C1M, C2M, C3M, PRO-C2, and CRPM in serum reflect different potential pathogenetic domains of osteoarthritis, data from check

Abstract

Purpose: The fragment of C-terminal cross-linked telopeptide of type II collagen (CTX-II) is released into circulation and subsequently secreted into urine as a result of articular cartilage degradation in osteoarthritis (OA) disease. The urinary CTX-II (uCTX-II), a competitive immunoassay, has been studied in numerous studies. It is considered as one of the best-validated biomarker in OA field. However, the CTX-II in blood have shown limited value, although there would be some advantages of blood versus urine measurement. We intended to develop a sensitive serological immunoassay of CTX-II (sCTX-II) and to quantify sCTX-II and uCTX-II in a cross-sectional osteoarthritis (OA) cohort. The correlation between sCTX-II and uCTX-II and clinical parameters was investigated as well. Methods: A serological CTX-II sandwich electrochemiluminescence immunoassay (ECLIA), sCTX-II, was developed on the MesoScale Discovery (MSD) platform by employing the same antibody as in the uCTX-II. The uCTX-II was quantified by Urine CartiLaps ELISA (IDS, UK). The concentration of urinary creatinine was analyzed by using the QuantiChrom Creatinine Assay Kit (BioAssay Systems, US). Firstly, a commercially available correlation panel consisting of 18 matched human sera and plasma was measured in sCTX-II to test its ability for different types of blood. In addition, EDTA-treated plasma and urine samples from 227 individuals with complete data in the C4Pain Study were assayed using sCTX-II and uCTX-II, respectively. To evaluate the correlation of the sCTX-II and uCTX-II, Pearson's correlation was performed. Biomarker levels were correlated with Kellgren-Lawrence grade (KL), as well as WOMAC pain, stiffness and function by multiple linear regression, adjusted for age, gender and body mass index (BMI). Results: A good performing sCTX-II immunoassay was developed (inter CV¼11%; intra CV¼3%) and exhibits more sensitivity in terms of Low Limit of Detection (LLOD) compared to uCTX-II (0.003 vs 0.2 ng/ml). The correlation panel between serum and EDTA-treated plasmas was relatively high (r¼0.99, P < 0.0001), showing that sCTX-II levels are independent of blood preparation method. The sCTX-II levels in plasma were not associated with uCTX-II in urine (Table 1). However, sCTX-II levels in urine were significantly correlated with uCTX-II ( Table 1), indicating that sCTX-II ECLIA measured, to some degree, the same analytes as uCTX-II did when measured in urine.Not surprisingly, uCTX-II levels were significantly associated with the pain and joint stiffness recorded by WOMAC (r¼0.13, P¼0.039; r¼0.18, P¼0.0029, respectively) after adjustment for age, BMI, and gender. In contrast, sCTX-II plasma levels were negatively associated with WOMAC pain and WOMAC stiffness (r¼ -0. 13, P ¼ 0.037; r¼ -0.13, P¼0.042, respectively). The WOMAC pain and stiffness levels were higher in the lowest sCTX-II tertile (T1) compared to the highest tertile (T3) (Fig. 1A, P<0.05, Fig. 1E, P<0.05). In contrast, an entirely reverse trend was observed for uCTX-II (Fig. 1D, P<0.01; Fig....

Soluble biological markers in osteoarthritis

“…In the Cohort Hip and Cohort Knee (CHECK) cohort of patients with an early OA phenotype and pain in the knee and/or the hip followed for 10 years, principal component analysis showed that serum C3M and serum CRPM levels may reflect different distinct inflammatory domains compared with serum C1M (a marker measuring type I collagen degradation), erythrocyte sedimentation rate, and hsCRP. 93 …”

“…In the Cohort Hip and Cohort Knee (CHECK) cohort of patients with an early OA phenotype and pain in the knee and/or the hip followed for 10 years, principal component analysis showed that serum C3M and serum CRPM levels may reflect different distinct inflammatory domains compared with serum C1M (a marker measuring type I collagen degradation), erythrocyte sedimentation rate, and hsCRP. 93 Finally, in a study including 99 patients with erosive and non-erosive hand OA, Fioravanti et al 94 in 2018 found higher serum visfatin levels in erosive hand OA compared with nonerosive hand OA. Visfatin has proinflammatory and immunomodulation functions contributing to cartilage degeneration.…”

Association of biochemical markers with bone marrow lesion changes on imaging—data from the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium

“…Together with C1M and C3M, CRPM, an MMP-dependent degradation of CRP in serum, appears to also reflect tissue inflammation in individuals with knee and/or hip pain likely related to primary OA [ 57 ]. Elevated CRPM has been observed in OA patients with higher C1M and CRP levels, supporting the concept of inflammation in a subset of the OA population [ 52 ].…”

“…No association with CRPM has been found in this study despite high levels being found to be prognostic of incident knee OA [ 50 , 58 ]. As C1M and C3M but not CRPM were found to have associations with BMLs, these biochemical markers may reflect distinct inflammatory domains or niches in OA [ 57 ].…”