低软骨形成和修复表型预测有症状膝关节骨关节炎的放射学进展。

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.

背景：骨关节炎（OA）是一种具有多种终末表型的疾病。OA 的一个标志是软骨丧失；然而，不同患者的软骨丧失率显然不同，这可能部分归因于软骨修复能力的差异。我们假设存在低软骨修复终末表型，并且此类终末表型更有可能进行放射学进展。本研究的目的是检查软骨形成水平与 OA 严重程度和放射学 OA 进展的相关性。我们使用基于血液的标志物 PRO-C2 来评估软骨形成水平，PRO-C2 反映 II 型胶原形成。

材料和方法：从纽约大学（NYU，n=106）和 III 期口服降钙素（sCT）试验 SMC021-2301（SMC，n=147）的亚队列中测量膝关节 OA 受试者的 II 型胶原前肽 PRO-C2 的血清/血浆水平。在 24 个月时，比较 PRO-C2 四分位数（极低、低、中、高）之间的内侧关节间隙狭窄（JSN）放射照相风险。对年龄、性别、BMI、种族、基线疼痛水平和基线关节间隙宽度进行调整。

结果：在 NYU 和 SMC 队列中，PRO-C2 水平较低的受试者与 PRO-C2 水平较高的受试者相比，JSN 更大。PRO-C2 水平非常低和非常高的受试者之间的 JSN 平均差异为 0.65mm（p=0.002），进展的风险高 3.4（1.4-8.6）倍。与安慰剂相比，在基于基线 PRO-C2 分层之前，sCT 治疗对 2 年内的 JSN 没有显著影响。然而，在 PRO-C2 非常低/低组的 sCT 臂中，进展者的比例明显低于中/高组（卡方=6.5，p=0.011）。

结论：血清/血浆中 II 型胶原形成的水平，PRO-C2，可能是低软骨修复终末表型的客观指标，显示放射学进展和对促合成代谢药物的优越反应。

证据水平：一项纵向队列的 III 级事后探索性分析和一项 III 期临床试验的子研究。