Patients with Joint Space Narrowing After ACL Reconstruction Have Significantly Increased Cleavage-to-Synthesis Ratios of Type-II Collagen Compared with Controls

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.

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

10.21203/rs.3.rs-21457/v1 ◽

2020 ◽

Author(s):

Yunyun Luo ◽

Jonathan Samuels ◽

Svetlana Krasnokutsky ◽

Inger Byrjalsen ◽

Virginia B. Kraus ◽

...

Keyword(s):

Cartilage Repair ◽

Radiographic Progression ◽

Type Ii Collagen ◽

Joint Space ◽

Phase Iii ◽

Type Ii ◽

Collagen Formation ◽

Cartilage Formation ◽

Symptomatic Knee Osteoarthritis ◽

Symptomatic Knee

Abstract Objective: 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 was 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. 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). The risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Progression was defined as two-year JSN > 0.35 mm. 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 to subjects with high PRO-C2. The 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 to placebo, on JSN over two 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 to the moderate/high group (chi-squared = 6.5, p = 0.011). Conclusions: 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.

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