Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis.
OBJECTIVE
The hallmark of osteoarthritis (OA) is the loss of articular cartilage. This loss arises from an imbalance between cartilage synthesis and cartilage degradation over a variable period of time. The aims of this study were to investigate the rates of these processes in patients with knee OA using two new molecular markers and to investigate whether the combined use of these markers could predict the progression of joint damage evaluated by both radiography and arthroscopy of the joints during a period of 1 year.


METHODS
Seventy-five patients with medial knee OA (51 women, 24 men; mean +/- SD age 63 +/- 8 years, mean +/- SD disease duration 4.8 +/- 5.2 years) were studied prospectively. At baseline, we measured serum levels of N-propeptide of type IIA procollagen (PIIANP) and urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX-II) as markers of type II collagen synthesis and degradation, respectively. Joint space width (JSW) on radiography and medial chondropathy at arthroscopy (assessed using a 100-mm visual analog scale [VAS]) were measured in all patients at baseline and in 52 patients at 1 year. Progression of joint destruction was defined as a decrease of > or =0.5 mm in JSW on radiography and as increased chondropathy (an increase in the VAS score of >8.0 units) between the baseline and 1-year evaluations.


RESULTS
At baseline, compared with 58 healthy age- and sex-matched controls, patients with knee OA had decreased serum levels of PIIANP (20 ng/ml versus 29 ng/ml; P < 0.001) and increased urinary excretion of CTX-II (618 ng/mmole creatinine [Cr] versus 367 ng/mmole Cr; P < 0.001). The highest discrimination between OA patients and controls was obtained by combining PIIANP and CTX-II in an uncoupling index (Z score CTX-II - Z score PIIANP), which yielded a mean Z score of 2.9 (P < 0.0001). Increased baseline values in the uncoupling index were associated with greater progression of joint damage evaluated either by changes in JSW (r = -0.46, P = 0.0016) or by VAS score (r = 0.36, P = 0.014). Patients with both low levels of PIIANP (less than or equal to the mean - 1 SD in controls) and high levels of CTX-II (greater than or equal to the mean + 1 SD in controls) had an 8-fold more rapid progression of joint damage than other patients (P = 0.012 and P < 0.0001 as assessed by radiography and arthroscopy, respectively) and had relative risks of progression of 2.9 (95% confidence interval [95% CI] 0.80-11.1) and 9.3 (95% CI 2.2-39) by radiography and arthroscopy, respectively.


CONCLUSIONS
Patients with knee OA are characterized by an uncoupling of type II collagen synthesis and degradation which can be detected by assays for serum PIIANP and urinary CTX-II. The combination of these two new markers could be useful for identifying knee OA patients at high risk for rapid progression of joint damage.
Garnero
Patrick
P
INSERM Unit 403, E. Herriot Hospital and Synarc, Pavillon F, 69437 Lyon Cedex 03, France. patrick.garnero@synarc.com
Ayral
Xavier
X
Rousseau
Jean-Charles
JC
Christgau
S
S
Sandell
Linda J
LJ
Dougados
Maxime
M
Delmas
Pierre D
PD
D000368:Aged; D015415:Biomarkers; D002135:Calcium-Binding Proteins / Q000097:blood; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000097:blood; D024043:Collagen Type II / Q000096:biosynthesis* / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000097:blood* / Q000473:pathology; D010446:Peptide Fragments / Q000097:blood; D011237:Predictive Value of Tests; D011347:Procollagen / Q000097:blood
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D024043:Collagen Type II; D010446:Peptide Fragments; D011347:Procollagen; C040072:chondrocalcin; C041876:procollagen Type III-N-terminal peptide; D003094:Collagen