## 4 Discussion
Interestingly, in patients with preoperative values above the median, the biomarker of oxidative damage--Coll2-1 NO2 levels--significantly and progressively decreased postoperatively, but tended to increase in patients with preoperative Coll2-1 NO2 values below the median. Our results are consistent with the results of [PERSON] et al. : abnormal type II collagen degradation in the knee had a major influence on high preoperative Coll2-1 levels. It was proposed that the sustained level of Coll2 degradation markers after TKR was caused by persistent Coll2 degradation in different structures of a single joint, although the presence of OA lesions in other joints cannot be excluded. The opposite knee could be considered the most likely secondary source. We demonstrated a quite common involvement of both knees (in a quarter of cases); however, we found no associations between uC2C levels and previous history of TKR. Moreover, we were not able to prove an association between uC2C and the summary pain score of other joints. Of course, a more detailed investigation--not just of pain--is needed in order to measure the total body burden of OA [42]. Moreover, several authors have demonstrated that a rather large proportion of kOA patients may have a generalized joint disease [43, 44]. However, we found that the individual dynamics of uC2C levels were rather heterogeneous: some patients had an increase, while others had a decrease. Interestingly, we demonstrated that the preoperative uC2C values could predict the postoperative status: if the preoperative value was low, this meant that Coll2 degradation had become more intense, and the reverse was true for high preoperative values. This finding was widely observed in females. The sex-related differences in the course of OA--and probably in its pathogenesis--should be emphasized, as they are often overlooked by researchers [45, 46, 47, 48, 49]. We have previously found that higher uC2C levels--especially in women--could predict further kOA progression [40]. Notably, the uC2C levels of the rapidly progressive study group in the present study, with gOA grade 3 according to the Nottingham system, were markedly higher compared to the uC2C levels of the same disease severity group for our middle-aged population cohort [40]. Thus, high levels of uC2C could help us to estimate the structural status of the knee in the preoperative period. However, we must not forget that one of the factors influencing uC2C levels is the severity of kOA, as assessed by X-ray [30; 50]. Improvement in quality of life and knee function is common after TKR. We found that preoperative uC2C levels could predict the improvement of the KOOS symptoms score, but only in females. At the same time, the KOOS pain score was correlated with the uC2C value in men during the preoperative period. There is no good explanation for the contradiction between associations of uC2C with pain and other kOA symptoms, but they probably show different aspects of the disease. A possible explanation is that the pain in OA is recognized to be multifactorial [51; 52], and may arise from multiple different structural changes [53; 54]. Furthermore, obvious associations between increased levels of hs-CRP and greater kOA pain were observed among women, but not men [48; 55]. Surprisingly, we did not demonstrate a correlation between the knee-function tests and uC2C levels; this needs more detailed study in the future. This study has several limitations. First, our study group was small in number, although sufficient to allow a general assessment of uC2C behavior in TKR surgical patients in the initial study. In the case of a larger cohort, additional relationships are likely to emerge, e.g., a larger cohort is needed for the evaluation of sex-related differences in the pathogenesis of kOA. Second, we did not measure the synthesis of Coll2; therefore, we could not evaluate the balance between the synthesis and degradation of Coll2. Third, one year may be too short a period to evaluate far-reaching changes in OA biomarkers after TKR.