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ORIGINAL ARTICLE

Biomarkers in Osteoarthritis

Pravin V Ingle, Vibhavari K Lathi, Prakash H Patil, Sanjay J Surana

Department of Clinical Pharmacy, R.C.Patel Institute of Pharmaceutical Education & Research, Shirpur.

Address for Correspondence:

Pravin V Ingle
Lecturer, Department of Clinical Pharmacy,
R.C.Patel Institute of Pharmaceutical Education & Research,
Shirpur, Dist: Dhule (M.S.), India – 425405

Phone:
  
+91 9960721624
Fax    :   02563- 25180
E-mail:
 vibha.lathi@gmail.com

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.

Reference :

  1. Goldring  SR, Goldring  MB. Clinical  aspects,  pathology  and pathophysiology  of  osteoarthritis.  J Musculoskelet  Neuronal  Interact 2006;  6(4):  376-8.

  2. Piercarlo  SP,  Marco  AC,  Raffaele  S,  et al.  Osteoarthritis:  An Overview  of  the  Disease  and  Its Treatment  Strategies.  Semin Arthritis  Rheum  2005;  35 (suppl 1): 1-10.

  3. Antonella  F, Luca  C, Marta  F,  et al.  Methods  Used  to  Assess Clinical  Outcome  and  Quality  of Life  in  Osteoarthritis.  Semin Arthritis  Rheum  2004;  70-72.

  4. Gineyts  E,  Mo  JA,  Ko  A,  et al.  Effects  of  ibuprofen  on  molecular markers  of  cartilage  and synovium  turnover  in  patients  with  knee osteoarthritis.  Ann  Rheum  Dis  2004;  63:  857–61.

  5. Naoki  I,  Toshisha  K,  Polle  AR.  Mechanism  of  cartilage  destruction in  osteoarthritis.  Nagoya  J. Med.  Sci.  2002;  65:  73 – 84.

  6. Garnero  P,  Rousseau  JC,  Delmas  PD.  Molecular  basis  and  clinical use  of  biochemical  markers  of bone,  cartilage,  and  synovium  in joint  disease.  Arthritis  Rheum  2000;  43:  953-68.

  7. Garnero  P, Geusens  P, Landewe  R.  Biochemical  markers  of  joint  tissue  turnover  in  early rheumatoid  arthritis. Clin  Exp  Rheumatol 2003;  21 (Suppl. 31): 54-58.

  8. Rousseau  JC, Pierre  DD. Biological  markers  in  osteoarthritis. Nat Clin  pra  rheum  2007;  3(6):  346-56.

  9. Biomarkers  and  surrogate  endpoints:  Preferred  Definitions  and  conceptual  framework. Clin pharmacol  ther  2001;  69: 89-95.

  10. Frank  R, Hargreaves  R. Clinical  biomarkers  in  drug  discovery and development. Nat  Rev  Drug Discov  2003;  2: 567-80.

  11. Kane  ED.  Biomarkers  aid  early  detection  of  joint  disease,  bone damage.  DVM  Newsmagazine, Feb  2007.

  12. Ofluoglu  D,  Ofluoglu  O.  Assessment  of  Disease  Activity  and Progression  of  Osteoarthritis  with Using  Molecular  Markers  of Cartilage  and  Synovium  Turnover. Current  Rheumatology  Reviews, 2005;  1:  29-32.

  13. Elsaid KA, Chichester CO. Collagen markers in early arthritic diseases. Clinica Chimica Acta , 2006; 365: 68 – 77.

  14. Grimmer  C,  Balbus  N,  Lang  U, et.al.  Regulation  of  Type  II Collagen  Synthesis  during Osteoarthritis  by  Prolyl-4-Hydroxylases Possible  Influence  of  Low  Oxygen  Levels.  Am  J  Pathol 2006; 169: 491– 502.

  15. Chevalier  X,  Conrozier  T.  Biological  markers  for  osteoarthritis:  an  update.  [letter]   JBS  2005; 72:  106-9.

  16. Cahue  S,  Sharma  L ,  Dunlop  D ,  et al.  The  ratio  of  type  II  collagen  breakdown  to  synthesis and  its  relationship  with  the progression  of  knee  osteoarthritis.  Osteoarthritis  Cartilage  2007; 15; 819-23.

  17. Sharif  M,  Kirwan  J,  Charni  N,  et al.  A  5-yr  longitudinal  study  of type  IIA  collagen  synthesis   and  total  type  II  collagen degradation  in  patients  with  knee  osteoarthritis— association  with disease progression.  Rheumatology  2007;  46: 938–43.

  18. Roughley  PJ.  Articular  cartilage  and  changes  in  arthritis Noncollagenous  proteins  and proteoglycans  in  the  extracellular matrix  of  cartilage.  Arthritis  Res  2001;  3:  342-47.

  19. Tabassi NCB, Desmarais S, Bay jenson AC, Delaisse JM, Percival MD, Garnero P. The type II collagen fragments Helix-II and CTX-II reveal different  enzymatic pathways of human cartilage collagen degradation. Osteoarthritis Cartilage  2008;  16:  1183-91.

  20. Sharma  G,  Saxena  RK,  Mishra  P.  Synergistic  effect  of  chondroitin  sulfate  and  cyclic  pressure  on  biochemical  and morphological  properties  of  chondrocytes  from  articular  cartilage. Osteoarthritis Cartilage  2008;  16:  1387-94.

  21. Sandy  JD,  Flannery  CR,  Neame  PJ, et al .  The  Structure  of Aggrecan  Fragments  in  Human Synovial  Fluid  Evidence  for  the Involvement  in  Osteoarthritis  of  a  Novel  Proteinase  Which  Cleaves the  Glu  373-Ala  374  Bond   of  the  Interglobular  Domain. J.  Clin.  Invest.  1992;  89:  1512-16.

  22. Huebner  JL,  Kraus  VB.  Assessment  of  the  utility  of  biomarkers  of  osteoarthritis  in  the  guinea pig.  Osteoarthritis   Cartilage  2006; 14:  923-30.

  23. Wakitani  S,  Nawata  M,  Kawaguchi  A,  et al.  Serum  keratan  sulfate  is  a  promising  marker  of early  articular  cartilage breakdown.  Rheumatology  2007;  46: 1652–6.

  24. Plaas  AHK,  West  LA,  Wong-Palms  S,  et al.  Glycosaminoglycan Sulfation  in  Human Osteoarthritis  Disease  related  alterations  at  the  non-reducing  termini  of  chondroitin  and  dermaten sulfate.  J Biol  Chem  1998;  273: 12642–9.

  25. Belcher  C, Yaqub  R,  Fawthrop  F,  et al.  Synovial  fluid  chondroitin  and  keratan  sulphate  epitopes,  glycosaminoglycans,  and hyaluronan  in  arthritic  and  normal  knees.  Ann  Rheum  Dis  1997;   56:  299-307.

  26. Lecaille F, Broome D, Lalmanach G. Biochemical properties and regulation of cathepsin K activity. Biochimie  2008; 90:  208 – 26.

  27. Vinardell T, Dejica V, Polle AR, Richard H, Lavarty S. Evidence to suggest that cathepsin K degrades articular cartilage in naturally occurring equine osteoarthritis. Osteoarthritis Cartilage 2009; 17: 375 83.

  28. Lohmander  LS,  Saxne  T,  Heineg  DK.  Release  of  cartilage oligomeric  matrix  protein  (COMP) into  joint  fluid  after  knee  injury and  in  Osteoarthritis.  Ann  Rheum  Dis.  1994;  53:  8-13.

  29. Petersson  F,   Boegarerd  T,  Svensson  B,  et al.  Changes  in cartilage  and  bone  metabolism identified  by  serum  markers  in early  osteoarthritis  of  the  knee  joint.  Br  J  Rheumatol  1998;  37: 46- 50

  30. Andersson  MLE,  Petersson  IF,  Karlsson  KE,  et.al.  Diurnal  variation in  serum  levels  of  cartilage oligomeric  matrix  protein  in  patients with  knee  osteoarthritis  or  rheumatoid  arthritis.  Ann  Rheum Dis 2006;  65:  1490–4.

  31. Mundermann  A,  Dyrby  CO,  Andriacchi  TP,  et al.  Serum concentration  of  cartilage  oligomeric matrix  protein  (COMP)  is sensitive  to  physiological  cyclic  loading  in  healthy  adults. Osteoarthritis Cartilage  2005;  13:  34-8.

  32. Tanimoto  K,  Imada  M,  Ohno  S,  et al.  Association  between  Craniofacial  Growth  and  Urinary Bone  Metabolic  Markers (Pyridinoline, Deoxypyridinoline)  in  Growing  Rats.  J  Dent  Res 2003; 82(1):  28-32.

  33. Arican  M,  Kolyu  O,  Uyaroglu  A,  et al.  Diagnostic  importance  of deoxypyridinoline  and osteocalcine  in  equine  osteoarthritis.  Acta Vet.  Brno  2004;  73:   491–6.

  34. Pietschmann  P,  Machold  KP,  Wolosczuke  W,  et al.  Serum osteocalcin  concentrations  in  patients with  rheumatoid  arthritis.  Ann  Rheum  Dis. 1989; 48:  654- 7.

  35. Salisbury  C,  Sharif  M.  Relations  between  synovial  fluid  and  serum  concentrations  of  osteocalcin and  other  markers  of  joint tissue  turnover  in  the  knee  joint  compared  with  peripheral  blood. Ann Rheum  Dis  1997;  56;  558-61.

  36. Gineyts  E,  Mo  JA,  Ko  A,  et.al.  Effects  of  ibuprofen  on  molecular markers  of  cartilage  and synovium  turnover  in  patients  with  knee osteoarthritis.  Ann  Rheum  Dis  2004;  63;  857-61.

  37. Jordan  KM,  Syddall  HE,  Garnero  P,  et al.  Urinary  CTX-II  and glucosyl-galactosyl-pyridinoline  are  associated  with  the  presence and  severity  of  radiographic  knee  osteoarthritis  in  men.  Ann Rheum  Dis  2006;  65;  871-7.

  38. Gineyts  E,  Garnero  P,  Delmas  PD.  Urinary  excretion  of  glucosyl-galactosyl pyridinoline:  a specific  biochemical  marker  of  synovium degradation.  Rheumatology (Oxford)  2001;  40:  315-23.

  39. Wieland  HA,  Michaelis  M,  Kirschbaum  BJ  et al.  Osteoarthritis — an untreatable  disease?  Nat Rev  Drug  Discov  2005;  4:  331- 44.

  40. Johnsean  JA,  Balsund  BO,  Garbarsch  C,  et.al.  YKL-40  in  giant cells  and  macrophages  from patient  with  giant  cell  arteries. Arthritis  Rheum  1999;  42:  2624-30.

  41. Vignon  Erick.  Is  glycoprotein  YKL-40  a  new  marker  for  joint disorders?  [letter]  JBS  2001;  68:   454-6.

  42. Bigg  HF,  Wait  R,  Rowan  AD,  et al.  The  Mammalian  Chitinase-like Lectin,  YKL-40,  Binds Specifically  to  Type  I  Collagen  and Modulates  the  Rate  of  Type  I  Collagen  Fibril  Formation .  J Biol Chem  2005;  281:  21082–95.

  43. Moreland  LW.  Intra-articular  hyluronan  (hyaluronic acid)  and hylans for  the  treatment  of osteoarthritis:  mechanisms  of   action.  Arthritis  Res  Ther  2003;  5:  54-67.

  44. Altman  RD.  Intra- articular  sodium  hyaluronate  in  osteoarthritis  of the  knee.  Semin  Arthritis Rheum  2000 ;  30:  11-8.

  45. Murphy  G,  Knauper  V,  Atkinson  S,  et al.  Matrix  metalloproteinases  in  arthritic  disease.  Arthritis Res  2002;  4 (suppl 3):  39-49.

  46. Struglics  A,  Larsson  S,  Pratta  MA,  et al.  Human  osteoarthritis synovial  fluid  and  joint  cartilage contain  both  aggrecanase  and matrix  metalloproteinase-  generated  aggrecan  fragments. OsteoArthritis Cartilage  2006;  14:  101-13.

  47. Rengel  Y,  Ospelt  C,  Gay  S.  Proteinases  in  joint:  Clinical relevance  of  proteinases  in  joint destruction.  Arthritis  Res  Ther 2007;  9:  221.

  48. Lark  MW,  Bayne  EK,  Flanagan  J,  et.al.  Aggrecan  Degradation  in Human  Cartilage  Evidence  for   both  Matrix  Metalloproteinase  and Aggrecanase  Activity  in  Normal,  Osteoarthritic,  and  Rheumatoid Joints.  J.  Clin.  Invest. 1997;  100:  93–06.        

  49. Bobacz  K,  Maier  R,  Fialka  C,  et.al.  Is  pro-matrix metalloproteinase-3  a  marker  for  posttraumatic  cartilage degradation?  Osteoarthritis  Cartilage  2003;  11:  665–72.

  50. Ishiguro  N,  Ito  T,  Ito  H,  et.al.  Relationship  of  Matrix metalloproteinases  and  their  inhibitors  to cartilage  proteoglycan and  collagen  turnover:  Analyses  of  Synovial  Fluid  from  Patients with Osteoarthritis.  Arthritis  Rheuma  1999;  42:  129-36.

  51. Naito  K,  Takahashi  M,  Kushida  K,  et.al.  Measurement  of  matrix  metalloproteinases  and  tissue inhibitor  of  matrix  metalloproteinases -1  in  patients  with  knee  osteoarthritis: comparison  with generalized  osteoarthritis.  Rheumatology  1999; 38: 510-5.

  52. Bauer  DC,  Hunter  DJ,  Abramson  SB,  et.al  Classification  of osteoarthritis  biomarkers:  a  proposed  approach.  Osteoarthritis Cartilage  2006;  14:  723 -7.

This is a peer reviewed paper 

Please cite as: Pravin V Ingle: Biomarkers in Osteoarthritis.

J.Orthopaedics 2009;6(4)e10

URL: http://www.jortho.org/2009/6/4/e10

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Copyright of articles belongs to the respective authors unless otherwise specified.Verbatim copying, redistribution and storage of this article permitted provided no restrictions are imposed on the access and a hyperlink to the original article in Journal of Orthopaedics maintained. All opinion stated are exclusively that of the author(s).
Journal of Orthopaedics upholds the policy of Open Access to Scientific literature.