Risk Assessment of the Progression of Early Knee Osteoarthritis by Collagen Neoepitope C2C: A Longitudinal Study of an Estonian Middle-Aged Cohort.

One of the unmet needs to be addressed is prognostic biomarkers for early knee osteoarthritis (kOA). We aimed to study the association of urinary collagen type-II C-terminal cleavage neoepitope (uC2C) with the emergence and progression of kOA. The longitudinal data of 330 subjects (aged 32-60 years) from an Estonian population-based cohort were used. The radiographic progression was evaluated by the grading system of Nagaosa et al. of knee compartments at baseline and three years later. The emerging kOA consisted of subjects with developing osteophytes or joint space narrowing, whereas kOA progressors showed aggravation of radiographic grade. Baseline uC2C levels were measured by the IBEX-uC2C assay. At baseline, the subjects were middle-aged (mean age, 47.6 years) and overweight (mean BMI, 28.0 kg/m2), and the majority of them (51.2%) had a diagnosis of kOA grade 1. Multiple logistic regression models adjusted for sex, age, and BMI were used for risk calculations. We demonstrate that increased uC2C accurately predicted the risk of emerging of kOA (OR = 5.87 (1.71-20.22); AUC = 0.79) compared with controls without radiographic kOA over 12 years. However, the most accurate prediction of progression by the biomarker was found in women (OR = 23.0 (2.2-245), AUC = 0.91). In conclusion, uC2C may be a promising candidate as a prognostic biomarker for kOA progression, particularly of emerging kOA in women.

Cartilage collagen neoepitope C2C in urine as an integrative diagnostic marker for early knee osteoarthritis.

Objective: To investigate the suitability of urinary collagen type-II C-terminal cleavage neoepitope (uC2C) as a marker for early knee osteoarthritis (kOA). Design: We examined 302 Estonian subjects (mean age, 49 years): 186 subjects with and 20 control subjects without knee symptoms, and 96 patients treated by arthroscopy. For the latter, cartilage lesions were characterized using Société Francaise d'Arthroscopie (SFA) scores. Standardized radiographs of bilateral tibiofemoral (TF) and patellofemoral (PF) joints were assessed for osteoarthritis (OA) features. Osteophytes (Ophs) and joint space narrowing (JSN) were graded separately. uC2C was measured by the uC2C-HUSA assay. Logistic and linear regression models were used for data analysis. Results: Of the kOA cases, 50% were isolated (TF or PF) grade 1; 10% were grade 2. JSN with Ophs was more frequent in females than in males (52% vs. 34%, p = 0.01). Increased uC2C level was associated with gradual increase in the risk of kOA grade of severity (odds ratio = 2.14-3.7) including grade 1 vs. 0. TF-OA and PF-OA equally predicted uC2C concentration (R 2 = 0.33-0.35). uC2C prediction was better for females than for males (R 2 = 0.42 vs. 0.22 by TF-OA). The best predictive model for uC2C level (R 2 = 0.75) included three OA features: macroscopic cartilage lesions, TF Ophs, and PF-JSN. Conclusions: uC2C as an integrative marker of kOA is associated with cartilage degradation and Oph formation in the PF- and TF-joints. Increased uC2C concentration could be used as an early diagnostic marker for kOA in clinical studies.

Two Single-Nucleotide Polymorphisms in ADAM12 Gene Are Associated with Early and Late Radiographic Knee Osteoarthritis in Estonian Population.

Objectives. To investigate associations of selected single-nucleotide polymorphisms (SNPs) in ADAM12 gene with radiographic knee osteoarthritis (rKOA) in Estonian population. Methods. The rs3740199, rs1871054, rs1278279, and rs1044122 SNPs in ADAM12 gene were genotyped in 438 subjects (303 women) from population-based cohort, aged 32 to 57 (mean 45.4). The rKOA features were evaluated in the tibiofemoral joint (TFJ) and patellofemoral joint. Results. The early rKOA was found in 51.4% of investigated subjects (72% women) and 12.3% of participants (63% women) had advanced stage of diseases. The A allele of synonymous SNP rs1044122 was associated with early rKOA in TFJ, predominantly with the presence of osteophytes in females (OR 1.57; 95% CI 1.08-2.29, P = 0.018). The C allele of intron polymorphism rs1871054 carried risk for advanced rKOA, mostly to osteophyte formation in TFJ in males (OR 3.03; 95% CI 1.11-7.53, P = 0.018). Also the CCAA haplotype of ADAM12 was associated with osteophytosis, again mostly in TFJ in males (P = 0.014). For rs3740199 and rs1278279, no statistically significant associations were observed. Conclusion. ADAM12 gene variants are related to rKOA risk during the early and late stages of diseases. The genetic risk seems to be predominantly associated with the appearance of osteophytes-a marker of bone remodelling and neochondrogenesis.