor changes so their measurement provides an accurate
metabolic status of joint. As osteoarthritis mainly
affects bone, cartilage, and synovium, biomarker related
to their metabolism act as specific marker for
osteoarthritis. Analyses of cartilage markers such as
cartilage oligomeric matrix protein, keratan sulfate etc.
provide a useful technique to diagnose osteoarthritis at
early stages. Osteocalcin measurement provides
information about bone while glucosyl- galactosyl pyridinoline
reflect synovium turnover. The measurement of inflammatory
markers such as YKL-40, matrixmetalloproteinases etc. help
to detect target joints. The clinical utility of
biomarkers described using BIPED approach. The biomarkers
for osteoarthritis used to diagnose disease at an early
stage, assess severity of disease and measure efficacy
of treatments. Matrix metalloproteinases and pro matrix
metalloproteinase are sensitive markers of disease
severity and response to treatment.
J.Orthopaedics 2009;6(4)e10
Keywords:
Skeletal marker; Inflammatory marker; Cartilage; Bone;
Synovium.
Introduction:
Osteoarthritis (OA) is the most common joint disorder,
and there is evidence that a majority of individuals
over the age of 65 have radiographic and / or clinical
evidence of OA.[1]
Osteoarthritis (OA) is currently defined by the American
College of Rheumatology (ACR) as a heterogeneous group
of conditions that leads to joint signs and symptoms,
which are associated with defective integrity of articular
cartilage, in addition to related changes in the
underlying bone at the joint margins.[2]
The main emphasis is on biomarkers used in
osteoarthritis so the course of disease progression and
clinical symptoms reviewed briefly. OA is a multifactorial
disease considered as the cumulative result of mechanical
and biological events that induce an imbalance between
the degradation and synthesis within articular joint
tissues.[3] Cartilage acts as a shock absorber and, with
synovial fluid, provides a smooth, low-friction surface
for movement. [4] After initiation of cartilage
degradation process, synovial fluid starts to secrete proinflammatory
cytokines, which are considered as accelerators of
cartilage degradation process. The proteolytic
enzymes play an important role in degradation of
cartilage, which is produced in response to stimulation
of cytokines. Among proteolytic enzymes, matrix metalloproteinases
are most important. The other proteolytic enzyme such as
thiol and serine proteases plays a role in activation
of metalloproteinases. The fundamental anatomic-
pathologic aspects of OA are alteration of the hyaline
cartilage , sclerosis of subchondral bone, osteophytosis,
presence of modest synovial inflammation, and involvement
of the periarticular structures (capsule, ligaments);
thus, the clinical picture involves the entire joint.[5]
The symptoms of OA are often associated with significant
functional impairment. Clinically OA is characterized by
joint pain, crepitus, stiffness after immobility for
less than 30 minutes and limitation of movement. Articular
gelling, Joint enlargement are also seen in OA.[2].
Diagnosis:
The diagnosis of OA is mainly based on physical
examination and radiographs supported by laboratory tests
such as C - reactive protein and erythrocyte
sedimentation rate (ESR). Radiographs provide semi -
quantitative measure of bone erosion and cartilage loss
but this technique have poor sensitivity and provide
positive results after significant progression of
disease.[6] Although C - reactive protein and erythrocyte
sedimentation rate are indicators of inflammation but
these are not site specific. Arthroscopy is an another
technique that gives direct and magnified view of
cartilage, mainly used to see damage to
cartilage that is not visible on X - ray. Arthroscopy
is an invasive technique. Magnetic resonance imaging is
a non - invasive technique used to determine the
functional status of cartilage. This technique allows
visualization of joint and soft tissues in three
dimensions. Rheumatoid factor and cyclic citrulinated
peptide antibody are tested to differentiate rheumatoid
arthritis from osteoarthritis. Analysis of synovial
fluid done to detect presence of crystals and signs
of inflammation in the joint. [ 7- 8]
Biomarkers:
According to NIH , biomarker can be defined as a
characteristic that is objectively measured and
evaluated as an indicator of normal biologic processes,
pathogenic processes, or pharmacologic responses to a
therapeutic intervention.[9]
Biomarkers that monitor specific physiological or
pharmacological mechanisms can be used to select
between multiple therapeutic targets for a drug by
identifying those that are most sensitive to the
intervention. Biomarkers can also reveal drug targets as
well as optimize selection of molecules that interact
with these targets for further development. For drugs
with a large therapeutic index, these biomarkers can
allow fast progression from Phase I to Phase II
clinical studies based on quantification of target
modulation rather than achievement of maximum tolerated
dose.[10]
These biomarkers can be used to clarify pathobiological
processes in the joint, and differentiate diagnostically
between affected and non - affected joints, and
distinguish the degree of degradation in articular
cartilage.[11]
The markers released into biological fluids reflect joint
tissue metabolism, their measurement probably provide the
most accurate reflection of the current metabolic status
of arthritis in any one joint. These biomarkers are
released in biological fluids during bone turnover
process.[8] Bone marker measurements have the advantage
that changes in bone marker concentrations can also be
seen earlier than changes in bone mineral density.
Biomarkers are direct and indirect indicators of
abnormal skeletal turnover. As biomarkers are direct
and indirect markers of skeletal turnover, they provide
information about anabolism and catabolism of bone and
release of products in response to stress and damage to
the joint respectively. [11]
1.
Skeletal marker:
Skeletal markers provide information about cartilage, bone
and synovium metabolism. These markers provide diagnosis
of osteoarthritis at early stages. Various skeletal
markers are investigated, markers of major importance
are reviewed here.
A.
Cartilage marker:
The articular cartilage mainly consists of water,
collagen and chondrocytes. The destruction of joint
cartilage is of central importance in human arthritic
disease. Analyses of cartilage markers provide a useful
technique to diagnose osteoarthritis at early stages as
well as define efficacy of various drugs.
As collagen is the main constituent of cartilage. Type
II collagen synthesized as a procollagen molecule with
noncollagenous amino and carboxy extension peptides, by
articular chondrocytes and measurement of its marker can be
considered as a marker of cartilage degradation. Collagen
markers can be used as formation and degradation markers. During
early stages of OA, the synthesis of collagen type II increases
as an attempt to repair process, which leads to increase
Procollagen type II C-propeptide (PIICP)
content in OA cartilage compared to normal cartilage.
Procollagen type II C-propeptide (PIICP)
used as a formation marker for collagen.[13] Proteolytic
enzymes secreted by chondrocytes degrade type - II collagen. In
OA, chondrocytes became metabolically active and increase
expression of proteolytic enzymes.[14] Due to increase
expression of proteolytic enzymes degradation of collagen
type - II increases which is detected by using
elevated levels of CTX - II. It is a very early marker
of collagen degradation and thereby of osteoarthritis. [15
– 16] Sharif M. and others conducted a study involving
five-year follow up came to conclusion that active
degradation of type II collagen continues during the
course of progression of disease. [17]
The MMPs subfamily collagenases
preferentially cleave collagen type II between Gly794 and Leu795
generating two fragments that are 3/4 and 1/4 the size of the
collagen precursor. Following initial cleavage, the triple helix
of CII fragments unwind, providing a denatured substrate
susceptible to further degradation by a variety of proteolytic
enzymes. Owing to its extensive and exclusive presence in
cartilage, markers of collagen type II metabolism in synovial
fluid (SF), serum, and urine can reflect joint status marking
the onset, and progression of OA.
Urinary levels of C-terminal neo-epitope of the 3/4 fragment of
type II collagen have been reported to be 2.5 times higher in OA
patients than in healthy controls. Since
alteration in CII metabolism occurs prior to detectable
radiographic changes, it is a specific and early marker of
arthritic joint diseases.
Type II collagen helical
peptide (HELIXII) is a product of
proteolytic degradation of collagen.
Urinary levels of HELIXII have been
shown to be significantly
elevated in OA patients compared to healthy controls, can be considered as
degradation marker of collagen. HELIX II shows diurnal variation
between morning activities and rest of the day. Tabassi NCB and
others conducted a study on patients with knee OA and found that
release of HELIXII and CTX-II is by different pathways. They
concluded that CTX-II and HELIXII alone could not reflect
collagenolytic activity of MMPs and cathepsin but cautiously
interpreted results of their combination may provide
complimentary information on cartilage degradation. [18]
Aggrecan is the noncollagenous protein present in
cartilage.[19] The high keratan sulfate (KS) and
chondroitin sulfate content of aggrecan and its ability
to attach hyluronan are essential features of articular
cartilage. Major aggrecan products present in these synovial
fluids are relatively large and are composed of a
segment of the interglobular domain attached to the G2
domain, the KS domain, and variable lengths of the chondroitin
sulfate domain. The loss of aggrecan is at all
stages of osteoarthritis promoted by the action of a
cartilage proteinase, which cleaves human aggrecan at the
Glu 373 - Ala 374 bond.[19-20] The level of aggrecan
synthesis can be determined by using Chondroitin sulfate
and Keratan sulfate act as degradation marker. The
molecular weight of Keratan sulfate and Chondroitin
sulfate are 4 - 20 kDa and 12 - 20 kDa respectively.
Keratan sulfate and chondroitin sulfate are the
components of glycosaminoglycan (GAGs). The Chondroitin
sulfate domain is the largest domain of aggrecan. Keratan
sulfate and chondroitin sulfate can be used as marker
for detection of early stages in OA as the
process of articular cartilage destruction starts with
loss of GAGs. Keratan sulfate is
a sulfated glycosaminoglycan component of aggrecan, the
second most abundant protein in articular cartilage. [21]
Keratan
sulfate
mainly
originates from articular cartilage and intervertebral
discs. Thus, the serum concentration of keratan sulfate
is not only a marker of articular cartilage, but also
of intervertebral discs. Therefore, the test requires an
important consideration to exclude the possibility of spondyloarthropathy
before concluding that the elevated serum concentrations
of keratan sulfate are due to OA. Keratan sulfate
increases in case of mechanical injuries within a few
months after injury, which indicate that, the release of
cartilaginous GAG in the early stage after injury in
spite of moderate cartilaginous damage that is
undetectable by radiography.[22- 23] Chondroitin sulfate
is the most abundant glycosaminoglycan in articular
cartilage. Chondroitin sulfate with collagen and other noncollagenous
proteins provide resiliency and enables cartilage to
withstand to compression. Various studies suggested that
osteoarthritis causes changes in chondroitin sulfate
chains and its sulfation process. [24] Certain neo -
epitopes on CS chains, recognized by the monoclonal
antibodies 3 - B - 3 and 7 –D - 4, may also reflect
aspects of the OA process. These epitopes are absent
or only weakly expressed in adult canine cartilage, but
occur in very high levels in experimental OA
cartilage. Increased levels also occur in human
articular cartilage from OA knees. [25]
Hydrophilic aggrecans
are the second main component, which are responsible for the
compressive stiffness of
cartilage. Degradation or loss of
components of cartilage molecules results in the destruction of
articular
cartilage. Cathepsin K is involved in the hydrolysis
of aggrecan and collagen
by forming
active proteolytic complexes with chondroitin or keratan
sulfates.
The primary
specific cleavage site by cathepsin k
is close to the N-terminus of type II collagen triple helix.
The expression of
cathepsin K increased in OA and its measurement would correlate
to disease severity. [26-27]
COMP is one of the best-studied markers for OA. The
research group of Professor Dick Heinegard COMP is a
non-collagenous, non-aggrecan glycoprotein component of the
articular cartilaginous matrix first described in 1992.
[28] It is produced by chondrocytes as well as
synviocytes and can serve as a marker for either
cartilage degradation or synovium turnover or both.[6]
COMP have a role in the regulation of fibril
assembly and maintenance of the mature collagen network.
COMP is a 524 - kd, homopentameric, extracellular
matrix glycoprotein. The total amount of COMP in
osteoarthritic cartilage is same as normal cartilage but
with higher proportion of degraded fragments. These
fragments diffuse into joint fluid and thereby appear in
circulation. The high c circulating levels indicate
increased cartilage degradation, which occurs in
osteoarthritis. [29- 30] Cyclic loading can change the
levels of COMP. One study shows that walking for 30
minutes can increase the level of COMP. [31]
B. Bone markers:
Bone mainly consist of type I collagen and noncollagenous
protein such as osteocalcin, proteoglycan etc. Type I
collagen degradation can be assessed by measurement of pyridinoline
cross-links in urine; their excretion is significantly
elevated in patients with OA. Pyridinoline and
deoxypyridinoline are the markers for bone resorption. Pyridinoline
is primarily located in cartilage. Deoxypyridinoline found
predominantly in type I collagen of bone. Pyridinoline (Pyr)
and its minor analog, deoxypyridinoline (Dpyr), are trifunctional
3-hydroxypyridinium cross-links between collagen molecules
i.e. type I, type II and type III collagen and
contribute to stabilizing and reinforcing the whole
structure of such collagenous tissues as bone and
cartilage. These intermolecular cross-links are
discharged in the circulation as small peptides during
the disintegration of mature collagen, and excreted into
urine without metabolization. [32- 33]
A
noncollagenous protein in bone osteocalcin used as a
marker for bone formation. Osteocalcine is one of the
most abundant non-collagenous proteins of the bone,
constituting up to 3% of total bone protein. Osteocalcine
plays role in bone tissue formation as produced by osteoblasts,
therefore act as a marker for bone formation. The
anabolic activity of osteoblasts may be determined by
measuring serum concentrations of osteocalcine. Osteocalcine
levels reflect bone turnover. Serum osteocalcine is known
to increase with age and is generally higher in women
than men. Bone synthesis reflected by the release
of osteocalcine into sera. Elevated osteocalcin
concentrations in human OA patients accompanied by
increased bone turnover. [34-36]
Synovium Turnover marker:
Synovial membrane is a soft tissue lining the joint
space. Glucosyl Galactosyl Pyridinoline (Glu-Gal-Pyd) is a
non-reducible link of collagen present in human synovial
tissue but absent from bone, cartilage and other soft
tissue. Due to its absence from other sites in human
body, it acts as a specific marker for synovium
turnover. It indicates the degradation of synovial
membrane. It is a glycosylated analogue of Pyridinoline.
It is the maturation product of two hydroxylysine
residues from the C- or N- telopeptide of collagen with
a glycosylated
hydroxylysine from the alpha - helix of another collagen
molecule. Osteoarthritis individuals show high urinary
levels of glucosyl and they correlate to extent of
joint destruction. [37 - 38]
2. Inflammatory markers:
Inflammatory markers are valuable for detecting the
target joints. OA is not a
disease driven by inflammation, some degree of episodic,
non-erosive synovial inflammation is common in OA, even
during early stages of the disease. [39] As C-
reactive protein and ESR is not site specific, these
inflammatory markers could be beneficial. YKL-40 a
noncollagenous glycoprotein act as an inflammatory marker
for OA. YKL-40, or human cartilage glycoprotein 39 is a
glycoprotein similar to some chitinases but lacking
enzymatic activity. Its molecular weight is approximately
40 KDa. [40 -41] It is a mammalian glycoprotein produced
by synovial cells, chondrocytes and others. YKL - 40
thought to have a capacity of inducing a T –cell
mediated immune response. It is absent from healthy
cartilage from young adults, but sparse expression is
sometimes found in healthy cartilage from older adults,
possibly reflecting deterioration of the tissue with age.
Increased levels compared with normal subjects found in
the serum of patients with osteoarthritis. The increase
level of YKL -40 is produced by chondrocytes in response
to altered biochemical or biomechanical properties of
cartilage. [42]
Hyluronic acid is a putative marker of synovial
inflammation. Hyluronic acid is a high molecular weight
polysaccharide produced mainly by fibroblasts and other
specialized connective tissue cells. Hyluronic acid is one
of the most important biomolecule of articular
cartilage. In OA, both the
concentration and molecular weight of synovial hyluronic
acid decreased, leaving the cartilage more susceptible
for cartilage degradation. Hyluronic acid may
contribute to inflammation of the joint, with subsequent
articular damage. [43- 44]
Proteases and their inhibitors also act as an
inflammatory marker for osteoarthritis. Matrix
metalloproteinases and pro matrix metalloproteinase are
sensitive markers of disease severity and response to
treatment. Matrix metalloproteinases secreted by chondrocytes.
[45] Matrix metalloproteinases are essential for the
initiation of the osteoclastic resorption process by
removing the collagenous layer from the bone surface.
Matrix metalloproteinases causes proteolysis of aggrecan.
An increased level of matrix metalloproteinases in synovium
and cartilage is the main cause of cartilage
degradation. [46] There are two types of matrix metalloproteinases,
which show hyperactivity in OA. They are Stremolysin -1
and Gelatinase-B. They both are absent in normal
synovial fluid but can be measured in synovial fluid of
patients suffering from OA. [47- 48]
Pro-matrix metalloproteinase-3 is the inactive form
of metalloproteinase-3. Pro-matrix metalloproteinase-3 has
lower affinity towards tissue inhibitor of matrix
metalloproteinases than active form. The measurement of
proMMP-3 concentrations may be useful in predicting
cartilage degradation, as this, pro-enzyme found to be
elevated in synovial fluid in conditions of cartilage
damage of the knee. [49]
Tissue inhibitors of matrix metalloproteinase (TIMP) are
22 to 30 kDa proteins that inhibit MMPs by forming a
1:1 complex with a target
matrix metalloproteinase. Matrix metalloproteinases are regulated by tissue
inhibitors of
metalloproteinases. These inhibitors (TIMP-1 and TIMP-2) and
the MMPs collagenases 1 (MMP-1) and stromelysin (MMP-3)
have been identified in the synovial fluid of patients
with arthritis. Their presence may reflect disease
activity at the level of proteolysis. Imbalances in proteinase
/ inhibitor content that
favor proteolysis is been found in OA. In osteoarthritis,
plasma levels of MMP and TIMP can be used as an
index of cartilage degradation. [50-51]
The clinical utility of biomarkers in osteoarthritis can
be described using BIPED approach: [8, 52].
1.
Diagnostic marker:
Diagnostic markers are used to differentiate individuals
as diseased or non-diseased. The markers such as COMP, CTX-II,
Inflammatory markers can be used as diagnostic markers.
Increased levels of COMP are more related to the hip
osteoarthritis when radiographs do not show any change.
2. Burden of disease:
Burden of disease markers are used to assess the
severity of disease and not related to the economic or
social burden of disease. The markers such as COMP, CTX-II,
and Hyluronan can be used as a marker to assess the
severity of disease. The diagnostic and burden of
disease markers are very similar, so the biomarkers are
present in both the categories.
3. Prognostic marker:
As the name suggest they can be used to predict the
onset of OA in individuals without signs of OA at
baseline or the progression of OA in individuals with
existing OA. Matrix metalloproteinases, COMP, osteocalcin
etc. used as prognostic markers.
4. Efficacy of intervention marker:
Efficacy of intervention marker is the biomarkers used
to assess treatment effect. Various markers used to assess
the efficacy of treatment such as, chondroprotective
drugs efficacy can be assessed by determining levels of CTX-II,
COMP, or anti-inflammatory activity using collagenases,
Stremolysin activity.
5. Investigative marker:
Investigative markers are the markers having insufficient
data to include them in other Categories of BIPED
classification. There are some studies that show
mutations in genes such as IL-1, estrogen receptor
susceptible to OA and show differences
in the nature of the genetic susceptibility to OA at
different joint sites.
Conclusion:
These
biomarkers possess various advantages over conventional
methods such as, the changes in biomarker concentration
seen earlier than changes in bone mineral density. The
biomarkers are very sensitive to minor changes in articular
cartilage as compare to radiography so they can be used
as surrogate for radiography. Several biomarkers are
suitable to detect degenerative diseases at their initial
stages. However, biomarkers provide relevant information
regarding assessment, progression and treatment efficacy in
osteoarthritis in comparison to radiography, combined use
of markers is necessary to predict their use in clinical
practice. The challenge is to select small set of
biomarkers from a wide variety of biomarkers to predict
correct diagnosis and further monitoring of an individual
patient. As biological markers have rapid responsiveness
toward detection of joint damage after trauma or injury,
and in monitoring the treatment effects of various
drugs, their use should be encouraged in regular
clinical practice in patients with OA. As OA is a
multifactorial disease whose initiation, progression, and
severity influenced by multiple environmental factors with
multiple genes in a given individual, so there is a
need for further research on genes involved in OA,
which may provide various biomarkers having potential
clinical utility.
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