## 1 Introduction  
Studies over the past two decades have enriched us with a wealth of important information about knee osteoarthritis (kOA), including the surprising heterogeneity of the disease [1]. kOA is a highly prevalent, disabling, whole-joint disorder that has doubled in prevalence since the mid-20 th century, mainly due to obesity and the aging of the population [2, 3]. However, other factors--such as diet, dysbiosis, physical inactivity, and metabolism--have also contributed to the marked increase. Women are more affected than men. The multifactorial nature of kOA and the complexity of the disease mechanism determine variability in the manifestation of the disease. Different phenotypes have been recognized, and different definitions have been proposed [4, 5]. The presence of many subtypes has thus far hampered the discovery of disease-modifying therapies [6, 7]. Longitudinal studies have shown that, of all cases of kOA, the disease progresses in only a minority [8, 9], and OA progression is not a continuous but a phased process [10, 11, 12]. As noted in the previous studies, around one in seven cases progress continuously, thus reaching the final stage at an accelerated rate [12, 13]. Clinically, patients in middle age (<65 yearsof age) undergoing total knee replacement (TKR) surgery due to OA are unequivocally recognized as rapidly progressive cases of the disease [14; 15]. Dozens of biochemical markers have been proposed as candidate prognostic markers of the quick progression of kOA [16; 17; 18]. However, because cartilage degradation is a key feature of OA's pathogenesis, particular attention has been paid to molecules originating from cartilage. Recently, the FNIH OA Biomarkers Consortium compared the prognostic values of eight selected biomarkers, carefully adjusted for possible confounding factors; two of them--urinary C-terminal telopeptide of type II collagen (uCTXII), and urinary collagen type II C-terminal cleavage neoepitope (uC2C)--predicted the progression of kOA a little better than other markers [19]. Recently, we reported that urinary collagenase-generated C2C neoepitope fragments of human collagen type II (Coll2) have good prognostic value, and are therefore promising prospective integrative characteristics of different tissues of the knee--especially in females [20]. TKR is considered to be a reflection of joint failure, and is the most common joint arthroplasty procedure worldwide [21]. TKR has been proposed as the clinical endpoint for the estimation of disease-modifying OA drugs (DMOADs), e.g., inhibitors of Wnt/\(\beta\)-catenin signaling (SM04690), inhibitors of aggrecanases (GLPG1972/S201086) and cathepsin K (MIV-711), or fibroblast growth factor-18 (sprifermin) [22; 23]. The determination of a biomarker at this stage of the disease could also serve as a model for elucidating the potential of the marker in question--in the best case, both before and after the TKR. The knowledge of levels of biomarkers is therefore important for the description of the stage of the disease. Despite excellent outcomes, some studies have reported dissatisfaction with the outcome of TKR in up to 20% of patients [24; 25]. Moreover, the dynamics of the biomarkers after TKR are also necessary for a comparison of the treatment's effect if DMOADs are to be used instead of or in addition to TKR. In view of these important aspects, it is astonishing that the time course of OA biomarkers after the total joint replacement has never been analyzed systematically, and the few results obtained have been divergent [10; 26; 27; 28]. [PERSON] et al. [10], in a long-term study, discovered a rise in serum cartilage oligomeric matrix protein (COMP) after TKR. However, [PERSON] et al. [27] described the normalization of the levels of a denaturation epitope of collagen II (Coll2-1) three months after surgery; however, levels of its nitrated form--Coll2-1 NO2--remained elevated; the authors concluded that Coll2-1 was a sensitive and disease-specific marker of the structural changes occurring in a single joint [27].