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Subchondral bone structure and synovial fluid metabolism are altered in injured and contralateral limbs 7 days after non-invasive joint injury in skeletally-mature C57BL/6 mice

Published:September 19, 2022DOI:https://doi.org/10.1016/j.joca.2022.09.002

      Summary

      Objective

      Post-traumatic osteoarthritis (PTOA) commonly develops after ACL injury, but early changes to the joint soon after injury are insufficiently understood. The objectives of this study were (1) evaluate the response of subchondral bone tissue modulus to joint injury and (2) identify which bone structural, material, and metabolic outcomes are local (i.e., injured joint only) or systemic (i.e., injured and contralateral-to-injured).

      Design

      Female C57Bl∖6N mice (19 weeks at injury) underwent tibial compression overload to simulate ACL injury (n = 8) or a small pre-load (n = 8). Synovial fluid was harvested at euthanasia 7 days later for metabolomic profiling. Bone outcomes included epiphyseal and SCB microarchitecture, SCB nanoindentation modulus, SCB formation rate, and osteoclast number density.

      Results

      Injury decreased epiphyseal bone volume fraction ([-5.29, −1.38%], P = 0.0016) and decreased SCB thickness for injured vs sham-injured limbs ([2.2, 31.4 μm], P = 0.017)). Epiphyseal bone loss commonly occurred for contralateral-to-injured limbs. There was not sufficient evidence to conclude that SCB modulus changes with injury. Metabolomic analyses revealed dysregulated synovial fluid metabolism with joint injury but that many metabolic pathways are shared between injured and contralateral-to-injured limbs.

      Conclusion

      This study demonstrates rapid changes to bone structure and synovial fluid metabolism after injury with the potential for influencing the progression to PTOA. These changes are often evidenced in the contralateral-to-injured limb, indicating that systemic musculoskeletal responses to joint injury should not be overlooked.

      Keywords

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      References

        • Thomas A.C.
        • Hubbard-Turner T.
        • Wikstrom E.A.
        • Palmieri-Smith R.M.
        Epidemiology of posttraumatic osteoarthritis.
        J Athl Train. 2017; 52: 491-496https://doi.org/10.4085/1062-6050-51.5.08
        • Cinque M.E.
        • Dornan G.J.
        • Chahla J.
        • Moatshe G.
        • LaPrade R.F.
        High rates of osteoarthritis develop after anterior cruciate ligament surgery: an analysis of 4108 patients.
        Am J Sports Med. 2018; 46: 2011-2019https://doi.org/10.1177/0363546517730072
        • Kramer W.C.
        • Hendricks K.J.
        • Wang J.
        Pathogenetic Mechanisms of Posttraumatic Osteoarthritis: Opportunities for Early Intervention.
        2011
        • Anderson D.D.
        • Chubinskaya S.
        • Guilak F.
        • Martin J.
        • Oegema T
        • Olson S.
        • et al.
        Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention.
        J Orthop Res. 2011; 29: 802-809https://doi.org/10.1002/jor.21359
        • Hsia A.W.
        • Jbeily E.H.
        • Mendez M.E.
        • Cunningham H.
        • Biris K.
        • Bang H.
        • et al.
        Post-traumatic osteoarthritis progression is diminished by early mechanical unloading and anti-inflammatory treatment in mice.
        Osteoarthritis Cartilage. 2021; 29: 1709-1719https://doi.org/10.1016/j.joca.2021.09.014
        • Anderson M.J.
        • Diko S.
        • Baehr L.M.
        • Bodine S.C.
        • Christiansen B.A.
        Contribution of mechanical unloading to trabecular bone loss following non-invasive knee injury in mice.
        J Orthop Res. 2016; (Published online January 30)https://doi.org/10.1002/jor.23178
        • Lockwood K.A.
        • Chu B.T.
        • Anderson M.J.
        • Haudenschild D.R.
        • Christiansen B.A.
        Comparison of loading rate-dependent injury modes in a murine model of post-traumatic osteoarthritis.
        J Orthop Res. 2014; 32: 79-88https://doi.org/10.1002/jor.22480
        • Christiansen B.A.
        • Anderson M.J.
        • Lee C.A.
        • Williams J.C.
        • Yik J.H.N.
        • Haudenschild D.R.
        Musculoskeletal changes following non-invasive knee injury using a novel mouse model of post-traumatic osteoarthritis.
        Osteoarthritis Cartilage. 2012; 20: 773-782https://doi.org/10.1016/j.joca.2012.04.014
        • Khorasani M.S.
        • Diko S.
        • Hsia A.W.
        • Genetos D.
        • Haudenschild D.
        • Christiansen B.
        Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate ligament rupture in mice.
        Arthritis Res Ther. 2015; 17https://doi.org/10.1186/s13075-015-0546-0
        • Wegner A.M.
        • Campos N.R.
        • Robbins M.A.
        • Haddad A.
        • Cunningham H.
        • Yik J.
        • et al.
        Acute changes in NADPH oxidase 4 in early post-traumatic osteoarthritis.
        J Orthop Res. 2019; 37: 2429-2436https://doi.org/10.1002/jor.24417
        • Stock J.T.
        Wolff's law (bone functional adaptation).
        in: The International Encyclopedia of Biological Anthropology. John Wiley & Sons, 2018: 1-2https://doi.org/10.1002/9781118584538.ieba0521
        • Maycas M.
        • Esbrit P.
        • Gortázar A.R.
        Molecular mechanisms in bone mechanotransduction.
        Histol Histopathol. 2017; 32: 751-760https://doi.org/10.14670/HH-11-858
        • Mazur C.M.
        • Woo J.J.
        • Yee C.S.
        • Fields A.
        • Acevedo C.
        • Bailey K.
        • et al.
        Osteocyte dysfunction promotes osteoarthritis through MMP13-dependent suppression of subchondral bone homeostasis.
        Bone Research. 2019; 7https://doi.org/10.1038/s41413-019-0070-y
        • Alliston T.
        • Hernandez C.J.
        • Findlay D.M.
        • Felson D.T.
        • Kennedy O.D.
        Bone marrow lesions in osteoarthritis: what lies beneath.
        J Orthop Res. 2018; 36: 1818-1825https://doi.org/10.1002/jor.23844
        • Mcmahon M.
        • Block J.A.
        The Risk of Contralateral Total Knee Arthroplasty after Knee Replacement for Osteoarthritis. vol. 30. 2003
        • Christiansen B.A.
        • Emami A.J.
        • Fyhrie D.P.
        • Satkunananthan P.B.
        • Hardisty M.R.
        Trabecular bone loss at a distant skeletal site following noninvasive knee injury in mice.
        J Biomech Eng. 2015; 137https://doi.org/10.1115/1.4028824
        • White M.S.
        • Brancati R.J.
        • Lepley L.K.
        Relationship between altered knee kinematics and subchondral bone remodeling in a clinically translational model of ACL injury.
        J Orthop Res. 2022; 40: 74-86https://doi.org/10.1002/jor.24943
        • Yik J.H.
        • Hu Z.
        • Christiansen B.A.
        • Haudenschild D.R.
        Early transient induction of IL-6 in a mouse joint injury model.
        Osteoarthritis Cartilage. 2013; 21: S235-S236https://doi.org/10.1016/j.joca.2013.02.484
        • Swärd P.
        • Frobell R.
        • Englund M.
        • Roos H.
        • Struglics A.
        Cartilage and bone markers and inflammatory cytokines are increased in synovial fluid in the acute phase of knee injury (hemarthrosis) - a cross-sectional analysis.
        Osteoarthritis Cartilage. 2012; 20: 1302-1308https://doi.org/10.1016/j.joca.2012.07.021
      1. Marcucci G, Iantomasi T, Brandi ML, Vincenzini MT. Oxidative Stress in Bone Remodeling: Role of Antioxidants.

        • Vashishth D.
        • Gibson G.J.
        • Khoury J.I.
        • Schaffler M.B.
        • Kimura J.
        • Fyhrie D.P.
        Influence of Nonenzymatic Glycation on Biomechanical Properties of Cortical Bone.
        2001
        • das Neves Borges P.
        • Vincent T.L.
        • Marenzana M.
        Automated assessment of bone changes in cross-sectional micro-CT studies of murine experimental osteoarthritis.
        PLoS One. 2017; 12https://doi.org/10.1371/journal.pone.0174294
        • McCulloch K.
        • Huesa C.
        • Dunning L.
        • Litherland G.
        • Van T Hof R
        • Lockhart J.
        • et al.
        Accelerated post traumatic osteoarthritis in a dual injury murine model.
        Osteoarthritis Cartilage. 2019; 27: 1800-1810https://doi.org/10.1016/j.joca.2019.05.027
        • Patti G.J.
        • Yanes O.
        • Siuzdak G.
        Innovation: metabolomics: the apogee of the omics trilogy.
        Nat Rev Mol Cell Biol. 2012; 13: 263-269https://doi.org/10.1038/nrm3314
        • Hahn A.K.
        • Wallace C.W.
        • Welhaven H.D.
        • Brooks E.
        • McAlpine M.
        • Christiansen B.A.
        • et al.
        The microbiome mediates epiphyseal bone loss and metabolomic changes after acute joint trauma in mice.
        Osteoarthritis Cartilage. 2021; 29: 882-893https://doi.org/10.1016/j.joca.2021.01.012
      2. Wallace CW, Hislop B, Hahn AK, Erdogan AE, Brahmachary PP, June RK. Correlations between Metabolites in the Synovial Fluid and Serum: A Mouse Injury Study. doi:10.1101/2021.08.30.458234

        • Olah T.
        • Madry H.
        The osteochondral unit: the importance of the underlying subchondral bone.
        in: Cartilage Restoration. 2018: 13-22
        • Souza RL de
        • Matsuura M.
        • Eckstein F.
        • Rawlinson S.C.F.
        • Lanyon L.E.
        • Pitsillides A.A.
        Non-invasive axial loading of mouse tibiae increases cortical bone formation and modifies trabecular organization: a new model to study cortical and cancellous compartments in a single loaded element.
        Bone. 2005; 37: 810-818https://doi.org/10.1016/j.bone.2005.07.022
        • Bouxsein M.L.
        • Boyd S.K.
        • Christiansen B.A.
        • Guldberg R.E.
        • Jepsen K.J.
        • Müller R.
        Guidelines for assessment of bone microstructure in rodents using micro-computed tomography.
        J Bone Miner Res. 2010; 25: 1468-1486https://doi.org/10.1002/jbmr.141
        • Schindelin J.
        • Arganda-Carreras I.
        • Frise E.
        • Kaynig V.
        • Longair M.
        • Pietzsch T.
        • et al.
        Fiji: an open-source platform for biological-image analysis.
        Nat Methods. 2012; 9: 676-682
        • Vahidi G.
        • Flook H.
        • Sherk V.
        • Mergy M.
        • Lefcort F.
        • Heveran C.M.
        Bone biomechanical properties and tissue-scale bone quality in a genetic mouse model of familial dysautonomia.
        Osteoporos Int. 2021; 32: 2335-2346https://doi.org/10.1007/s00198-021-06006-1/Published
        • Bushby A.J.
        • Ferguson V.L.
        • Boyde A.
        Nanoindentation of bone: comparison of specimens tested in liquid and embedded in polymethylmethacrylate.
        J Mater Res. 2004; 19: 249-259https://doi.org/10.1557/jmr.2004.19.1.249
        • Kim S.
        • Hwang J.
        • Xuan J.
        • Jung Y.H.
        • Cha H.S.
        • Kim K.H.
        Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid arthritis from other inflammatory arthritis.
        PLoS One. 2014; 9e97501https://doi.org/10.1371/journal.pone.0097501
        • Carlson A.K.
        • Rawle R.A.
        • Adams E.
        • Greenwood M.C.
        • Bothner B.
        • June R.K.
        Application of global metabolomic profiling of synovial fluid for osteoarthritis biomarkers.
        Biochem Biophys Res Commun. 2018; 499: 182-188https://doi.org/10.1016/j.bbrc.2018.03.117
        • Domingo-Almenara X.
        • Montenegro-Burke J.R.
        • Ivanisevic J.
        • Thomas A.
        • Sidie J.
        • Teav T.
        • et al.
        XCMS-MRM and METLIN-MRM: a cloud library and public resource for targeted analysis of small molecules.
        Nat Methods. 2018; 15: 681-684https://doi.org/10.1038/s41592-018-0110-3
        • Li S.
        • Park Y.
        • Duraisingham S.
        • Strobel F.
        • Khan N.
        • Soltow Q.
        • et al.
        Predicting network activity from high throughput metabolomics.
        PLoS Comput Biol. 2013; 9https://doi.org/10.1371/journal.pcbi.1003123
        • Aggarwal C.C.
        • Procopiuc C.
        • Wolf J.L.
        • Yu P.S.
        Fast Algorithms for Projected Clustering.
        1999
        • Ronan T.
        • Qi Z.
        • Naegle K.M.
        Avoiding common pitfalls when clustering biological data.
        Sci Signal. 2016; 9: 1-13https://doi.org/10.1126/scisignal.aad1932
        • Maerz T.
        • Newton M.D.
        • Fleischer M.
        • Hartner S.
        • Gawronski K.
        • Junginger L.
        • et al.
        Traumatic joint injury induces acute catabolic bone turnover concurrent with articular cartilage damage in a rat model of posttraumatic osteoarthritis.
        J Orthop Res. 2021; 39: 1965-1976https://doi.org/10.1002/jor.24903
        • Ji M.
        • Yu Q.
        Primary osteoporosis in postmenopausal women.
        Chronic Diseases and Translational Medicine. 2015; 1: 9-13https://doi.org/10.1016/j.cdtm.2015.02.006
        • Manitta L.
        • Fayolle C.
        • Olive L.
        • Berteau J.P.
        Nanoindentation of subchondral bone during osteoarthritis pathological process using atomic force microscopy.
        in: International Symposium on Computer Methods in Biomechanics and Biomedical Engineering. 2019: 505-517
        • Klein-Nulend J.
        • van der Plas A.
        • Semeins C.M.
        • Ajubi N.
        • Erangos J.
        • Nijweide P.
        • et al.
        Sensitivity of osteocytes to biomechanical stress in vitro.
        Faseb J. 1995; 9: 441-445https://doi.org/10.1096/fasebj.9.5.7896017
        • Fritton S.P.
        • Weinbaum S.
        Fluid and solute transport in bone: flow-induced mechanotransduction.
        Annu Rev Fluid Mech. 2009; 41: 347-374https://doi.org/10.1146/annurev.fluid.010908.165136
        • Blewis M.E.
        • Nugent-Derfus G.E.
        • Schmidt T.A.
        • Schumacher B.L.
        A model of synovial fluid lubricant composition in normal and injured joints.
        Eur Cell Mater. 2007; 13: 26-39
        • Jay G.D.
        • Torres J.R.
        • Warman M.L.
        • Laderer M.C.
        • Breuer K.S.
        The Role of Lubricin in the Mechanical Behavior of Synovial Fluid.
        2007
        • Haudenschild D.R.
        • Carlson A.K.
        • Zignego D.L.
        • Yik J.H.N.
        • Hilmer J.K.
        • June R.K.
        Inhibition of early response genes prevents changes in global joint metabolomic profiles in mouse post-traumatic osteoarthritis.
        Osteoarthritis Cartilage. 2019; 27: 504-512https://doi.org/10.1016/j.joca.2018.11.006