## 5 Conclusions  
uC2C excretion was high in most of the patients before TKR surgery. We found that TKR does not stop the degradation of Coll2 in tissues in the majority of cases, which is supported by a rather heterogenic dynamic of the marker uC2C in the postoperative period. Partial improvements in quality of life and knee function are common after TKR. These changes are sex- and person-specific, and are multidirectional. The preoperative uC2C level could predict improvement in the KOOS symptoms score, but only in females; uC2C levels were significantly higher in patients with advanced radiological changes, and particularly in women. Obvious trends were observed in that higher preoperative uC2C levels decreased postoperatively, and vice versa. Therefore, uC2C could be considered a prospective pre- and postoperative biomarker for the characterization of the pathogenic process and treatment of kOA in the future. Moreover, continuous and probably systemic pathogenic processes of OA after TKR could be hypothesized in rapidly progressive cases. Conceptualization, A.O.T., A.E.T., K.K. and L.K. ; methodology, K.K., A.O.T. and L.K. ; validation, J.K., A.M., A.O.T. and K.K. ; formal analysis, L.K. and K.K. ; investigation, J.K., K.J., A.M., A.E.T., K.K. and L.K. ; resources, A.O.T., A.E.T., K.K., and L.K. ; data curation, K.K. ; writing--original draft preparation, K.K., L.K., A.O.T. and A.E.T. ; writing--review and editing, K.K., L.K., A.O.T., J.K., K.J. and A.M.; visualization, K.K. and L.K. ; supervision, K.K. and A.O.T. ; project administration, K.K. ; funding acquisition, A.O.T. and K.K. All authors have read and agreed to the published version of the manuscript. This work was supported by the Estonian Ministry of Social Affairs, Estonian Science Foundation grant No 5308, and by the EU's 7 th Framework Programme NMP-2008-4.0-1, GRANT AGREEMENT No 228929 (NanoDiaRA), as well as by basic financing of the Institute of Clinical Medicine, University of Tartu; Estonian Institutional Research Funding project IUT2-8. This study was conducted according to the guidelines of the Declaration of Helsinki, and approved by The Research Ethics Committee of the University of Tartu (protocol 265/T-22, 19 December 2016). Written informed consent was obtained from all subjects involved in the study. All data generated or analyzed during this study are included in the published article. We give special thanks to the orthopedic surgeons [PERSON], [PERSON], [PERSON], [PERSON], [PERSON], [PERSON], [PERSON], and [PERSON], who graded the status of knee cartilage during the TKR, and to [PERSON] for help conducting the knee-function tests. We would also like to thank [PERSON] and [PERSON] for management of the subjects' data and materials. The authors declare no conflict of interest. **Figure A3. The association of preoperative uC2C levels with uni- or bilateral kOA status. U WG (unilateral kOA without previous TKR in the whole group); B WG (bilateral kOA with previous TKR in the whole group); U Male (unilateral kOA without previous TKR in males); B Male (bilateral kOA with previous TKR in males); U Female (unilateral kOA without previous TKR in females); B Female (bilateral kOA with previous TKR in females). Boxplot with 10 th-90 th percentiles, Wilcoxon test \(p\)-values. ** \begin{tabular}{c c c} \hline \hline
**Radiographic kOA Grades** & **gOA** \\ \hline KL & Grade 2 & Grade 3 \\ \hline Grade 2 & 3 & 1 \\ \hline Grade 3 & 11 & 28 \\ \hline Grade 4 & 2 & 41 \\ \hline \hline \end{tabular}   
KL--the severity grade of knee OA assessed by the Kellgren-Lawrence system; gOA--the highest grade of knee OA changes in two knee joint compartments (tibiofemoral and/or patellofemoral joints) assessed by the Nottingham system (NSy).