FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Osteoarthritis Cartilage / Synovial fluid mitochondrial DNA concentration reflects the ...
Osteoarthritis and cartilage2023; 31(8); 1056-1065; doi: 10.1016/j.joca.2023.03.013

Synovial fluid mitochondrial DNA concentration reflects the degree of cartilage damage after naturally occurring articular injury.

Abstract: To evaluate mitochondrial DNA (mtDNA) release from injured chondrocytes and investigate the utility of synovial fluid mtDNA concentration in early detection of posttraumatic osteoarthritis. We measured mtDNA release using four models of osteoarthritis: in vitro interleukin-1β stimulation of cultured equine chondrocytes, ex vivo mechanical impact of bovine cartilage explants, in vivo mechanical impact of equine articular cartilage, and naturally occurring equine intraarticular fracture. In our in vivo model, one group was treated with an intraarticular injection of the mitoprotective peptide SS-31 following cartilage injury. mtDNA content was quantified using qPCR. For naturally occurring cases of joint injury, clinical data (radiographs, arthroscopic video footage) were scored for criteria associated with degenerative joint disease. Chondrocytes released mtDNA in the acute time frame following inflammatory and mechanical cellular stress in vitro. mtDNA was increased in equine synovial fluid following experimental and naturally occurring injury to the joint surface. In naturally occurring posttraumatic osteoarthritis, we found a strong positive correlation between the degree of cartilage damage and mtDNA concentration (r = 0.80, P = 0.0001). Finally, impact-induced mtDNA release was mitigated by mitoprotective treatment. Changes in synovial fluid mtDNA occur following joint injury and correlate with the severity of cartilage damage. Mitoprotection mitigates increases in synovial fluid mtDNA suggesting that mtDNA release may reflect mitochondrial dysfunction. Further investigation of mtDNA as a potentially sensitive marker of early articular injury and response to mitoprotective therapy is warranted.
Copyright © 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Get Full Text
Publication Date: 2023-04-06 PubMed ID: 37028640PubMed Central: PMC10524327DOI: 10.1016/j.joca.2023.03.013Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article investigates the potential of using mitochondrial DNA released from injured cartilage cells as an early detection marker for posttraumatic osteoarthritis. The research found a significant correlation between the level of cartilage damage and the concentration of this DNA in the synovial fluid that lubricates joints.

Objective and Methodology

  • The goal of the research was to evaluate the release of mitochondrial DNA (mtDNA) from injured so-called chondrocytes (cartilage cells), and explore the possibility of using this DNA as an early detection biomarker for posttraumatic osteoarthritis.
  • The release of mitochondrial DNA was measured using four models of osteoarthritis: cultured equine chondrocytes stimulated with interleukin-1β, mechanically impacted bovine cartilage, mechanically impacted equine articular cartilage, and equine intraarticular fracture.
  • For the in vivo model, one group was treated with SS-31, a mitoprotective peptide, after cartilage injury to assess its impact on DNA release.
  • Mitochondrial DNA was quantified using quantitative PCR (qPCR). For natural joint injury cases, clinical data like radiographs and arthroscopic video footage were scored for degenerative joint disease criteria.

Findings and Implications

  • The study found that chondrocytes released mtDNA following inflammatory and mechanical stress.
  • The concentration of mtDNA was found to increase in the synovial fluid following experimental and naturally occurring joint injury.
  • The researchers discovered a strong correlation (r = 0.80, p = 0.0001) between cartilage damage scales and mtDNA concentration for naturally occurring posttraumatic osteoarthritis cases. This indicates that the more severe the cartilage damage, the higher the concentration of mtDNA.
  • The inclusion of a mitoprotective treatment showed that it was possible to mitigate the release of mtDNA post-impact, suggesting that mtDNA release could be linked to mitochondrial dysfunction.
  • Overall, the results suggest that changes in synovial fluid mtDNA are indicative of joint injury severity and hence, mtDNA could be a potentially sensitive marker for early detection of articular injury.
  • The findings also open up avenues for further investigation into the potential of mitoprotective therapy in managing osteoarthritis, especially in mitigating posttraumatic mtDNA release.

Cite This Article

APA
Seewald LA, Sabino IG, Montney KL, Delco ML. (2023). Synovial fluid mitochondrial DNA concentration reflects the degree of cartilage damage after naturally occurring articular injury. Osteoarthritis Cartilage, 31(8), 1056-1065. https://doi.org/10.1016/j.joca.2023.03.013

Publication

Osteoarthritis and cartilage
ISSN: 1522-9653
NlmUniqueID: 9305697
Country: England
Language: English
Volume: 31
Issue: 8
Pages: 1056-1065

Researcher Affiliations

Seewald, L A
  • College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Electronic address: las498@cornell.edu.
Sabino, I G
  • College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Electronic address: igs26@cornell.edu.
Montney, K L
  • College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Electronic address: km884@cornell.edu.
Delco, M L
  • College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Electronic address: mld12@cornell.edu.

MeSH Terms

  • Animals
  • Horses
  • Cattle
  • Synovial Fluid / chemistry
  • DNA, Mitochondrial / metabolism
  • Cartilage, Articular / metabolism
  • Mitochondria
  • Osteoarthritis / metabolism
  • Joint Diseases
  • Chondrocytes

Grant Funding

  • K08 AR068470 / NIAMS NIH HHS
  • R03 AR075929 / NIAMS NIH HHS

Conflict of Interest Statement

Conflict of interest: The authors declare no competing interests.

References

This article includes 50 references
  1. Anderson DD, Chubinskaya S, Guilak F, Martin JA, Oegema TR, Olson SA. Post-traumatic osteoarthritis: Improved understanding and opportunities for early intervention.. J Orthop Res 2011;29(6):802–809.
    doi: 10.1002/jor.21359pmc: PMC3082940pubmed: 21520254google scholar: lookup
  2. Kramer WC, Hendricks KJ, Wang J. Pathogenetic mechanisms of posttraumatic osteoarthritis: Opportunities for early intervention.. Int J Clin Exp Med 2011;4(4):285–298.
    pmc: PMC3228584pubmed: 22140600
  3. Carbone A, Rodeo S. Review of current understanding of post-traumatic osteoarthritis resulting from sports injuries.. J Orthop Res 2017;35(3):397–405.
    doi: 10.1002/jor.23341pubmed: 27306867google scholar: lookup
  4. Blanco FJ, Rego I, Ruiz-Romero C. The role of mitochondria in osteoarthritis.. Nat Rev Rheumatol 2011;7(3):161–169.
    doi: 10.1038/nrrheum.2010.213pubmed: 21200395google scholar: lookup
  5. López-Armada MJ, Caramés B, Martín MA, Cillero-Pastor B, Lires-Dean M, Fuentes-Boquete I. Mitochondrial activity is modulated by TNFα and IL-1β in normal human chondrocyte cells.. Osteoarthr Cartil 2006;14(10):1011–1022.
    doi: 10.1016/j.joca.2006.03.008pubmed: 16679036google scholar: lookup
  6. Johnson K, Jung A, Murphy A, Andreyev A, Dykens J, Terkeltaub R. Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization.. Arthritis Rheum 2000;43(7):1560–1570.
    doi: 10.1002/1529-0131(200007)43:7<1560::AID-ANR21>3.0.CO;2-Spubmed: 10902761google scholar: lookup
  7. Delco ML, Bonnevie ED, Szeto HS, Bonassar LJ, Fortier LA. Mitoprotective therapy preserves chondrocyte viability and prevents cartilage degeneration in an ex vivo model of posttraumatic osteoarthritis.. J Orthop Res 2018;36(8):2147–2156.
    doi: 10.1002/jor.23882pmc: PMC6105558pubmed: 29469223google scholar: lookup
  8. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics.. Br J Pharmacol 2014;171:2029–2050.
    doi: 10.1111/bph.2014.171.issue-8pmc: PMC3976620pubmed: 24117165google scholar: lookup
  9. Dela Cruz CS, Kang M-J. Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases.. Mitochondrion 2018;41:37–44.
    doi: 10.1016/j.mito.2017.12.001pmc: PMC5988941pubmed: 29221810google scholar: lookup
  10. Grazioli S, Pugin J. Mitochondrial damage-associated molecular patterns: From inflammatory signaling to human diseases.. Front Immunol 2018;9:832.
    doi: 10.3389/fimmu.2018.00832pmc: PMC5946030pubmed: 29780380google scholar: lookup
  11. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W. Circulating mitochondrial DAMPs cause inflammatory responses to injury.. Nature 2010;464:104–107.
    doi: 10.1038/nature08780pmc: PMC2843437pubmed: 20203610google scholar: lookup
  12. Wang L, Xie L, Zhang Q, Cai X, Tang Y, Wang L. Plasma nuclear and mitochondrial DNA levels in acute myocardial infarction patients.. Coron Artery Dis 2015;26(4):296–300.
    doi: 10.1097/MCA.0000000000000231pmc: PMC4415965pubmed: 25714070google scholar: lookup
  13. Ryu C, Sun H, Gulati M, Herazo-Maya JD, Chen Y, Osafo-Addo A. Extracellular mitochondrial DNA is generated by fibroblasts and predicts death in idiopathic pulmonary fibrosis.. Am J Respir Crit Care Med 2017;196(12):1571–1581.
    doi: 10.1164/rccm.201612-2480OCpmc: PMC5754440pubmed: 28783377google scholar: lookup
  14. Hajizadeh S, DeGroot J, TeKoppele JM, Tarkowski A, Collins LV. Extracellular mitochondrial DNA and oxidatively damaged DNA in synovial fluid of patients with rheumatoid arthritis.. Arthritis Res Ther 2003;5(5):R234–R240.
    doi: 10.1186/ar787pmc: PMC193725pubmed: 12932286google scholar: lookup
  15. Contis A, Mitrovic S, Lavie J, Douchet I, Lazaro E, Trutchetet M-E. Neutrophil-derived mitochondrial DNA promotes receptor activator of nuclear factor κB and its ligand signalling in rheumatoid arthritis.. Rheumatology 2017;56(7):1200–1205.
    doi: 10.1093/rheumatology/kex041pubmed: 28340056google scholar: lookup
  16. Hauser CJ, Sursal T, Rodriguez EK, Appleton PT, Zhang Q, Itagaki K. Mitochondrial DAMPs from femoral reamings activate neutrophils via formyl peptide receptors and P44/42 MAP Kinase.. J Orthop Trauma 2010;24(9):534–538.
    doi: 10.1097/BOT.0b013e3181ec4991pmc: PMC2945259pubmed: 20736789google scholar: lookup
  17. Yamanouchi S, Kudo D, Yamada M, Miyagawa N, Furukawa H, Kushimoto S. Plasma mitochondrial DNA levels in patients with trauma and severe sepsis: Time course and the association with clinical status.. J Crit Care 2013;28(6):1027–1031.
    doi: 10.1016/j.jcrc.2013.05.006pubmed: 23787023google scholar: lookup
  18. Bernardi P, Scorrano L, Colonna R, Petronilli V, Di Lisa F. Mitochondria and cell death: Mechanistic aspects and methodological issues.. Eur J Biochem 1999;264(3):687–701.
    doi: 10.1046/j.1432-1327.1999.00725.xpubmed: 10491114google scholar: lookup
  19. Lin J-Y, Jing R, Lin F, Ge W, Dai H, Pan L. High tidal volume induces mitochondria damage and releases mitochondrial DNA to aggravate the ventilator-induced lung injury.. Front Immunol 2018;9:1477.
    doi: 10.3389/fimmu.2018.01477pmc: PMC6037891pubmed: 30018615google scholar: lookup
  20. Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy.. Arch Biochem Biophys 2007;462(2):245–253.
    doi: 10.1016/j.abb.2007.03.034pmc: PMC2756107pubmed: 17475204google scholar: lookup
  21. Delco ML, Goodale M, Talts JF, Pownder SL, Koff MF, Miller AD. Integrin a10b1-selected mesenchymal stem cells mitigate the progression of osteoarthritis in an equine talar impact model.. Am J Sports Med 2020;48(3):612–623.
    doi: 10.1177/0363546519899087pubmed: 32004077google scholar: lookup
  22. Bonnevie ED, Delco ML, Fortier LA, Alexander PG, Tuan RS, Bonassar LJ. Characterization of tissue response to impact loads delivered using a hand-held instrument for studying articular cartilage injury.. Cartilage 2015;6(4):226–232.
    doi: 10.1177/1947603515595071pmc: PMC4568733pubmed: 26425260google scholar: lookup
  23. Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells.. Biochem J 2011;435:297–312.
    doi: 10.1042/BJ20110162pmc: PMC3076726pubmed: 21726199google scholar: lookup
  24. Bustin S, Huggett J. qPCR primer design revisited.. Biomol Detect Quantif 2017;14:19–28.
    doi: 10.1016/j.bdq.2017.11.001pmc: PMC5702850pubmed: 29201647google scholar: lookup
  25. Eitner A, Müller S, König C, Wilharm A, Raab R, Hofmann GO. Inhibition of Inducible Nitric Oxide Synthase Prevents IL-1β-Induced Mitochondrial Dysfunction in Human Chondrocytes.. Int J Mol Sci 2021;22(5):2477.
    doi: 10.3390/IJMS22052477pmc: PMC7957659pubmed: 33804447google scholar: lookup
  26. Delco ML, Bonnevie ED, Bonassar LJ, Fortier LA. Mitochondrial dysfunction is an acute response of articular chondrocytes to mechanical injury.. J Orthop Res 2018;36(2):739–750.
    doi: 10.1002/jor.23651pmc: PMC5764818pubmed: 28696002google scholar: lookup
  27. Delco ML, Kennedy JG, Bonassar LJ, Fortier LA. Post-traumatic osteoarthritis of the ankle: A distinct clinical entity requiring new research approaches.. J Orthop Res 2017;35(3):440–453.
    doi: 10.1002/jor.23462pmc: PMC5467729pubmed: 27764893google scholar: lookup
  28. Raikin SM, Elias I, Zoga AC, Morrison WB, Besser MP, Schweitzer ME. Osteochondral lesions of the talus: Localization and morphologic data from 424 patients using a novel anatomical grid scheme.. Foot Ankle Int 2007;28(2):154–161.
    doi: 10.3113/FAI.2007.0154pubmed: 17296131google scholar: lookup
  29. McIlwraith CW, Nixon AJ, Wright IM. Diagnostic and Surgical Arthroscopy of the Carpal Joints.. In: Diagnostic and Surgical Arthroscopy in the Horse. Elsevier; 2015:45–110.
    doi: 10.1016/b978-0-7234-3693-5.00004-7google scholar: lookup
  30. Melki I, Allaeys I, Tessandier N, Lévesque T, Cloutier N, Laroche A. Platelets release mitochondrial antigens in systemic lupus erythematosus.. Sci Transl Med 2021;13(581):eeav5928.
    doi: 10.1126/scitranslmed.aav5928pubmed: 33597264google scholar: lookup
  31. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: The release of damage-associated molecular patterns and its physiological relevance.. Immunity 2013;38(2):209–223.
    doi: 10.1016/j.immuni.2013.02.003pubmed: 23438821google scholar: lookup
  32. Kai Y, Takamatsu C, Tokuda K, Okamoto M, Irita K, Takahashi S. Rapid and random turnover of mitochondrial DNA in rat hepatocytes of primary culture.. Mitochondrion 2006;6(6):299–304.
    doi: 10.1016/J.MITO.2006.10.002pubmed: 17098481google scholar: lookup
  33. Filograna R, Mennuni M, Alsina D, Larsson N-G. Mitochondrial DNA copy number in human disease: the more the better?. FEBS Lett 2021;595(8):976–1002.
    doi: 10.1002/1873-3468.14021pmc: PMC8247411pubmed: 33314045google scholar: lookup
  34. Clay Montier LL, Deng JJ, Bai Y. Number matters: control of mammalian mitochondrial DNA copy number.. J Genet Genomics 2009;36:125–131.
    doi: 10.1016/S1673-8527(08)60099-5pmc: PMC4706993pubmed: 19302968google scholar: lookup
  35. Zhang Q, Itagaki K, Hauser CJ. Mitochondrial DNA is released by shock and activates neutrophils via P38 map kinase.. Shock 2010;34(1):55–59.
    doi: 10.1097/SHK.0b013e3181cd8c08pubmed: 19997055google scholar: lookup
  36. Gu X, Wu G, Yao Y, Zeng J, Donghong S, Lv T. Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9-p38 MAPK pathway.. Free Radic Biol Med 2015;83:149–158.
    doi: 10.1016/j.freeradbiomed.2015.02.034pubmed: 25772007google scholar: lookup
  37. Collins LV, Hajizadeh S, Holme E, Jonsson I, Tarkowski A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses.. J Leukoc Biol 2004;75:995–1000.
    doi: 10.1189/jlb.0703328.1pubmed: 14982943google scholar: lookup
  38. Gursel I, Gursel M, Yamada H, Ishii KJ, Takeshita F, Klinman DM. Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation.. J Immunol 2003;171(3):1393–1400.
    doi: 10.4049/JIMMUNOL.171.3.1393pubmed: 12874230google scholar: lookup
  39. Bartell LR, Fortier LA, Bonassar LJ, Szeto HH, Cohen I, Delco ML. Mitoprotective therapy prevents rapid, strain-dependent mitochondrial dysfunction after articular cartilage injury.. J Orthop Res 2020;38(6):1257–1267.
    doi: 10.1002/jor.24567pmc: PMC7225065pubmed: 31840828google scholar: lookup
  40. Bonnevie ED, Delco ML, Bartell LR, Jasty N, Cohen I, Fortier LA. Microscale frictional strains determine chondrocyte fate in loaded cartilage.. J Biomech 2018;74:72–78.
    doi: 10.1016/j.jbiomech.2018.04.020pmc: PMC6367731pubmed: 29729853google scholar: lookup
  41. Brouillette MJ, Ramakrishnan PS, Wagner VM, Sauter EE, Journot BJ, McKinley TO. Strain-dependent oxidant release in articular cartilage originates from mitochondria.. Biomech Model Mechanobiol 2014;13(3):565–572.
    doi: 10.1007/s10237-013-0518-8pmc: PMC3940668pubmed: 23896937google scholar: lookup
  42. Guescini M, Guidolin D, Vallorani L, Casadei L, Gioacchini AM, Tibollo P. C2C12 myoblasts release micro-vesicles containing mtDNA and proteins involved in signal transduction.. Exp Cell Res 2010;316:1977–1984.
    doi: 10.1016/j.yexcr.2010.04.006pubmed: 20399774google scholar: lookup
  43. Patrushev M, Kasymov V, Patrusheva V, Ushakova T, Gogvadze V, Gaziev A. Mitochondrial permeability transition triggers the release of mtDNA fragments.. Cell Mol Life Sci 2004;61:3100–3103.
    doi: 10.1007/s00018-004-4424-1pmc: PMC11924515pubmed: 15583871google scholar: lookup
  44. Pérez-Treviño P, Velásquez M, García N. Mechanisms of mitochondrial DNA escape and its relationship with different metabolic diseases.. BBA - Mol Basis Dis 2020;1866(6):165761.
    doi: 10.1016/j.bbadis.2020.165761pubmed: 32169503google scholar: lookup
  45. McIlwraith CW, Frisbie DD, Kawcak CE. The horse as a model of naturally occurring osteoarthritis.. Bone Joint Res 2012;1(11):297–309.
    doi: 10.1302/2046-3758.111.2000132pmc: PMC3626203pubmed: 23610661google scholar: lookup
  46. Bertoni L, Jacquet-Guibon S, Branly T, Legendre F, Desancé M, Mespoulhes C. An experimentally induced osteoarthritis model in horses performed on both metacarpophalangeal and metatarsophalangeal joints: Technical, clinical, imaging, biochemical, macroscopic and microscopic characterization.. PLoS One 2020;15(6):e0235251.
    doi: 10.1371/journal.pone.0235251pmc: PMC7316256pubmed: 32584901google scholar: lookup
  47. Graham RJTY Rosanowski SM, McIlwraith CW. A 10-year study of arthroscopic surgery in racing Thoroughbreds and Quarter Horses with osteochondral fragmentation of the carpus.. Equine Vet J 2020;52(2):225–231.
    doi: 10.1111/evj.13145pubmed: 31230383google scholar: lookup
  48. Kannegieter NJ, Ryan N. Racing performance of Thoroughbred horses after arthroscopic surgery of the carpus.. Aust Vet J 1991;68(8):258–260.
    doi: 10.1111/J.1751-0813.1991.TB03233.Xpubmed: 1953548google scholar: lookup
  49. McIlwraith C, Yovich J, Martin G. Arthroscopic surgery for the treatment of osteochondral chip fractures in the equine carpus.. J Am Vet Med Assoc 1987;191(5):531–540.
    pubmed: 3667408
  50. Lakkireddy M, Bedarakota D, Vidyasagar JVS, Rapur S, Karra M. Correlation among radiographic, arthroscopic and pain criteria for the diagnosis of knee osteoarthritis.. J Clin Diagnostic Res 2015;9(12):RC04–RC07.
    doi: 10.7860/JCDR/2015/17152.6889pmc: PMC4717733pubmed: 26816954google scholar: lookup
Subscribe to our newsletter
Join 99,344 horse owners like you who receive our email updates on horse health and nutrition.