A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis

Abstract

Background Osteoarthritis (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 methods The 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. Results In 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). Conclusion Serum/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 evidence Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.

Osteoarthritis endotype discovery via clustering of biochemical marker data

“…However, despite being a multifaceted and heterogeneous syndrome, there is an opportunity to target different treatments to patients according to their disease drivers characterised by molecular endotypes (a description of a subset of patients with common molecular characteristics) and clinical phenotypes (an observable characteristic or trait of a disease) 9 10. OA may be amenable to tailored treatments that target specific phenotypes, including inflammatory, low repair, subchondral bone, metabolic or articular cartilage-driven phenotypes 11–17…”

Development of a highly sensitive chemiluminescence immunoassay for quantification of aggrecanase-generated ARGS aggrecan fragments in serum

“…Similarly, low levels of blood ARGS provided an odds ratio (OD) of 3 for the identification of fast radiographic progressors (JSN≥0.5 ​mm) over 2 years in the present study. A possible explanation for this could be that the lower serum ARGS levels reflect a lower aggrecanase activity, but also a lower tissue-formation/repair capacity as measured by a type II collagen formation biomarker, PRO-C2, in our previously published paper [ 32 ]. We speculated that there is a subgroup of OA indicated by lower serum ARGS levels in combination with lower PRO-C2 levels that are likely to progress radiographically and deteriorate over time.…”

Blood and urine biomarkers in osteoarthritis – an update on cartilage associated type II collagen and aggrecan markers

“…Compared with healthy controls ( n = 22), PRO-C2 and PIIANP in serum samples were lower in knee OA patients with a KL grade of 2–4 ( n = 123) [ 15 ]. Assessed two independent knee OA cohorts of 106 and 147 participants, Luo et al reported that low serum levels of PRO-C2 were associated with 3.4-fold higher likelihood of radiographic progression than those with high levels of PRO-C2 [ 16 ▪ ]. This suggests that low cartilage repair capacity, assessed by markers such as PRO-C2 and PIIANP, is a risk factor for OA.…”