{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:36:09Z","timestamp":1781195769709,"version":"3.54.1"},"update-to":[{"DOI":"10.12688\/f1000research.131702.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T00:00:00Z","timestamp":1705017600000}}],"reference-count":65,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T00:00:00Z","timestamp":1705017600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["159871"],"award-info":[{"award-number":["159871"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016015","name":"Universit\u00e4tsspital Basel","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>Background This study aimed to quantify the mechanoresponse of 10 blood marker candidates for joint metabolism to a walking stress test in patients with knee osteoarthritis and to determine the association among marker kinetics and with accumulated load and patient reported outcomes. Methods 24 patients with knee osteoarthritis completed questionnaires, and a 30-minute walking stress test with six blood serum samples and gait analysis. Concentrations of cartilage oligomeric matrix protein (COMP), matrix metalloproteinases (MMP)-1, -3, and -9, epitope resulting from cleavage of type II collagen by collagenases (C2C), type II procollagen (CPII), interleukin (IL)-6, proteoglycan (PRG)-4, A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and resistin were determined by enzyme-linked immunosorbent assays, Joint load (moments and compartmental forces) was estimated using musculoskeletal modeling using gait analysis data. Results COMP and MMP-3 showed an immediate increase after the walking stress followed by a decrease. MMP-9 and resistin showed a delayed decrease below pre-stress levels. \u2206COMP correlated with \u2206MMP-3 for most time points. \u2206MMP-9 correlated with \u2206resistin for most time points. The load-induced increase in blood marker levels correlated among blood markers and time points. C2C and resistin correlated positively and C2C\/CPII and MMP2 correlated negatively with load during gait. Immediate relative \u2206CPII and \u2206MMP1 and delayed relative \u2206COMP, \u2206IL6, \u2206C2C, \u2206CPII, \u2206MMP1 and \u2206MMP3 correlated with the load accumulated during the walking stress. Baseline C2C levels correlated with Knee Osteoarthritis Outcome Score (KOOS) subscales and load-induced changes in MMP-3 with KOOS and Short Form 36 quality of life subscores (P&lt;0.05). Conclusions The distinct and differentiated physiological response to the walking stress depends on accumulated load and appears relevant for patient reported osteoarthritis outcome and quality of life and warrants further investigation in the context of disease progression. ClinicalTrials.gov registration: NCT02622204<\/ns4:p>","DOI":"10.12688\/f1000research.131702.2","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T11:20:21Z","timestamp":1705058421000},"page":"299","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Load-induced blood marker kinetics in patients with medial knee compartment osteoarthritis are associated with accumulated load and patient reported outcome measures"],"prefix":"10.12688","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-1689","authenticated-orcid":false,"given":"Annegret","family":"M\u00fcndermann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7526-9536","authenticated-orcid":false,"given":"Corina","family":"N\u00fcesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0739-1959","authenticated-orcid":false,"given":"Simon","family":"Herger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0739-1959","authenticated-orcid":false,"given":"Anna-Maria","family":"Liphardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9rique","family":"Chammartin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1077-6294","authenticated-orcid":false,"given":"Enrico","family":"De Pieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Egloff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2024,1,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2401-2420","DOI":"10.1007\/s00421-019-04232-4","article-title":"The time course and mechanisms of change in biomarkers of joint metabolism in response to acute exercise and chronic training in physiologic and pathological conditions.","volume":"119","author":"H Roberts","year":"2019","journal-title":"Eur. 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Physiol."},{"key":"ref66","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.7648802","author":"A M\u00fcndermann","year":"2023","journal-title":"Zenodo."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/12-299\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/12-299\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/12-299\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T07:30:33Z","timestamp":1718350233000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/12-299\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,12]]},"references-count":65,"URL":"https:\/\/doi.org\/10.12688\/f1000research.131702.2","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/f1000research.131702.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.161249.r237602","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.161249.r289957","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.161249.r289957","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.161249.r237602","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,12]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/12-299\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.161249.r237602, Stephen Cornish, Faculty\u00a0of\u00a0Kinesiology\u00a0and\u00a0Recreation\u00a0Management, University of Manitoba, Winnipeg, Manitoba, 25 Jan 2024, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/12-299\/v2#referee-response-237602","order":0,"name":"referee-response-237602","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.144570.r206343, Amelie M Lutz, Radiology, Stanford University, Stanford, 17 Oct 2023, version 1, 2 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/12-299\/v1#referee-response-206343","order":1,"name":"referee-response-206343","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Annegret M&uuml;ndermann<\/b>; \n<i>Posted: 10 Jan 2024<\/i>; \u201cThis is a well-written manuscript on an explorative study of load-induced blood marker kinetics in patients with medial knee compartment osteoarthritis are associated with accumulated load and patient-reported outcome measures. The authors measured six blood serum biomarkers of cartilage synthesis, cartilage degradation, joint lubrication, or inflammation after a walking test for an extended period up to 5.5 h after the walking test. Of these six blood biomarkers, only COMP and MMP-3 showed a consistent increase immediately after the walking test, and COMP and MMP-3 kinetics in response to the mechanostimulus correlated as did load-induced MMP-9 and resistin kinetics.\u201d Thank you.  \u201cThe main limitation of the study is the low patient number. The authors list additional limitations.\u201d Thank you. We have focused our discussion on limitations that are potentially relevant to the interpretation of our data.  Specific comments for the authors: \u201cIn the introduction, please change the listing of the evaluated blood biomarkers according to their category, meaning list which ones belong to the cartilage synthesis, cartilage degradation groups and so on. This will make it a much more valuable manuscript also to more general physician readers.\u201d Thank you for this suggestion. We have restructured this section accordingly.  Materials and Methods: \u201cHow long was the walking activity? I did not see a defined time period of walking in this section, only briefly mentioned in a subsentence in the discussion (30 minutes?). Was the time duration the same for everybody?\u201d Thank you for noting this oversight. The walking stress test include a 30-minute walking activity. We have added this information to the Abstract and Methods section for clarity.  \u201cHow were the time intervals for blood draws chosen? Please explain.\u201d The time intervals were chosen based on the literature described and cited in the Introduction section. We have added this information to the Methods section accordingly. &nbsp; \u201cHow accurate do the authors think their estimates are of the load accumulated during the walking stress test and assessing the effect of the accumulated load on blood marker kinetics in response to load? Can this really correct for the variability of stress at a self-paced walking exercise?\u201d In this study, we assessed accumulated load using two different approaches. In approach 1, the maximum, rate of increase and impulse of the vertical ground reaction force during treadmill walking were multiplied by the number of steps taken during the walking stress. In the more advanced approach 2, the maximum and impulse of the knee adduction moment, knee flexion moment, total knee compressive force, medial and lateral compartment compressive force as well as medio-lateral shear force were calculated from musculoskeletal modeling for the affected knee during overground walking multiplied by the number of steps taken during the walking stress. The number of steps taken during the walking stress and hence the number of load cycles was counted and hence are an accurate measure. Ideally, one would measure the load directly at the tissue level, but this is not possible in vivo in humans for obvious reasons. Any musculoskeletal model used to estimate joint level load is based on some assumptions. In our models, we scaled the generic model to patient-specific anthropometrics and adjusted the varus\/valgus alignment estimated from the marker position as described in the cited articles. The accuracy of these models can be further improved by increasing the personalization of the models (i.e., person-specific morphology taken from medical imaging such as magnetic resonance imaging vs. scaled based on anthropometrics) and estimating compartment-specific tissue level pressures. The latter was beyond the scope of this study but will be considered in future projects. We have added this potential limitation to the Limitations section. The reviewer is correct that there may be some variability in tissue level stress during a self-paced walking exercise within an individual. In this study, we measured blood marker kinetics after the walking stress and not during the stress, and we were primarily interested in the variability in blood marker kinetics in response to the walking stress and the variability in accumulated load between participants, which we found to be related. Overall, while the accuracy of the estimates depends on the underlying assumptions, but the observed correlations of blood marker kinetics and accumulated load supports our hypothesis.  \u201cIs the work clearly and accurately presented and does it cite the current literature? \u2013 Yes\u201d Thank you.  \u201cIs the study design appropriate and is the work technically sound? \u2013 Yes\u201d Thank you.  \u201cAre sufficient details of methods and analysis provided to allow replication by others? \u2013 Partly\u201d We have added information on the methods and analysis as requested that is important for allowing replication by others.  \u201cIf applicable, is the statistical analysis and its interpretation appropriate? \u2013 I cannot comment. A qualified statistician is required.\u201d All statistical analyses were performed by an experienced biostatistician.  \u201cAre all the source data underlying the results available to ensure full reproducibility? \u2013 Yes\u201d Thank you.  \u201cAre the conclusions drawn adequately supported by the results? \u2013 Partly\u201d We hope that with the revisions made, the reviewer agrees that our conclusions are supported by the results.","URL":"https:\/\/f1000research.com\/articles\/12-299\/v2#referee-comment-10874","order":2,"name":"referee-comment-10874","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.161249.r289957, Jiacan Su, Shanghai University, Shanghai, 14 Jun 2024, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/12-299\/v2#referee-response-289957","order":3,"name":"referee-response-289957","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This study is funded by the Swiss National Science Foundation (SNSF #159871) and the Department of Orthopaedics and Traumatology of the University Hospital Basel, Switzerland. The funding sources had no involvement in the study design, collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}