## 4 Discussion  
The present study is the first to present the dynamics of uC2C levels in subjects in pre- and post-TKR periods. Surprisingly, the uC2C level of the whole group rose three months after TKR, and then reverted to the baseline level. Unlike in men, there was a significant decrease in uC2C levels in women one year after TKR. Interestingly, the postoperative levels of uC2C remained higher than levels in subjects without kOA (in the long-term control group) or with early kOA [20,40]. The behavior of biomarkers after TKR has been studied relatively little--probably due to the understanding that the operation is the \"end stage\" of the OA. To our knowledge, four similar studies of the dynamics of cartilage biomarkers in serum (keratan sulfate, cartilage \begin{table}
\begin{tabular}{l c c c c c} \hline \hline \multirow{2}{*}{**KOOS Subscale**} & \multicolumn{2}{c}{**Substantial Improvement Group \({}^{*}\)**} & \multicolumn{2}{c}{**No Change Group**} & \multirow{2}{*}{\(p\)**-Value (between**} \\ \cline{2-2} \cline{4-6}  & \(n\) & **uC2C ***, ng/mmol** & \(n\) & **uC2C ***, ng/mmol** & **Groups) ** \\ \hline KOOSsymp & 38 & 1016.9 (782.8–1204.9) & 29 & 718.8 (570.5–899.7) & 0.01 \\ \hline KOOSpain & 46 & 935.8 (637.7–1178.9) & 21 & 752.7 (703.1–1315.5) & 0.94 \\ \hline KOOSadl & 44 & 974.0 (626.3–1216.2) & 24 & 731.9 (668.7–978.0) & 0.16 \\ \hline KOOSsp/recr & 25 & 917.3 (608.8–1203.5) & 44 & 923.6 (687.9–1178.7) & 0.70 \\ \hline KOOSqol & 36 & 956.3 (626.3–1216.2) & 30 & 839.6 (685.4–1132.0) & 0.55 \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Comparison of preoperative uC2C between SCB subgroups of KOOS subscales. oligomeric matrix protein (COMP), and Coll2-derived fragments (Coll2-1 and Coll2-1 NO2)) have been performed in subjects with TKR [10, 26, 27, 28]. The first study found that, after a short preliminary decrease one week after TKR, keratan sulfate levels subsequently increased to be similar to preoperative levels after six months [26]. The second longitudinal study ([PERSON] et al.) demonstrated a substantial rise in serum COMP levels after TKR in all patients, persisting for up to 12 months following surgery [10]. Recently, [PERSON] et al. showed a short reduction in COMP levels a week after total hip replacement, after which its levels returned to the preoperative baseline [28]. These results were unexpected for researchers at both centers, as a decrease in COMP levels was expected; they were forced to consider the possibility that COMP could originate from sources other than the operated joint alone. The first group assumed that there might be an increased production or degradation of COMP in the contralateral knee joint, or an increased release of COMP from other tissues--such as ligaments, tendons, and capsules--of the TKR joint. The researchers in the second group attributed the results to changes in physical activity: patients with relieved pain were much more mobile than before TKR. Compared to COMP, uC2C is a more specific marker of certain pathogenetic processes of kOA--especially the degradation of Coll2. It should be noted that the reference values of the OA biomarkers were almost completely absent in published papers. Only [PERSON] et al. set up the references for several OA biomarkers, including uC2C-HUSA [41]. In the present study, almost all TKR patients had uC2C levels > 300 ng/mmol (only one patient had lower uC2C at baseline). [PERSON] et al. found no differences between the reference values of different sexes. Given the very high prevalence of OA with aging, lack of OA phenotyping could result in a reference \"normal\" population that can cause still-unsuitable reference values for the population--especially for older age groups. Similarly, investigation of Coll2-derived fragments demonstrated that the pathogenic metabolism of Coll2 persisted after TKR [27].