Association of biomarkers with pre-radiographically defined and radiographically defined knee osteoarthritis in a population-based study.
OBJECTIVE
To evaluate 10 biomarkers in magnetic resonance imaging (MRI)-determined, pre-radiographically defined osteoarthritis (pre-ROA) and radiographically defined OA (ROA) in a population-based cohort of subjects with symptomatic knee pain.


METHODS
Two hundred one white subjects with knee pain, ages 40-79 years, were classified into OA subgroups according to MRI-based cartilage (MRC) scores (range 0-4) and Kellgren/Lawrence (K/L) grades of radiographic severity (range 0-4): no OA (MRC score 0, K/L grade<2), pre-ROA (MRC score>or=1, K/L grade<2), or ROA (MRC score>or=1, K/L grade>or=2). Urine and serum samples were assessed for levels of the following biomarkers: urinary biomarkers C-telopeptide of type II collagen (uCTX-II), type II and types I and II collagen cleavage neoepitopes (uC2C and uC1,2C, respectively), and N-telopeptide of type I collagen, and serum biomarkers sC1,2C, sC2C, C-propeptide of type II procollagen (sCPII), chondroitin sulfate 846 epitope, cartilage oligomeric matrix protein, and hyaluronic acid. Multicategory logistic regression was performed to evaluate the association of OA subgroup with individual biomarker levels and biomarker ratios, adjusted for age, sex, and body mass index.


RESULTS
The risk of ROA versus no OA increased with increasing levels of uCTX-II (odds ratio [OR] 3.12, 95% confidence interval [95% CI] 1.35-7.21), uC2C (OR 2.13, 95% CI 1.04-4.37), and uC1,2C (OR 2.07, 95% CI 1.06-4.04), and was reduced in association with high levels of sCPII (OR 0.53, 95% CI 0.30-0.94). The risk of pre-ROA versus no OA increased with increasing levels of uC2C (OR 2.06, 95% CI 1.05-4.01) and uC1,2C (OR 2.06, 95% CI 1.12-3.77). The ratios of type II collagen degradation markers to collagen synthesis markers were better than individual biomarkers at differentiating the OA subgroups, e.g., the ratio of [uCTX-II][uC1,2C] to sCPII was associated with a risk of ROA versus no OA of 3.47 (95% CI 1.34-9.03) and a risk of pre-ROA versus no OA of 2.56 (95% CI 1.03-6.40).


CONCLUSIONS
Different cartilage degradation markers are associated with pre-ROA than are associated with ROA, indicating that their use as diagnostic markers depends on the stage of OA. Biomarker ratios contrasting cartilage degradation with cartilage synthesis are better able to differentiate OA stages compared with levels of the individual markers.
Cibere
Jolanda
J
University of British Columbia, and Arthritis Research Centre of Canada, Vancouver General Hospital, Vancouver, British Columbia, Canada. jcibere@arthritisresearch.ca
Zhang
Hongbin
H
Garnero
Patrick
P
Poole
A Robin
AR
Lobanok
Tatiana
T
Saxne
Tore
T
Kraus
Virginia B
VB
Way
Amanda
A
Thorne
Anona
A
Wong
Hubert
H
Singer
Joel
J
Kopec
Jacek
J
Guermazi
Ali
A
Peterfy
Charles
C
Nicolaou
Savvakis
S
Munk
Peter L
PL
Esdaile
John M
JM
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D002135:Calcium-Binding Proteins / Q000097:blood; D064236:Cartilage Oligomeric Matrix Protein; D002358:Cartilage, Articular / Q000000981:diagnostic imaging; D002809:Chondroitin Sulfates / Q000097:blood; D024042:Collagen Type I / Q000652:urine; D024043:Collagen Type II / Q000097:blood; D016326:Extracellular Matrix Proteins / Q000097:blood; D005260:Female; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood; D008279:Magnetic Resonance Imaging; D008297:Male; D064235:Matrilin Proteins; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000175:diagnosis* / Q000000981:diagnostic imaging; D010455:Peptides / Q000652:urine; D011859:Radiography
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D064236:Cartilage Oligomeric Matrix Protein; D024042:Collagen Type I; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; D010455:Peptides; C577553:TSP5 protein, human; C040072:chondrocalcin; C052929:collagen type I trimeric cross-linked peptide; D006820:Hyaluronic Acid; D002809:Chondroitin Sulfates