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Decay-Accelerating Factor Differentially Associates With Complement-Mediated Damage in Synovium After Meniscus Tear as Compared to Anterior Cruciate Ligament Injury

  • V. Michael Holers (Division of Rheumatology, School of Medicine, University of Colorado, Anschutz Medical Campus) ;
  • Rachel M. Frank (Department of Orthopedics and the Colorado Program for Musculoskeletal Research, School of Medicine, University of Colorado, Anschutz Medical Campus) ;
  • Michael Zuscik (Department of Orthopedics and the Colorado Program for Musculoskeletal Research, School of Medicine, University of Colorado, Anschutz Medical Campus) ;
  • Carson Keeter (Department of Orthopedics and the Colorado Program for Musculoskeletal Research, School of Medicine, University of Colorado, Anschutz Medical Campus) ;
  • Robert I. Scheinman (Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus) ;
  • Christopher Striebich (Division of Rheumatology, School of Medicine, University of Colorado, Anschutz Medical Campus) ;
  • Dmitri Simberg (Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus) ;
  • Michael R. Clay (Department of Pathology, School of Medicine, University of Colorado, Anschutz Medical Campus) ;
  • Larry W. Moreland (Division of Rheumatology, School of Medicine, University of Colorado, Anschutz Medical Campus) ;
  • Nirmal K. Banda (Division of Rheumatology, School of Medicine, University of Colorado, Anschutz Medical Campus)
  • Received : 2023.12.11
  • Accepted : 2024.04.08
  • Published : 2024.04.30
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Abstract

We have reported that anterior cruciate ligament (ACL) injury leads to the differential dysregulation of the complement system in the synovium as compared to meniscus tear (MT) and proposed this as a mechanism for a greater post-injury prevalence of post traumatic osteoarthritis (PTOA). To explore additional roles of complement proteins and regulators, we determined the presence of decay-accelerating factor (DAF), C5b, and membrane attack complexes (MACs, C5b-9) in discarded surgical synovial tissue (DSST) collected during arthroscopic ACL reconstructive surgery, MT-related meniscectomy, osteoarthritis (OA)-related knee replacement surgery and normal controls. Multiplexed immunohistochemistry was used to detect and quantify complement proteins. To explore the involvement of body mass index (BMI), after these 2 injuries, we examined correlations among DAF, C5b, MAC and BMI. Using these approaches, we found that synovial cells after ACL injury expressed a significantly lower level of DAF as compared to MT (p<0.049). In contrast, C5b staining synovial cells were significantly higher after ACL injury (p<0.0009) and in OA DSST (p<0.039) compared to MT. Interestingly, there were significantly positive correlations between DAF & C5b (r=0.75, p<0.018) and DAF & C5b (r=0.64 p<0.022) after ACL injury and MT, respectively. The data support that DAF, which should normally dampen C5b deposition due to its regulatory activities on C3/C5 convertases, does not appear to exhibit that function in inflamed synovia following either ACL injury or MT. Ineffective DAF regulation may be an additional mechanism by which relatively uncontrolled complement activation damages tissue in these injury states.

Keywords

Acknowledgement

Authors are thankful to Mr. Andrew Clauw who was involved in routine tissue collection, processing, and preservation of DSST from ACL injury and MT. All authors are also thankful to Ms. Jennifer Seifert who catalogued ACL and MT related DSST samples and kept the patients record securely using RedCap. We are also thankful to Ms. Terrin Manes for providing histology sections from ACL and MT DSST for synovial membrane DAF, macrophage and fibroblast MIHC studies. Thanks to Ms. Elizabeth Smith in the AMC Histopathology Clinical core for helping to standardize DAF and immune cell-related antibodies along with their antigen retrieval procedures. We are also thankful to Dr. Kimberley Jordan, and Mr. Troy Schedin from the University of Colorado Human Immune Monitoring Shared Resource (HIMSR) group for MIHC related work and specifically for generating composite images and helping in analysis. Supported by the National Institutes of Health grant R01 AR51749 to VMH (PI) and NKB (Co-I) and by the Institutional Joint Biology Program pilot grant to NKB (PI) and RMF (Co-I).

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