Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular biomarker approaches to prevention of post-traumatic osteoarthritis

Nature Reviews Rheumatology volume 20, pages 272–289 (2024)Cite this article

Subjects

Abstract

Up to 50% of individuals develop post-traumatic osteoarthritis (PTOA) within 10 years following knee-joint injuries such as anterior cruciate ligament rupture or acute meniscal tear. Lower-extremity PTOA prevalence is estimated to account for ≥12% of all symptomatic osteoarthritis (OA), or approximately 5.6 million cases in the USA. With knowledge of the inciting event, it might be possible to ‘catch PTOA in the act’ with sensitive imaging and soluble biomarkers and thereby prevent OA sequelae by early intervention. Existing biomarker data in the joint-injury literature can provide insights into the pathogenesis and early risk trajectory related to PTOA and can help to elucidate a research agenda for preventing or slowing the onset of PTOA. Non-traumatic OA and PTOA have many clinical, radiological and genetic similarities, and efforts to understand early risk trajectories in PTOA might therefore contribute to the identification and classification of early non-traumatic OA, which is the most prevalent form of OA.

Key points

  • Molecular biomarkers have potential for monitoring of the post-traumatic osteoarthritis (PTOA) trajectory, as treatment targets for the prevention of PTOA, and as indicators of the efficacy of PTOA prevention strategies.

  • The early inflammatory response to joint injury is acutely beneficial, but thereafter contributes to PTOA development; the optimal approach and timing of anti-inflammatory interventions are yet to be determined.

  • Biomarker expression varies with time after injury; the optimal timing and choice of biomarkers for definitive identification of a PTOA trajectory are yet to be determined.

  • Long-term elevation of elastase after injury could identify a group at a high risk of PTOA.

  • The early appearance of collagen biomarkers after injury, portending irreversible joint damage, suggests the possible need for very early intervention to prevent PTOA.

  • Haemarthrosis related to injury and surgery is a risk factor for cartilage degradation that deserves more widespread recognition and early amelioration in clinical practice to prevent PTOA.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The ‘osteoarthritis iceberg’ concept.
Fig. 2: Biomarkers in human studies predicting a PTOA trajectory.
Fig. 3: Pathophysiological mechanisms of PTOA elucidated by biomarkers.

Similar content being viewed by others

References

  1. Kraus, V. B. et al. Proposed study designs for approval based on a surrogate endpoint and a post-marketing confirmatory study under FDA’s accelerated approval regulations for disease modifying osteoarthritis drugs. Osteoarthritis Cartilage 27, 571–579 (2019).

    CAS  PubMed  Google Scholar 

  2. Hochberg, M. et al. Osteoarthritis. In: Liebowitz J, Seo P, (eds) Clinical Innovation in Rheumatology, Past, Present, and Future. 47–63 (CRC Press/Taylor and Francis, 2023).

  3. Mendez, M. E. et al. LPS-induced inflammation prior to injury exacerbates the development of post-traumatic osteoarthritis in mice. J. Bone Min. Res. 35, 2229–2241 (2020).

    CAS  Google Scholar 

  4. Long, H., Liu, Q., Zhang, Y., Guo, A. & Lin, J. Prevalence estimates of osteoarthritis from Global Burden of Disease Study 2019. Arthritis Rheumatol. https://doi.org/10.1002/art.42089 2022.

  5. Thomas, A. C., Hubbard-Turner, T., Wikstrom, E. A. & Palmieri-Smith, R. M. Epidemiology of posttraumatic osteoarthritis. J. Athl. Train. 52, 491–496 (2017).

    PubMed  PubMed Central  Google Scholar 

  6. Mahmoudian, A., Lohmander, L. S., Jafari, H. & Luyten, F. P. Towards classification criteria for early-stage knee osteoarthritis: a population-based study to enrich for progressors. Semin. Arthritis Rheum. 51, 285–291 (2021).

    PubMed  Google Scholar 

  7. Watt, F. E. Posttraumatic osteoarthritis: what have we learned to advance osteoarthritis? Curr. Opin. Rheumatol. 33, 74–83 (2021).

    CAS  PubMed  Google Scholar 

  8. Aman, Z. S. et al. Acute intervention with selective interleukin-1 inhibitor therapy may reduce the progression of posttraumatic osteoarthritis of the knee: a systematic review of current evidence. arthroscopy. J. Arthrosc. Relat. Surg. 38, 2543–2556 (2022).

    Google Scholar 

  9. Salman, L. A., Ahmed, G., Dakin, S. G., Kendrick, B. & Price, A. Osteoarthritis: a narrative review of molecular approaches to disease management. Arthritis Res. Ther. 25, 27 (2023).

    PubMed  PubMed Central  Google Scholar 

  10. Mahmoudian, A., Lohmander, L. S., Mobasheri, A., Englund, M. & Luyten, F. P. Early-stage symptomatic osteoarthritis of the knee — time for action. Nat. Rev. Rheumatol. 17, 621–632 (2021).

    PubMed  Google Scholar 

  11. Luyten, F. P. et al. Toward classification criteria for early osteoarthritis of the knee. Semin. Arthritis Rheum. 47, 457–463 (2018).

    CAS  PubMed  Google Scholar 

  12. Harkey, M. et al. Longitudinal change in the prevalence of early knee osteoarthritis symptoms across various time-periods after anterior cruciate ligament reconstruction. Osteoarthritis Cartilage 30, S232–S233 (2022).

    Google Scholar 

  13. Bedson, J. & Croft, P. R. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet. Disord. 9, 116 (2008).

    PubMed  PubMed Central  Google Scholar 

  14. Cameron, K. L., Shing, T. L. & Kardouni, J. R. The incidence of post-traumatic osteoarthritis in the knee in active duty military personnel compared to estimates in the general population. Osteoarthritis Cartilage 25, S184–S185 (2017).

    Google Scholar 

  15. Watt, F. E. et al. Towards prevention of post-traumatic osteoarthritis: report from an international expert working group on considerations for the design and conduct of interventional studies following acute knee injury. Osteoarthritis Cartilage 27, 23–33 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Group, M. et al. The clinical radiographic incidence of posttraumatic osteoarthritis 10 years after anterior cruciate ligament reconstruction: data from the MOON nested cohort. Am. J. Sports Med. 49, 1251–1261 (2021).

    Google Scholar 

  17. Williams, A., Winalski, C. S. & Chu, C. R. Early articular cartilage MRI T2 changes after anterior cruciate ligament reconstruction correlate with later changes in T2 and cartilage thickness. J. Orthop. Res. 35, 699–706 (2017).

    PubMed  Google Scholar 

  18. Li, A. K. et al. Six-month post-surgical elevations in cartilage T1rho relaxation times are associated with functional performance 2 years after ACL reconstruction. J. Orthop. Res. 38, 1132–1140 (2020).

    PubMed  Google Scholar 

  19. Nambi, G. et al. Comparative effects of virtual reality training and sensory motor training on bone morphogenic proteins and inflammatory biomarkers in post-traumatic osteoarthritis. Sci. Rep. 10, 15864 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hu, Y., Shen, Y., Chen, D. & Zhong, W. Effects of arthroscopic anterior cruciate ligament reconstruction combined with sodium hyaluronate on knee function and inflammatory markers in anterior cruciate ligament injury patients with or without knee osteoarthritis. Adv. Clin. Exp. Med. 32, 533–538 (2023).

    PubMed  Google Scholar 

  21. Nambi, G. et al. Effects of isokinetic knee muscle training on bone morphogenetic proteins and inflammatory biomarkers in post-traumatic osteoarthritis after anterior cruciate ligament injury: a randomized trial. J. Rehabil. Med. 52, jrm00098 (2020).

    PubMed  Google Scholar 

  22. Larsson, S., Struglics, A., Lohmander, L. S. & Frobell, R. Surgical reconstruction of ruptured anterior cruciate ligament prolongs trauma-induced increase of inflammatory cytokines in synovial fluid: an exploratory analysis in the KANON trial. Osteoarthritis Cartilage 25, 1443–1451 (2017).

    CAS  PubMed  Google Scholar 

  23. Kingery, M. T. et al. Changes in the synovial fluid cytokine profile of the knee between an acute anterior cruciate ligament injury and surgical reconstruction. Am. J. Sports Med. 50, 451–460 (2022).

    PubMed  Google Scholar 

  24. Elsaid, K. A. et al. Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury. Arthritis Rheum. 58, 1707–1715 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Sullivan, B. et al. Human synovial fluid interleukin-6, but not type II collagen breakdown, positively correlated with pain after anterior cruciate ligament injury and reconstruction. J. Orthop. Res. 41, 300–306 (2023).

    CAS  PubMed  Google Scholar 

  26. Heilmeier, U. et al. Infrapatellar fat pad abnormalities are associated with a higher inflammatory synovial fluid cytokine profile in young adults following ACL tear. Osteoarthritis Cartilage 28, 82–91 (2020).

    CAS  PubMed  Google Scholar 

  27. Struglics, A., Larsson, S., Kumahashi, N., Frobell, R. & Lohmander, L. S. Changes in cytokines and aggrecan ARGS neoepitope in synovial fluid and serum and in C-terminal crosslinking telopeptide of type II collagen and N-terminal crosslinking telopeptide of type I collagen in urine over five years after anterior cruciate ligament rupture: an exploratory analysis in the knee anterior cruciate ligament, nonsurgical versus surgical treatment trial. Arthritis Rheumatol. 67, 1816–1825 (2015).

    CAS  PubMed  Google Scholar 

  28. Jacobs, C. A. et al. The Inflamma-type: a patient phenotype characterized by a dysregulated inflammatory response after lower extremity articular fracture. Inflamm. Res. 72, 9–11 (2023).

    CAS  PubMed  Google Scholar 

  29. Watt, F. E. et al. Acute molecular changes in synovial fluid following human knee injury: association with early clinical outcomes. Arthritis Rheumatol. 68, 2129–2140 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Clair, A. J. et al. Alterations in synovial fluid biomarker levels in knees with meniscal injury as compared with asymptomatic contralateral knees. Am. J. Sports Med. 47, 847–856 (2019).

    PubMed  Google Scholar 

  31. Marchand, L. S., Rothberg, D. L., Higgins, T. F. & Haller, J. M. Greater acute articular inflammatory response in tibial plafond fractures as compared to ankle fractures. Foot Ankle Int. 43, 1465–1473 (2022).

    PubMed  Google Scholar 

  32. Liu, B. et al. Matrix metalloproteinase activity and prostaglandin E2 are elevated in the synovial fluid of meniscus tear patients. Connect. Tissue Res. 58, 305–316 (2017).

    CAS  PubMed  Google Scholar 

  33. Roemer, F. W. et al. Molecular and structural biomarkers of inflammation at two years after acute anterior cruciate ligament injury do not predict structural knee osteoarthritis at five years. Arthritis Rheumatol. 71, 238–243 (2019).

    CAS  PubMed  Google Scholar 

  34. Catterall, J. B., Stabler, T. V., Flannery, C. R. & Kraus, V. B. Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254). Arthritis Res. Ther. 12, R229 (2010).

    PubMed  PubMed Central  Google Scholar 

  35. Lattermann, C. et al. A multicenter study of early anti-inflammatory treatment in patients with acute anterior cruciate ligament tear. Am. J. Sports Med. 45, 325–333 (2017).

    PubMed  Google Scholar 

  36. Lohmander, L. S., Atley, L. M., Pietka, T. A. & Eyre, D. R. The release of crosslinked peptides from type II collagen into human synovial fluid is increased soon after joint injury and in osteoarthritis. Arthritis Rheum. 48, 3130–3139 (2003).

    CAS  PubMed  Google Scholar 

  37. Jacobs, C. A. et al. Increased effusion synovitis for those with a dysregulated inflammatory response after an anterior cruciate ligament injury. Cureus 15, e37862 (2023).

    PubMed  PubMed Central  Google Scholar 

  38. Tiderius, C. J., Olsson, L. E., Nyquist, F. & Dahlberg, L. Cartilage glycosaminoglycan loss in the acute phase after an anterior cruciate ligament injury: delayed gadolinium-enhanced magnetic resonance imaging of cartilage and synovial fluid analysis. Arthritis Rheum. 52, 120–127 (2005).

    CAS  PubMed  Google Scholar 

  39. Neuman, P., Dahlberg, L. E., Englund, M. & Struglics, A. Concentrations of synovial fluid biomarkers and the prediction of knee osteoarthritis 16 years after anterior cruciate ligament injury. Osteoarthritis Cartilage 25, 492–498 (2017).

    CAS  PubMed  Google Scholar 

  40. Neuman, P., Larsson, S., Lohmander, L. S. & Struglics, A. Higher aggrecan 1-F21 epitope concentration in synovial fluid early after anterior cruciate ligament injury is associated with worse knee cartilage quality assessed by gadolinium enhanced magnetic resonance imaging 20 years later. BMC Musculoskelet. Disord. 21, 798 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lohmander, L. S., Neame, P. J. & Sandy, J. D. The structure of aggrecan fragments in human synovial fluid. Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis. Arthritis Rheum. 36, 1214–1222 (1993).

    CAS  PubMed  Google Scholar 

  42. Kraus, V. B. et al. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthritis Cartilage 20, 271–278 (2012).

    CAS  PubMed  Google Scholar 

  43. Markus, D. H. et al. Concentration of synovial fluid biomarkers on the day of anterior cruciate ligament (ACL)-reconstruction predict size and depth of cartilage lesions on 5-year follow-up. Knee Surg. Sports Traumatol. Arthrosc. 31, 1753–1760 (2023).

    PubMed  Google Scholar 

  44. Svoboda, S. J. et al. Changes in serum biomarkers of cartilage turnover after anterior cruciate ligament injury. Am. J. Sports Med. 41, 2108–2116 (2013).

    PubMed  Google Scholar 

  45. Nishida, Y. et al. Serum cartilage oligomeric matrix protein detects early osteoarthritis in patients with anterior cruciate ligament deficiency. Arthroscopy 38, 873–878 (2022).

    PubMed  Google Scholar 

  46. Yoshida, H. et al. Relationship between pre-radiographic cartilage damage following anterior cruciate ligament injury and biomarkers of cartilage turnover in clinical practice: a cross-sectional observational study. Osteoarthritis Cartilage 21, 831–838 (2013).

    CAS  PubMed  Google Scholar 

  47. Hsueh, M.-F. et al. Association of matrix metallopeptidase 9 with neutrophil elastase in joint injury and osteoarthritis progression. Osteoarthritis Cartilage 29, S65–S66 (2021).

    Google Scholar 

  48. Rodriguez, K. M., Curran, M. T. & Palmieri-Smith, R. M. The influence of sex, body mass index, and age on cartilage metabolism biomarkers in patients after anterior cruciate ligament injury and reconstruction. J. Athl. Train. 57, 478–484 (2022).

    PubMed  Google Scholar 

  49. Carter, T. E. et al. In vivo cartilage strain increases following medial meniscal tear and correlates with synovial fluid matrix metalloproteinase activity. J. Biomech. 48, 1461–1468 (2015).

    PubMed  PubMed Central  Google Scholar 

  50. Ding, L. et al. Association of chemokine expression in anterior cruciate ligament deficient knee with patient characteristics: implications for post-traumatic osteoarthritis. Knee 27, 36–44 (2020).

    PubMed  Google Scholar 

  51. Keller, L. et al. Complement system dysregulation in synovial fluid from patients with persistent inflammation following anterior cruciate ligament reconstruction surgery. J Cartil. Jt. Preserv. 3, 100114 (2023).

    PubMed  PubMed Central  Google Scholar 

  52. Cui, Z. et al. Correlation between sialic acid levels in the synovial fluid and the radiographic severity of knee osteoarthritis. Exp. Ther. Med. 8, 255–259 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Sun, B. Y., Sun, Z. P., Pang, Z. C., Huang, W. T. & Wu, S. P. Decreased synovial fluid pituitary adenylate cyclase-activating polypeptide (PACAP) levels may reflect disease severity in post-traumatic knee osteoarthritis after anterior cruciate ligament injury. Peptides 116, 22–29 (2019).

    CAS  PubMed  Google Scholar 

  54. Palmieri-Smith, R. M., Wojtys, E. M. & Potter, H. G. Early cartilage changes after anterior cruciate ligament injury: evaluation with imaging and serum biomarkers-a pilot study. Arthroscopy 32, 1309–1318 (2016).

    PubMed  Google Scholar 

  55. Scuderi, G. J. et al. Identification of a novel fibronectin-aggrecan complex in the synovial fluid of knees with painful meniscal injury. J. Bone Jt. Surg. Am. 93, 336–340 (2011).

    Google Scholar 

  56. Lohmander, L., Saxne, T. & Heinegard, D. Increased concentrations of bone sialoprotein in joint fluid after knee injury. Ann. Rheum. Dis. 55, 622–626 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Jacobs, C. A. et al. Periostin regulation and cartilage degradation early after anterior cruciate ligament reconstruction. Inflamm. Res. 72, 387–394 (2023).

    CAS  PubMed  Google Scholar 

  58. Sobue, Y. et al. Prediction of progression of damage to articular cartilage 2 years after anterior cruciate ligament reconstruction: use of aggrecan and type II collagen biomarkers in a retrospective observational study. Arthritis Res. Ther. 19, 265 (2017).

    PubMed  PubMed Central  Google Scholar 

  59. Shimizu, T. et al. Predictors of cartilage degeneration in patients with subchondral insufficiency fracture of the femoral head: a retrospective study. Arthritis Res. Ther. 22, 150 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Evans-Pickett, A. et al. Synovial fluid concentrations of matrix Metalloproteinase-3 and Interluekin-6 following anterior cruciate ligament injury associate with gait biomechanics 6 months following reconstruction. Osteoarthritis Cartilage 29, 1006–1019 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Yang, J. H., Eun, S. P., Park, D. H., Kwak, H. B. & Chang, E. The effects of anterior cruciate ligament reconstruction on individual quadriceps muscle thickness and circulating biomarkers. Int. J. Environ. Res. Public Health 16, 4895 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Davis, H. C. et al. Time between anterior cruciate ligament injury and reconstruction and cartilage metabolism six-months following reconstruction. Knee 25, 296–305 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. Lisee, C. et al. Delayed cartilage oligomeric matrix protein response to loading is associated with femoral cartilage composition post-ACLR. Eur. J. Appl. Physiol. 123, 2525–2535 (2023).

    CAS  PubMed  Google Scholar 

  64. Huebner, K. D., Shrive, N. G. & Frank, C. B. New surgical model of post-traumatic osteoarthritis: isolated intra-articular bone injury in the rabbit. J. Orthop. Res. 31, 914–920 (2013).

    CAS  PubMed  Google Scholar 

  65. Bertuglia, A., Pagliara, E., Grego, E., Ricci, A. & Brkljaca-Bottegaro, N. Pro-inflammatory cytokines and structural biomarkers are effective to categorize osteoarthritis phenotype and progression in Standardbred racehorses over five years of racing career. BMC Vet. Res. 12, 246 (2016).

    PubMed  PubMed Central  Google Scholar 

  66. Brown, S. B. et al. Characterization of post-traumatic osteoarthritis in rats following anterior cruciate ligament rupture by non-invasive knee injury (NIKI). J. Orthop. Res. 38, 356–367 (2020).

    CAS  PubMed  Google Scholar 

  67. Kremen, T. J. Jr et al. A translational porcine model for human cell-based therapies in the treatment of posttraumatic osteoarthritis after anterior cruciate ligament injury. Am. J. Sports Med. 48, 3002–3012 (2020).

    PubMed  PubMed Central  Google Scholar 

  68. Liddle, D. M. et al. Integrated immunomodulatory mechanisms through which long-chain n-3 polyunsaturated fatty acids attenuate obese adipose tissue dysfunction. Nutrients 9, 1289 (2017).

    PubMed  PubMed Central  Google Scholar 

  69. Farimani, A. R. et al. The effect of n-3 PUFAs on circulating adiponectin and leptin in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol. 55, 641–652 (2018).

    CAS  PubMed  Google Scholar 

  70. Huang, C. W. et al. Role of n-3 polyunsaturated fatty acids in ameliorating the obesity-induced metabolic syndrome in animal models and humans. Int. J. Mol. Sci. 17, 1689 (2016).

    PubMed  PubMed Central  Google Scholar 

  71. Kimmerling, K. A. et al. Transgenic conversion of ω-6 to ω-3 polyunsaturated fatty acids via fat-1 reduces the severity of post-traumatic osteoarthritis. Arthritis Res. Ther. 22, 83 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Haslauer, C. M. et al. Loss of extracellular matrix from articular cartilage is mediated by the synovium and ligament after anterior cruciate ligament injury. Osteoarthritis Cartilage 21, 1950–1957 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Girling, S. L. et al. Use of biochemical markers of osteoarthritis to investigate the potential disease-modifying effect of tibial plateau levelling osteotomy. J. Small Anim. Pract. 47, 708–714 (2006).

    CAS  PubMed  Google Scholar 

  74. Noordwijk, K. J. et al. Metabolism and global protein glycosylation are differentially expressed in healthy and osteoarthritic equine carpal synovial fluid. Equine Vet. J. 54, 323–333 (2022).

    PubMed  Google Scholar 

  75. Peal, B. T. et al. Synovial fluid lubricin and hyaluronan are altered in equine osteochondral fragmentation, cartilage impact injury, and full-thickness cartilage defect models. J. Orthop. Res. 38, 1826–1835 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Elsaid, K. A., Machan, J. T., Waller, K., Fleming, B. C. & Jay, G. D. The impact of anterior cruciate ligament injury on lubricin metabolism and the effect of inhibiting tumor necrosis factor ɑ on chondroprotection in an animal model. Arthritis Rheum. 60, 2997–3006 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Coyle, C. H., Henry, S. E., Haleem, A. M., O’Malley, M. J. & Chu, C. R. Serum CTXii correlates with articular cartilage degeneration after anterior cruciate ligament transection or arthrotomy followed by standardized exercise. Sports Health 4, 510–517 (2012).

    PubMed  PubMed Central  Google Scholar 

  78. Wang, Y. et al. Synovial fluid lubricin increases in spontaneous canine cruciate ligament rupture. Sci. Rep. 10, 16725 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Desai, S. et al. Stable human cartilage progenitor cell line stimulates healing of meniscal tears and attenuates post-traumatic osteoarthritis. Front. Bioeng. Biotechnol. 10, 970235 (2022).

    PubMed  PubMed Central  Google Scholar 

  80. Thomas, N. P. et al. Attenuation of cartilage pathogenesis in post-traumatic osteoarthritis (PTOA) in mice by blocking the stromal derived factor 1 receptor (CXCR4) with the specific inhibitor, AMD3100. J. Orthop. Res. 33, 1071–1078 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Adepu, S. et al. Biglycan neo-epitope (BGN(262)), a novel biomarker for screening early changes in equine osteoarthritic subchondral bone. Osteoarthritis Cartilage 30, 1328–1336 (2022).

    CAS  PubMed  Google Scholar 

  82. Teeple, E. et al. Effects of supplemental intra-articular lubricin and hyaluronic acid on the progression of posttraumatic arthritis in the anterior cruciate ligament-deficient rat knee. Am. J. Sports Med. 39, 164–172 (2011).

    PubMed  Google Scholar 

  83. Goto, H. et al. Gene therapy for meniscal injury: enhanced synthesis of proteoglycan and collagen by meniscal cells transduced with a TGFβ1 gene. Osteoarthritis Cartilage 8, 266–271 (2000).

    CAS  PubMed  Google Scholar 

  84. Kitamura, H. et al. Increased concentrations of protein gene product 9.5 in the synovial fluid from horses with osteoarthritis. Jpn. J. Vet. Res. 49, 115–123 (2001).

    CAS  PubMed  Google Scholar 

  85. Maerz, T. et al. Metabolomic serum profiling after ACL injury in rats: a pilot study implicating inflammation and immune dysregulation in post-traumatic osteoarthritis. J. Orthop. Res. 36, 1969–1979 (2018).

    CAS  PubMed  Google Scholar 

  86. Seewald, L. A., Sabino, I. G., Montney, K. L. & Delco, M. L. Synovial fluid mitochondrial DNA concentration reflects the degree of cartilage damage after naturally occurring articular injury. Osteoarthritis Cartilage 31, 1056–1065 (2023).

    CAS  PubMed  Google Scholar 

  87. Kung, L. H. et al. Utility of circulating serum miRNAs as biomarkers of early cartilage degeneration in animal models of post-traumatic osteoarthritis and inflammatory arthritis. Osteoarthritis Cartilage 25, 426–434 (2017).

    CAS  PubMed  Google Scholar 

  88. Wang, B. & Liu, X. Long non-coding RNA KCNQ1OT1 promotes cell viability and migration as well as inhibiting degradation of CHON-001 cells by regulating miR-126-5p/TRPS1 axis. Adv. Rheumatol. 61, 31 (2021).

    PubMed  Google Scholar 

  89. Erhart-Hledik, J. C. et al. A relationship between mechanically-induced changes in serum cartilage oligomeric matrix protein (COMP) and changes in cartilage thickness after 5 years. Osteoarthritis Cartilage 20, 1309–1315 (2012).

    CAS  PubMed  Google Scholar 

  90. Roos, E. M. & Lohmander, L. S. The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis. Health Qual. Life Outcomes 1, 64 (2003).

    PubMed  PubMed Central  Google Scholar 

  91. Reed, A. et al. Surgery induces second cytokine storm in individuals who experience an anterior cruciate ligament tear. Osteoarthritis Cartilage 30, S100–S101 (2022).

    Google Scholar 

  92. Wilkinson, D. J. et al. Matrix metalloproteinase-13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, ɑ-1 antitrypsin: implications for osteoarthritis. FEBS J. 289, 121–139 (2022).

    CAS  PubMed  Google Scholar 

  93. Hsueh, M.-F., Zhang, X., Wellman, S. S., Bolognesi, M. P. & Kraus, V. B. Synergistic roles of macrophages and neutrophils in osteoarthritis progression. Arthritis Rheumatol. 73, 89–99 (2021).

    CAS  PubMed  Google Scholar 

  94. Little, C. B. & Hunter, D. J. Post-traumatic osteoarthritis: from mouse models to clinical trials. Nat. Rev. Rheumatol. 9, 485–497 (2013).

    CAS  PubMed  Google Scholar 

  95. Pedersen, M. et al. Four distinct 5-year trajectories of knee function emerge in patients who followed the Delaware-Oslo ACL cohort treatment algorithm. Am. J. Sports Med. 50, 2944–2952 (2022).

    PubMed  PubMed Central  Google Scholar 

  96. Hollis, B. et al. Lifetime risk and genetic predisposition to post-traumatic OA of the knee in the UK Biobank. Osteoarthritis Cartilage 31, 1377–1387 (2023).

    CAS  PubMed  Google Scholar 

  97. Evers, B. J. et al. Post-traumatic knee osteoarthritis; the role of inflammation and hemarthrosis on disease progression. Front. Med. 9, 973870 (2022).

    Google Scholar 

  98. Boehme, K. A. & Rolauffs, B. Onset and progression of human osteoarthritis-can growth factors, inflammatory cytokines, or differential miRNA expression concomitantly induce proliferation, ECM degradation, and inflammation in articular cartilage? Int. J. Mol. Sci. 19, 2282 (2018).

    PubMed  PubMed Central  Google Scholar 

  99. Lieberthal, J., Sambamurthy, N. & Scanzello, C. R. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage 23, 1825–1834 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Rai, M. F. et al. Heritability of articular cartilage regeneration and its association with ear wound healing in mice. Arthritis Rheum. 64, 2300–2310 (2012).

    PubMed  PubMed Central  Google Scholar 

  101. Rai, M. F. & Sandell, L. J. Regeneration of articular cartilage in healer and non-healer mice. Matrix Biol. 39, 50–55 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Chinzei, N. et al. Evidence for genetic contribution to variation in posttraumatic osteoarthritis in mice. Arthritis Rheumatol. 71, 370–381 (2019).

    PubMed  PubMed Central  Google Scholar 

  103. Rai, M. F., Schmidt, E. J., McAlinden, A., Cheverud, J. M. & Sandell, L. J. Molecular insight into the association between cartilage regeneration and ear wound healing in genetic mouse models: targeting new genes in regeneration. G3 3, 1881–1891 (2013).

    PubMed  PubMed Central  Google Scholar 

  104. Ward, B. D. et al. Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse. Arthritis Rheum. 58, 744–753 (2008).

    PubMed  Google Scholar 

  105. Lewis, J. S. Jr et al. Genetic and cellular evidence of decreased inflammation associated with reduced incidence of posttraumatic arthritis in MRL/MpJ mice. Arthritis Rheum. 65, 660–670 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Olson, S. A., Furman, B. D., Kraus, V. B., Huebner, J. L. & Guilak, F. Therapeutic opportunities to prevent post-traumatic arthritis: lessons from the natural history of arthritis after articular fracture. J. Orthop. Res. 33, 1266–1277 (2015).

    PubMed  PubMed Central  Google Scholar 

  107. Kimmerling, K. A. et al. Sustained intra-articular delivery of IL-1RA from a thermally-responsive elastin-like polypeptide as a therapy for post-traumatic arthritis. Eur. Cell Mater. 29, 124–139 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kandhwal, M. et al. Role of matrix metalloproteinase in wound healing. Am. J. Transl. Res. 14, 4391–4405 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lattermann, C. et al. Select biomarkers on the day of anterior cruciate ligament reconstruction predict poor patient-reported outcomes at 2-year follow-up: a pilot study. Biomed. Res. Int. 2018, 9387809 (2018).

    PubMed  PubMed Central  Google Scholar 

  110. Riyazi, N. et al. Association of the risk of osteoarthritis with high innate production of interleukin-1β and low innate production of interleukin-10 ex vivo, upon lipopolysaccharide stimulation. Arthritis Rheum. 52, 1443–1450 (2005).

    CAS  PubMed  Google Scholar 

  111. Goekoop, R. J. et al. Low innate production of interleukin-1β and interleukin-6 is associated with the absence of osteoarthritis in old age. Osteoarthritis Cartilage 18, 942–947 (2010).

    CAS  PubMed  Google Scholar 

  112. de Craen, A. J. et al. Heritability estimates of innate immunity: an extended twin study. Genes. Immun. 6, 167–170 (2005).

    PubMed  Google Scholar 

  113. Jurynec, M. J. et al. NOD/RIPK2 signalling pathway contributes to osteoarthritis susceptibility. Ann. Rheum. Dis. 81, 1465–1473 (2022).

    CAS  PubMed  Google Scholar 

  114. Mendez, M. E., Murugesh, D. K., Christiansen, B. A. & Loots, G. G. Antibiotic treatment prior to injury abrogates the detrimental effects of LPS in STR/ort mice susceptible to osteoarthritis development. JBMR Plus 7, e10759 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Mendez, M. E. et al. Antibiotic treatment prior to injury improves post-traumatic osteoarthritis outcomes in mice. Int. J. Mol. Sci. 21, 6424 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Stabler, T. V., Huang, Z., Montell, E., Verges, J. & Kraus, V. B. Chondroitin sulphate inhibits NF-κB activity induced by interaction of pathogenic and damage associated molecules. Osteoarthritis Cartilage 25, 166–174 (2017).

    CAS  PubMed  Google Scholar 

  117. Mehta, N. N. et al. A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial. J. Transl. Med. 10, 124 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Miller, M. A. et al. Ethnic and sex differences in circulating endotoxin levels: a novel marker of atherosclerotic and cardiovascular risk in a British multi-ethnic population. Atherosclerosis 203, 494–502 (2009).

    CAS  PubMed  Google Scholar 

  119. Wu, C. L. et al. Conditional macrophage depletion increases inflammation and does not inhibit the development of osteoarthritis in obese macrophage Fas-Induced Apoptosis-Transgenic Mice. Arthritis Rheumatol. 69, 1772–1783 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Cornelis, F. M. F. et al. Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice. Osteoarthritis Cartilage 27, 513–525 (2019).

    CAS  PubMed  Google Scholar 

  121. Little, C. B. & Zaki, S. What constitutes an “animal model of osteoarthritis” — the need for consensus? Osteoarthritis Cartilage 20, 261–267 (2012).

    CAS  PubMed  Google Scholar 

  122. Wei, L. et al. Comparison of differential biomarkers of osteoarthritis with and without posttraumatic injury in the Hartley guinea pig model. J. Orthop. Res. 28, 900–906 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Sutipornpalangkul, W., Morales, N. P., Charoencholvanich, K. & Harnroongroj, T. Lipid peroxidation, glutathione, vitamin E, and antioxidant enzymes in synovial fluid from patients with osteoarthritis. Int. J. Rheum. Dis. 12, 324–328 (2009).

    PubMed  Google Scholar 

  124. Jansen, N. W., Roosendaal, G., Bijlsma, J. W., Degroot, J. & Lafeber, F. P. Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: an in vitro study. Arthritis Rheum. 56, 199–207 (2007).

    PubMed  Google Scholar 

  125. Pulles, A. E. et al. The combination of urinary CTX-II and serum CS-846: promising biochemical markers to predict radiographic progression of haemophilic arthropathy — An exploratory study. Haemophilia 24, e278–e280 (2018).

    CAS  PubMed  Google Scholar 

  126. van Vulpen, L. F. D. et al. Biochemical markers of joint tissue damage increase shortly after a joint bleed; an explorative human and canine in vivo study. Osteoarthritis Cartilage 23, 63–69 (2015).

    PubMed  Google Scholar 

  127. Lombardi, M. & Cardenas, A. C. Hemarthrosis. In: StatPearls. (StatPearls Publishing LLC, Treasure Island, FL) NBK525999 (2023).

  128. Adams, S. B. et al. Inflammatory cytokines and matrix metalloproteinases in the synovial fluid after intra-articular ankle fracture. Foot Ankle Int. 36, 1264–1271 (2015).

    PubMed  Google Scholar 

  129. Adams, S. B. et al. Inflammatory microenvironment persists after bone healing in intra-articular ankle fractures. Foot Ankle Int. 38, 479–484 (2017).

    PubMed  Google Scholar 

  130. Vassilopoulou-Sellin, R., Oyedeji, C. O. & Samaan, N. A. Bilirubin inhibits cartilage metabolism and growth in vitro. Metabolism 38, 759–762 (1989).

    CAS  PubMed  Google Scholar 

  131. Kalakonda, A., Jenkins, B. A. & John, S. Physiology, Bilirubin. In: StatPearls. (StatPearls Publishing LLC, Treasure Island, FL) NBK470290 (2023).

  132. Bay-Jensen, A. C. et al. Which elements are involved in reversible and irreversible cartilage degradation in osteoarthritis? Rheumatol. Int. 30, 435–442 (2010).

    PubMed  Google Scholar 

  133. Ashruf, O. S. & Ansari, M. Y. Natural compounds: potential therapeutics for the inhibition of cartilage matrix degradation in osteoarthritis. Life 13, 102 (2022).

    PubMed  PubMed Central  Google Scholar 

  134. Lin, J. et al. Recent advances in small molecule inhibitors for the treatment of osteoarthritis. J. Clin. Med. 12, 1986 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Cahue, S. et al. The ratio of type II collagen breakdown to synthesis and its relationship with the progression of knee osteoarthritis. Osteoarthritis Cartilage 15, 819–823 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Kraus, V. B. et al. Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthritis Cartilage 19, 515–542 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Kraus, V. B. et al. Direct in vivo evidence of activated macrophages in human osteoarthritis. Osteoarthritis Cartilage 24, 1613–1621 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Jansen, N. W. et al. Interleukin-10 protects against blood-induced joint damage. Br. J. Haematol. 142, 953–961 (2008).

    CAS  PubMed  Google Scholar 

  139. van Meegeren, M. E. et al. IL-4 alone and in combination with IL-10 protects against blood-induced cartilage damage. Osteoarthritis Cartilage 20, 764–772 (2012).

    PubMed  Google Scholar 

  140. Chen, Y. et al. Pharmaceutical therapeutics for articular regeneration and restoration: state-of-the-art technology for screening small molecular drugs. Cell. Mol. Life Sci. 78, 8127–8155 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Black, R. M. et al. Proteomic analysis reveals dexamethasone rescues matrix breakdown but not anabolic dysregulation in a cartilage injury model. Osteoarthr. Cartil. Open. 2, 100099 (2020).

    PubMed  PubMed Central  Google Scholar 

  142. Black, R. M. et al. Proteomic clustering reveals the kinetics of disease biomarkers in bovine and human models of post-traumatic osteoarthritis. Osteoarthr. Cartil. Open 3, 100191 (2021).

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Duke Molecular Physiology Institute, Duke University, Durham, NC, USA

    Virginia Byers Kraus & Ming-Feng Hsueh

  2. Department of Medicine, Duke University School of Medicine, Durham, NC, USA

    Virginia Byers Kraus

  3. Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, USA

    Virginia Byers Kraus & Ming-Feng Hsueh

Authors
  1. Virginia Byers Kraus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming-Feng Hsueh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Virginia Byers Kraus.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Rheumatology thanks Changhai Ding, Simon Mastbergen and the other, anonymous, reviewer for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Global Health Data Exchange: https://vizhub.healthdata.org/gbd-results/

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kraus, V.B., Hsueh, MF. Molecular biomarker approaches to prevention of post-traumatic osteoarthritis. Nat Rev Rheumatol 20, 272–289 (2024). https://doi.org/10.1038/s41584-024-01102-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-024-01102-y

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing