ARTHRITIS & RHEUMATISMVol. 50, No. 8, August 2004, pp 2479–2488DOI 10.1002/art.20365© 2004, American College of Rheumatology

Suggestion of Nonlinear or Phasic Progression ofKnee Osteoarthritis Based on Measurements of

Serum Cartilage Oligomeric Matrix Protein LevelsOver Five Years

Mohammed Sharif, John R. Kirwan, Christopher J. Elson, Raquel Granell, and Shane Clarke

Objective. In many patients with knee osteoarthri-tis (OA), the disease progresses, and there is loss ofcartilage; in others, the disease stabilizes with time.Previous studies have demonstrated that concentrationsof serum proteins that reflect joint tissue metabolismcan identify knees that will deteriorate, leading to thesuggestion that OA disease activity is phasic or cyclical.The aim of the current study was to determine whetherlongitudinal measurements of one such protein, serumcartilage oligomeric matrix protein (COMP), are re-lated to disease outcome over a 5-year period.

Methods. Serum COMP levels were measured byenzyme-linked immunosorbent assay at study entry andevery 6 months thereafter in 115 patients with knee painand OA of mainly the tibiofemoral joint. Cartilage losswas determined from knee radiographs taken at entryand at 24, 36, and 60 months. Disease progression wasdefined as either a reduction in the tibiofemoral jointspace width by at least 2 mm or total knee replacement(TKR) in either knee at followup. COMP concentrationsat baseline and the area under the curve (AUC) ofmeasurements obtained over 5 years were comparedbetween progressors and nonprogressors by Student’s2-tailed t-test. The patterns and probability of progres-sion according to TKR or >2 mm of narrowing of the

tibiofemoral joint space were analyzed by logistic re-gression models.

Results. The mean � SD ages of the progressorsand nonprogressors were 64.2 � 7.8 years and 63.3 �10.6 years, respectively, and the proportion of femaleswas 51% and 56%, respectively. Of the 37 patients whoseOA progressed (22 by TKR and 15 by >2-mm reductionin tibiofemoral joint space), 13 lost cartilage during thefirst 2 years, and 18 lost cartilage during the last 2years. The mean � SD serum COMP concentration atbaseline was significantly higher in the progressorscompared with the nonprogressors (14.12 � 3.39 units/liter versus 12.62 � 3.25 units/liter; P < 0.036). SerumCOMP levels rose significantly after TKR; however,after allowing for the effect of TKR, the AUC/month wassignificantly higher in the progressors compared withthe nonprogressors (12.52 � 2.71 versus 10.82 � 2.71;P < 0.003). Serum COMP concentrations were higherduring periods of radiographic progression and identi-fied periods of progression that were nonlinear. Logisticregression analysis showed that on average, a 1-unitincrease in serum COMP levels increased the probabil-ity of radiographic progression by 15%.

Conclusion. The data suggest that serum COMPis related to progressive joint damage in knee OA. Thepatterns of progression for the early and late progres-sors are consistent with the hypothesis that knee OAprogression is episodic or phasic. Large between-subjectvariation precludes the use of individual values topredict progression with confidence. However, sequen-tial measurements of serum COMP levels may identifypatients whose OA is likely to progress over the nextyear or two.

Osteoarthritis (OA) is a heterogeneous, complexjoint disorder of uncertain etiology. It is the most

Supported by the Arthritis Research Campaign, UK,Hoffmann-La Roche Ltd., Basel, Switzerland, and Arakis Ltd., SaffronWalden, UK. Dr. Sharif is recipient of a Career Scientist award fromthe National Health Service Executive South West R&D Directorate,Bristol, UK.

Mohammed Sharif, PhD, John R. Kirwan, MD, ChristopherJ. Elson, PhD, Raquel Granell, MSc, Shane Clarke, MD: University ofBristol, Bristol, UK.

Address correspondence and reprint requests to MohammedSharif, PhD, Department of Anatomy, University of Bristol, SouthwellStreet, Bristol BS2 8EJ, UK. E-mail: mo.sharif@bristol.ac.uk.

Submitted for publication December 4, 2003; accepted inrevised form April 1, 2004.

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common joint disease, affecting �10% of the populationover the age of 50 years, and epidemiologic studiessuggest that the knee is the most important and mostcommon site of OA, causing pain and disability (1,2).Over the last two decades, there has been considerableresearch interest in joint tissue metabolism both inhealth and in OA. Animal studies have shown that thereare subtle biochemical changes in articular cartilage andother joint tissues well before any clinical or radiologicevidence of joint destruction (3,4). Our own studies inOA patients have shown that synovial fluid concentra-tions of structural proteins of bone, such as osteocalcin,are associated with bone remodeling in OA (5) and thatincreased serum hyaluronan (a possible marker of syno-vial inflammation) predicts loss of cartilage in patientswith OA of the knee joint (6). Moreover, a rise in serumconcentrations of cartilage oligomeric matrix protein(COMP) during the first year of followup was also foundto be associated with disease progression in knee OA (7).

COMP is an important cartilage matrix macro-molecule and is the largest matrix protein in articularcartilage after collagen and proteoglycan. COMP is apentameric molecule with a molecular weight of �500kd and belongs to the thrombospondin family (8).Initially, it was thought to be cartilage-specific, butrecent studies have shown the presence of COMP invarious other joint tissues, including menisci, ligaments(9), tendons (10), and the synovium (11). However, theconcentrations of COMP in these tissues are very lowcompared with those in cartilage (9). The physiologicrole of COMP is still unknown, although COMP hasbeen shown to interact with chondrocytes (12) and isthought to be involved in endochondral ossification (13).More recently, divalent cation–dependent interactionsbetween COMP and types I, II, and IX collagen weredemonstrated, suggesting that such interactions increasethe stability of the collagen network (14,15). Mutation ofthe COMP gene leads to various types of dysplasia andpremature development of OA (15,16). Thus, COMP isan important cartilage matrix macromolecule, and itsmetabolism could have profound effects on the structureand integrity of cartilage.

COMP had been investigated widely as a biomar-ker for OA and other joint diseases. However, of themany reports of serum COMP concentrations in OA(7,9,17–22), only a few have documented the changes inserum COMP levels over time (7,23,24). Cross-sectionalstudies determined the association of COMP with thepresence and severity of disease, while longitudinalstudies examined changes in serum COMP levels over 1year and 3 years, respectively, in relatively small cohorts

of OA patients. In 1997, we recruited 135 patients withpredominantly medial tibiofemoral OA to monitor thenatural progression of the disease sequentially (every 6months) over 5 years using clinical criteria, imaging(radiography, scintigraphy, and dual x-ray absorptio-metry), and serum biomarkers. The hypothesis beingtested is that progression of OA is not linear and thatthere is a relationship between progression over timeand changes in serum COMP levels over time. Wereport here longitudinal measurements of serum COMPin relation to disease outcome both during the course ofthe study and at 5 years of followup.

PATIENTS AND METHODS

Patients. One hundred thirty-five patients with persis-tent (�3 months) pain in one or both knees and radiographicevidence of tibiofemoral joint OA in at least 1 compartment ofat least 1 knee, as determined by the screening clinician, wererecruited from respondents to a survey of knee pain (Somersetand Avon Survey of Health), patients of general medicalpractices, and patients attending hospital rheumatology outpa-tient clinics. Individuals with severe OA (Kellgren/Lawrencegrade 4) (25), other forms of joint disease (e.g., rheumatoidarthritis), and conditions that prevented attendance wereexcluded from the study. Age, sex, body mass index, pain (on a0–100-mm visual analog scale), and the Western Ontario andMcMaster Universities Osteoarthritis Index (WOMAC; forpain, stiffness, and function) (26) were recorded at baseline todescribe the patient cohort. Approval for the study was givenby the institutional review board (Research Ethics Committee)of the United Bristol Healthcare National Health ServiceTrust.

Blood samples. Blood samples were obtained at base-line and at 6, 12, 18, 24, 30, 36, 42, 48, and 60 months. At eachvisit, 2 blood samples of 10 ml each were collected into glasstubes, allowed to clot, and then centrifuged at 2,800 revolu-tions per minute for 10 minutes. Serum was removed, sepa-rated into 6 1-ml aliquots, and kept frozen at –70°C untilrequired for the biomarker assay.

Measurement of serum COMP levels. Serum levels ofCOMP were measured using the COMP enzyme-linked immu-nosorbent assay (ELISA) kit (AnaMar Medical, Uppsala,Sweden). Briefly, standards (ranging from 0.4 units/liter to 3.2units/liter), test samples, and controls were diluted 1:10 andapplied to the ELISA plate that had been coated with a mousemonoclonal antibody to human COMP (AnaMar). In the samestep, a peroxidase-conjugated mouse anti-human COMP wasadded to the plate and incubated for 2 hours in a orbital shakerat room temperature. The plate was washed 6 times, and theenzyme substrate was added and incubated for 15 minutes asbefore. The reaction was stopped with the addition of 1Msulfuric acid, and the optical density of the assay plate was readat 450 nm in a SpectraMax plate reader using the SoftMaxProprogram.

Samples were assayed blind, without knowledge ofwhich patients were the progressors and which were thenonprogressors. All samples were analyzed in duplicate, and

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the values of the test samples were calculated from thestandard curve included on each plate. Any value with anintraassay variation of the duplicate that exceeded a 7%coefficient of variation (CV) was retested. One low control andone high control were added to each plate. The mean value ofthe low control was found to be 7.6 units/liter, with an SD of0.296, giving a confidence interval (CI) of 7.0–8.2 units/literand an interassay CV of 3.9%. The mean value of the highcontrol was found to be 16.5 units/liter, with an SD of 0.686,giving a CI of 15.5–17.7 units/liter and an interassay CV of4.2%.

Radiographs. Knee radiographs were obtained at base-line and at 24, 36, and 60 months. Plain radiographs were takenwith the patient standing for the anteroposterior view and withthe patient lying down for the lateral views, with the knee in 30degrees of flexion (27). All radiographs obtained at study entryand over the 5 years of followup were interpreted duringseveral sessions, in random order, with the identity labelsconcealed. Two experienced readers (JRK and SC) indepen-dently measured the joint space width as the narrowest inter-bone distance in the medial and lateral compartments andmade a visual assessment of patellofemoral joint space narrow-ing. Where measurements differed by more than 2 mm, thereaders reviewed the radiographs together and agreed on afinal measurement.

Progressors and nonprogressors were identified bypreviously used criteria (6,28), consisting of either a �2-mm

reduction in the width of the tibiofemoral joint space in eitherknee or total knee replacement (TKR) surgery for either kneeoccurring during the 5-year followup. A similar criterion wasused to measure progression between baseline and 2 years andbetween baseline and 3 years. A random sample of 20 radio-graphs was read twice to determine the reproducibility of thejoint space width measurements. The CV was 11.3% for themedial compartment. The variation measurements were ob-tained after radiographs had been refereed where necessary.To enable a reliable definition of radiographic progression tobe made, the critical difference was calculated. The criticaldifference was 1.5 mm, so that a variation of this distance ormore in the medial joint space has a 95% probability ofrepresenting real, rather than artifactual, change in the com-partment. Kellgren/Lawrence grades (25) are reported for theworst knee only as a score of 0–4. Where both observersdisagreed by 1 grade, the lower grade was used. Largerdisagreements were resolved by consensus.

Statistical analysis. Student’s unpaired 2-tailed t-testwas used to compare baseline clinical features and COMPlevels between progressors and nonprogressors and those whowere lost to followup. Serum COMP levels were analyzed atbaseline in men and women separately and over the 5 years offollowup using the area under the curve (AUC), and weregrouped together as progressors and nonprogressors. Thepattern of changes in COMP levels was also compared be-tween those who progressed at different times of followup. An

Table 1. Baseline demographic, clinical, and radiographic features of the study patients*

All patients(n � 135)

Patients whocompleted the study

(n � 115)

Patients whowere lost to followup

(n � 20)

Demographic variablesAge, mean � SD years 63.8 � 9.6 63.6 � 9.7 65.15 � 9.2No. of males/females 62/73 52/63 10/10Body mass index, mean � SD kg/m2 29.6 � 5.5 29.6 � 5.2 29.4 � 7.2No. of patients with Heberden’s nodes 48 42 6No. of patients taking NSAIDs 35 32 3

Clinical variables for most painful knee, mean � SDPain score by VAS 51.5 � 28.8 50.9 � 28.1 56.1 � 34.5WOMAC score

Pain 7.5 � 4.0 7.2 � 3.9 9.5 � 4.7Stiffness 3.6 � 1.8 3.5 � 1.7 4.3 � 2.0Function 24.8 � 12.8 23.8 � 12.0 32.9 � 16.8

Radiographic variablesMinimum medial compartment TF joint space

width in most painful knee, mean � SD mm3.2 � 1.9 3.2 � 1.9 3.3 � 2.0

Overall K/L grade in worst knee, % of patientsGrade 0 30 25 5Grade 1 13 12 1Grade 2 11 7 4Grade 3 75 67 8Grade 4 4 3 1

No. with K/L grade �2 in contralateral knee 56 50 6Reason for loss to followup, no. of patients

Died – – 6Moved away or declined followup – – 14

* At study entry, radiographic data were available for 129 of the total group of patients, all of the 115 patients who completedthe study, and 14 of the 20 patients who were lost to followup. NSAIDs � nonsteroidal antiinflammatory drugs; VAS � visualanalog scale; WOMAC � Western Ontario and McMaster Universities Osteoarthritis Index; TF � tibiofemoral; K/L �Kellgren/Lawrence.

SERUM COMP LEVELS AND PROGRESSION OF KNEE OA OVER 5 YEARS 2481

ordered logistic regression model was applied to determine theassociation between OA progression and COMP measure-ments, allowing for age and sex. In order to compare patientsbefore and after surgery, data from the 16 patients whoseCOMP levels were measured before and after surgery wereanalyzed further. COMP concentrations were standardized byexpressing the results for each patient as the number ofstandard deviations from the mean value for that patient. Theaverage of these values was then taken for each time pointbefore and after surgery.

RESULTS

From the initial 135 patients, radiographs ob-tained at study entry and at the 5-year followup wereavailable for 115. The demographic, clinical, and radio-graphic details of all the patients, including those lost tofollowup, are summarized in Table 1. There were nosignificant differences in these variables at baseline inpatients who were lost to followup and those whocompleted the 5-year study. There was no associationbetween serum COMP levels and the sex of the patients.The mean � SD concentrations of COMP in men andwomen were 13.58 � 2.94 units/liter and 12.67 � 3.65units/liter, respectively (P � 0.17). However, at baseline,the serum COMP levels were significantly higher inpatients over the age of 60 years compared with thoseunder the age of 60 years (13.58 � 2.43 versus 12.08 �2.43 units/liter; P � 0.034).

Of the 115 patients who completed the study, 37experienced OA progression: 22 by the TKR criterion

and 15 by the �2 mm of tibiofemoral joint spacenarrowing criterion. In addition to study radiographs,preoperative radiographs obtained before TKR surgerywere available for 19 patients, and all had �2 mm of

Figure 1. Changes in serum levels of cartilage oligomeric matrixprotein (COMP) over the entire study period in 25 randomly selectedosteoarthritis patients. COMP levels showed wide variations over timein some patients, which was due to total knee replacement (TKR). Forexample, patients A and B underwent TKR surgery between months12–18 and months 36–42, respectively.

Figure 2. Standardized serum cartilage oligomeric matrix protein(COMP) levels in relation to total knee replacement (TKR) surgery inthe 16 patients whose COMP levels were measured before and aftersurgery. Values are the mean and 95% confidence interval. N �number of patients.

Figure 3. Averages of all cartilage oligomeric matrix protein (COMP)levels measured (area under the curve [AUC] per month) during theentire study period in patients whose osteoarthritis (OA) had pro-gressed and in those whose OA had not progressed at the 5-yearfollowup assessment. To allow for the effect of surgery on serumCOMP concentrations, the AUC was calculated for each patient forthe duration of the study and for patients who underwent total kneereplacement surgery up to the point of the surgery. The AUC was thenexpressed as an average for the number of months of followup.Horizontal bars show the mean.

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tibiofemoral joint space narrowing. The mean � SDages of the progressors and nonprogressors were 64.2 �7.8 years and 63.3 � 10.6 years, respectively (P � 0.642),and the percentages of women were 19 � 51% and 44 �56%, respectively (P � 0.690). Patellofemoral jointspace narrowing was present at baseline in 34% ofpatients and was slightly less common in those whoexperienced OA progression in the tibiofemoral joint(26%). The mean baseline serum COMP concentrationwas significantly higher in the progressors comparedwith the nonprogressors (14.12 � 3.39 units/liter versus12.62 � 3.25 units/liter; P � 0.036).

Serum COMP levels varied widely both between

patients and within patients over the study period. Toillustrate these variations, changes in serum COMPlevels during the 5-year study period for a random subsetof 25 of the 115 patients who completed the study areshown in Figure 1. At first inspection, it appears that anumber of patients have abnormally high variations inCOMP levels (e.g., patients A and B). Analysis of thevariation in COMP measurements in individual patientsrevealed these to be patients who had undergone TKR.

Serum COMP concentrations in 16 of the pa-tients who underwent TKR and had appropriately timedblood samples were therefore oriented around the timeof surgery, and the standardized values during themonths before and after surgery are shown in Figure 2.There was a substantial rise in serum COMP levels aftersurgery, persisting for up to 12 months following sur-gery. When data were analyzed omitting serum COMPmeasurements following TKR, the variations betweenpatients approximated a normal distribution, and therewere no patients with abnormally high variations inCOMP levels. Accordingly, in order to avoid bias inCOMP measurements that may be due to TKR, postop-erative COMP levels were excluded from all subsequentanalyses.

The AUC for the COMP values during the entirestudy period (excluding the visits after surgery) in theprogressors and nonprogressors are shown in Figure 3.Although there was substantial overlap between the 2groups, the mean values differed significantly (P �0.003), and further analysis showed that COMP levels inthe progressors was higher at all visits compared withthose in the nonprogressors (see Figure 4).

The concentrations of serum COMP at studyentry and the 5-year followup and that AUC values forCOMP in relation to different types of progression areshown in Table 2. At baseline, the mean � SD COMPlevels in the TKR group were lower than those in the

Figure 4. Sequential changes in mean cartilage oligomeric matrixprotein (COMP) levels in patients whose osteoarthritis (OA) hadprogressed (n � 37) and in those whose OA had not progressed (n �78) at the 5-year followup assessment. Differences between thenonprogressors and progressors were statistically significant for 4 ofthe 10 visits (� � P � 0.05). Values are the mean � SEM.

Table 2. Serum COMP concentrations at baseline, the 5-year followup, and the AUC per month in relation to the radiographic progression statusof the patients at 5 years*

COMP levels innonprogressors

(n � 78)

Progressors(n � 37)

�2-mm reduction in TFjoint width (n � 15)

Total knee replacement(n � 22)

COMP level P COMP level P COMP level P

Baseline 12.62 � 3.25 14.12 � 3.39 �0.038 14.62 � 4.27 0.045 13.68 � 2.43 0.215-year followup 12.39 � 3.58 14.21 � 2.08 0.07 14.21 � 2.17 0.085 13.84 � 3.94 0.20Mean of all 10 visits

(AUC per month)10.82 � 2.71 12.52 � 2.71 �0.003 12.71 � 2.47 0.014 12.37 � 2.94 0.030

* There were no statistically significant differences (P � 0.05) in cartilage oligomeric matrix protein (COMP) levels (units/liter) between the groupwith a �2-mm reduction in the tibiofemoral (TF) joint space width and the group with total knee replacement for either the baseline assessment,the 5-year followup, or the area under the curve (AUC) per month. Values are the mean � SD. All P values are versus nonprogressors, asdetermined by 2-tailed t-test.

SERUM COMP LEVELS AND PROGRESSION OF KNEE OA OVER 5 YEARS 2483

group with �2 mm of tibiofemoral joint space narrowing(13.68 � 2.43 versus 14.62 � 4.27 units/liter), but thedifferences between the TKR group and the nonpro-gressors were not significant at study entry or at the5-year followup.

To further examine the patterns of serum COMPchanges in relation to OA progression, we assigned thepatients who progressed during the study period to 1 of3 groups. Group A patients were those whose OAprogressed during the first 2 years (n � 13; 10 by theTKR criterion and 3 by the �2 mm of tibiofemoral jointspace narrowing criterion). Group B patients were thosewhose OA progressed between years 2 and 3 (n � 6; 3 byTKR and 3 by �2 mm of tibiofemoral joint space

narrowing). Group C patients were those whose OAprogressed between years 3 and 5 (n � 18; 9 by TKR and9 by �2 mm of tibiofemoral joint space narrowing).Since the period of progression was very short in groupB (1 year) and there were only 6 patients in the group,the data are shown only for the 2 larger groups.

As shown in Figure 5, the mean serum COMPlevels in patients whose OA progressed over the first 2years of study (group A) increased from month 6 tomonth 18 before declining. In contrast, the mean serumCOMP levels in patients whose OA progressed fromyears 3–5 (group C) declined from month 0 to month 12before increasing during the radiographically identifiedprogression period (36–60 months). Group A patientsalso showed a rise in serum COMP levels toward the endof the study. This can be attributed to 4 of the 8 patientswho initially progressed by the �2 mm of tibiofemoraljoint space narrowing criterion, who then progressedagain by the same criterion toward the end of the study.

Figure 6 shows the probability of progression bythe 2 criteria for different levels of serum COMP andtheir frequency of occurrence in this cohort of OApatients. For these data, the mean of the baseline and6-month COMP concentrations was used in order tomake allowance for the variation in COMP levels. Theprobability of progression increased when the level ofCOMP increased. The binary logistic model showed thatthe probability of progression increased by 15% whenthe serum COMP concentration increased by 1 unit/liter. Thus, a patient with a COMP level (mean of 2readings) of 20 units/liter has an �30% chance ofprogression by the TKR criterion and a further 20%chance of progression by the �2 mm of tibiofemoraljoint space narrowing criterion over the following 4.5years.

DISCUSSION

This cohort of patients with predominantly me-dial tibiofemoral OA was established to determine thesequential change in serum COMP levels (and otherbiomarkers) and its relationship to radiographic changesover 5 years. During the 5-year study period, only 20patients (15%) were lost to followup. There were nosignificant differences at study entry in the demographic,clinical, or radiographic findings in these patients com-pared with the 2 groups of patients (progressors andnonprogressors) who completed the 5-year study. Ac-cordingly, this is a suitable cohort of patients with whichto investigate the relationship between serum COMP

Figure 5. Mean serum cartilage oligomeric matrix protein (COMP)levels in patients whose osteoarthritis (OA) had progressed betweenyears 0 and 2 (group A; n � 13) and between years 3 and 5 (group C;n � 18) of the 5-year study period. In both groups, there was a rise inserum COMP levels during the period of OA progression. Four of thepatients in group A whose OA had initially progressed according to thecriterion of �2 mm of narrowing of the tibiofemoral joint space alsoexperienced OA progression according to the same criterion duringthe last 24 months of followup.

2484 SHARIF ET AL

levels measured sequentially every 6 months and radio-graphic progression over 5 years.

We found that serum COMP levels increased inthe period following TKR. This was unexpected but wasconsistent across all patients who had undergone TKR.It is not clear why this should be so, but there may be anincreased production or degradation of COMP in thecontralateral knee joint or an increased release ofCOMP from other tissues, such as ligaments, tendons,and capsule, of the TKR joint. Further investigation ofthis finding and exploration of other biomarkers follow-ing surgery will be an important priority. In order toavoid bias in the interpretation of other results, patientswere excluded from further analyses after they under-went TKR; thus, the remaining conclusions are validwhatever the reason for this response to surgery.

Patients whose OA progressed over 5 years hadhigher serum COMP levels at baseline and throughoutthe study period compared with those whose OA did notprogress. Moreover, the probability of progression in-creased as the serum COMP value increased, suggestingthat COMP levels could be used to identify patients whoare at risk of OA progression. There was a large overlapin COMP concentrations between progressors and non-progressors (Figure 3). However, the data presented inthis study suggest that increasing serum COMP concen-

trations means greater risk of progression of tibiofemo-ral knee OA (see Figure 6).

Three earlier and smaller studies (46, 38, and 48patients, respectively) have shown that serum COMPlevels are associated with disease progression in kneeOA (7,19,24). The first two studies (7,19) reported thata rise in serum COMP levels over 1 and 3 years wasassociated with progressive joint damage, but baselinelevels were not associated with progression over thattime period. The third study (24) found that patientswho progressed by 2 Kellgren/Lawrence grades (sum ofboth knees) over 3 years had significantly higher serumCOMP levels at baseline and at study end. The datareported in the current study are based on a largercohort of patients (n � 115) with a well-defined intra-articular distribution of their knee OA and for whomsequential radiographs and measurements of COMPlevels were available for the entire study period. Thus, itwas possible to relate any temporal variation in COMPlevels to the time of OA progression. If progression ofknee OA is linear, it would be expected that temporalvariations in COMP levels would not be related toprogression. If knee OA progression is cyclic, thenCOMP levels should decrease after periods of progres-sion and increase prior to progression. The results are

Figure 6. Probability of osteoarthritis progression according to total knee replacement (TKR) surgery(E) (n � 22) and according to a �2-mm reduction of the tibiofemoral joint space width or TKR surgery(F) (n � 37). To compare the different types of progression, an ordered logistic regression model wasperformed. The model consisted of 2 equations, since the probabilities modeled are cumulative over thelower-ordered category. The probability of progression was calculated as 1/[1 � e(ak – bx)], where ak is theintercept on the y-axis, b is the coefficient of the exposure variables, and x is the mean of the exposurevariable (cartilage oligomeric matrix protein [COMP]) at visits 1 and 2. The chart on the right shows thefrequency of occurrence of the mean baseline and 6-month COMP concentrations in the study population.

SERUM COMP LEVELS AND PROGRESSION OF KNEE OA OVER 5 YEARS 2485

consistent with the hypothesis that progression of kneeOA is phasic.

At study entry, the group that progressed be-tween year 3 and year 5 had high COMP levels thatdeclined before increasing again prior to the period ofprogression, whereas COMP levels in the group thatprogressed early in the study (between year 0 and year 2)increased initially, declined toward and after the end ofthe period of progression, and rose again at the end ofthe study. It may be that one group of patients had beenprogressing just prior to study entry and the other wasabout to progress following completion of the study.However, in the absence of any progression data prior toentry or beyond 60 months, we cannot say conclusivelythat the data presented show cyclical progression inindividual patients. Nevertheless, sequential measure-ments of COMP levels in blood may identify patientswho are likely to experience OA progression within thenext year or two. Such patients may then be treatedmore effectively by targeting the treatment to the time ofrising serum COMP levels, and they may also provide aparticularly suitable group in which to test new treat-ments.

COMP is an important structural molecule of thearticular cartilage, and degradation of this protein istherefore likely to lead to reduced/absent interactionwith chondrocytes, collagens, and other matrix proteins,resulting ultimately in loss of cartilage. It has beenshown that synovial fluid from patients with inflamma-tory arthritis degrade COMP into smaller fragments,and these low molecular weight fragments (50–70 kd) ofCOMP have been reported to be 3 times higher in OAcompared with healthy controls (9). The assay used inthe present investigation detects low molecular weightCOMP fragments, although it is not known whetherthese fragments are from mature degraded COMPmolecules or newly formed COMP fragments. Neverthe-less, since serum COMP levels were persistently highthroughout the 5-year study period in patients withprogressive joint damage, serum concentrations ofCOMP may be reflecting active degradation and loss ofarticular cartilage.

Findings of a recent study suggest that there maybe specific proteases that regulate the degradation ofCOMP in cartilage (29). Thus, chondrocyte death maylead to the release of these and other enzymes thatpromote degradation of COMP and loss of cartilage.Osteoarthritic cartilage is hypocellular (30), and this islikely to reduce the ability of the cartilage to maintainthe matrix integrity. Hypocellularity in OA may beexplained by chondrocyte death by apoptosis, which is,

on average, 3 times higher in OA cartilage comparedwith age- and sex-matched controls (31). Therefore, ahigh rate of apoptosis in OA cartilage may contribute tothe degradation of COMP, as well as to loss of interac-tion between chondrocytes, COMP, and other matrixmacromolecules. Interestingly, various dysplasias havebeen associated with mutations of the COMP gene(15,16), and a recent study has shown that in the growthplate of patients with pseudoachondroplasia (a condi-tion characterized by short stature, shortening of thelong bones, and early-onset OA), there is an increasedrate of chondrocyte death by apoptosis compared withthat in control patients who had undergone surgery forconditions not associated with pseudochondroplasia(72% versus 45%), and it is associated with decreasedcartilage growth (32).

COMP has been investigated widely, and it islikely that serum COMP derives from the index joint,since there is a good positive correlation between serumCOMP levels and joint destruction in animal models ofarthritis (33,34) as well as between serum and synovialfluid levels in humans with OA (9,35). Moreover, theobservation that abnormal findings on scintigraphy scansof OA knee joints are positively correlated with serumCOMP levels (7,19) also suggests that serum COMP isderived from the arthritic joint. Some serum COMP islikely to be derived from nonarticular sources and/orasymptomatic joints. However, the concentrations ofCOMP in nonarticular tissues are very low comparedwith those in the cartilage and meniscus (9); therefore,articular chondrocytes are probably the main source ofCOMP in the joints.

In a recent study, Jordan et al (36) reported thatserum COMP is associated with both age and ethnicity.In the current study, all patients were Caucasian, andserum COMP levels were not associated with sex, butsome associations were found with age. These data areconsistent with those of several previous reports (9,21).The study by Clark et al (21) found that serum COMPlevels are significantly higher in patients who were overthe age of 65 years compared with patients who wereages 45–55 years. In our study, 56 patients were over theage of 60 years, and they had significantly higher serumCOMP levels compared with those in patients youngerthan 60 years.

In a large population-based study using radio-graphically defined controls, Clark et al (21) demon-strated that serum COMP levels are, on average, higherin patients with early OA than in unaffected individualsand that they were associated with OA severity as well aswith the number of joints involved. However, those

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authors concluded that due to overlap between the OApatients and the unaffected individuals, COMP cannotbe used as a diagnostic marker. The data presented hereshow that serum COMP is associated with the progres-sion status of the OA patients and that sequentialmeasurements can identify periods when patients’COMP levels change markedly. Thus, this biomarkermay help to target treatment during times when patientsare most likely to have cartilage destruction. The abilityto identify patients whose OA is likely to progress overthe coming years would help define the molecular basisand pathogenesis of OA and lead to the development ofscreening methods for early diagnosis and, therefore,more effective treatment.

In conclusion, the data presented here show thatserum concentrations of COMP in patients with kneeOA vary widely both between and within patients overtime. The concentrations of serum COMP increasedmarkedly during the year following TKR and werehigher in those over the age of 60 years, but wereunrelated to sex. The patients with progressive jointdamage had significantly higher serum COMP levels atstudy entry, and the high levels persisted over the 5-yearperiod of study. Moreover, the serum COMP concen-tration was increased during the period of clear radio-graphic progression and loss of cartilage. Although largebetween-subject variation precludes the use of individualvalues to predict progression with confidence, the meanof the two COMP values obtained 6 months apartprovided an indication of likely progression over thenext few years, and this might help to target treatment inthe individual patient and to select cohorts of patientswho are particularly suitable for trials of new disease-modifying drugs.

ACKNOWLEDGMENTS

We thank Prof. S. Frankel for access to the Avon andSomerset Survey of Health. We also thank the staff of AnaMarMedical (Uppsala, Sweden) for measuring the serum COMPlevels for this study.

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