Abstract
BackgroundOsteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation.Materials and methodsThe type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width.ResultsIn both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4–8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011).ConclusionSerum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug.Level of evidenceLevel III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.
Highlights
Osteoarthritis (OA), the most common arthritis, is characterized by progressive cartilage destruction, deterioration of subchondral bone, and synovial inflammation [1, 2]
In both the New York University (NYU) and SMC cohorts, subjects with low PRO-C2 levels had greater joint space narrowing (JSN) compared with subjects with high PRO-C2
There was no significant effect of salmon calcitonin (sCT) treat‐ ment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2
Summary
Osteoarthritis (OA), the most common arthritis, is characterized by progressive cartilage destruction, deterioration of subchondral bone, and synovial inflammation [1, 2]. Knee OA disease heterogeneity could be further explored with new biomarkers indicative of a particular endotype with distinct mechanistic pathways (e.g., low cartilage formation) and/or variable clinical presentations (e.g., radiographic fast progressors). Identification of such endotypes by validated biomarkers could assist in enabling a precision medicine approach for OA and eventually facilitate the development of targeted therapies for OA [7]. We used the blood-based marker PRO-C2, reflecting type II col‐ lagen formation, to assess levels of cartilage formation
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