A Ruiz1, A Duarte2, D Bravo3, E Ramos Gavilá4, C Zhang5, M K Cowman6, T Kirsch7, M Milne8, L G Luyt9, J G Raya10. 1. Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA; Tech4Health Institute, New York University Langone Health, New York, NY, USA. Electronic address: amparo.ruiz@nyumc.org. 2. Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA; Musculoskeletal Section, Diagnostic Imaging Departament, Hospital Universitario de la Fundación Santa Fe de Bogota, Bogota, Colombia. Electronic address: aleja125@hotmail.com. 3. Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA. Electronic address: dbravo@gmail.com. 4. Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA; Departmento de Radiología, Hospital Universitario San Juan de Alicante, Alicante, Spain. Electronic address: elisaramosgavila@gmail.com. 5. Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA; Tech4Health Institute, New York University Langone Health, New York, NY, USA. Electronic address: chongda.zhang@nyulangone.org. 6. Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA; Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY, USA. Electronic address: mary.cowman@nyu.edu. 7. Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, USA; Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, NY, USA. Electronic address: thorsten.kirsch@nyulangone.org. 8. The University of Western Ontario, London, ON, Canada; London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada. Electronic address: mark.milne@gmail.com. 9. The University of Western Ontario, London, ON, Canada; London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada. Electronic address: lluyt@uwo.ca. 10. Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA; Tech4Health Institute, New York University Langone Health, New York, NY, USA. Electronic address: jose.raya@nyulangone.org.
Abstract
OBJECTIVE: One driving factor in the progression to posttraumatic osteoarthritis (PTOA) is the perpetuation of the inflammatory response to injury into chronic inflammation. Molecular imaging offers many opportunities to complement the sensitivity of current imaging modalities with molecular specificity. The goal of this study was to develop and characterize agents to image hyaluronan (HA)-mediated inflammatory signaling. DESIGN: We developed optical (Cy5.5-P15-1) and magnetic resonance contrast agents (Gd-DOTA-P15-1) based in a hyaluronan-binding peptide (P15-1) that has shown anti-inflammatory effects on human chondrocytes, and validated them in vitro and in vivo in two animal models of PTOA. RESULTS: In vitro studies with a near infrared (NIR) Cy5.5-P15-1 imaging agent showed a fast and stable localization of Cy5.5-P15-1 on chondrocytes, but not in synovial cells. In vivo NIR showed significantly higher retention of imaging agent in PTOA knees between 12 and 72 h (n = 8, Cohen's d > 2 after 24 h). NIR fluorescence accumulation correlated with histologic severity in cartilage and meniscus (ρ between 0.37 and 0.57, P < 0.001). By using in vivo magnetic resonance imaging with a Gd-DOTA-P15-1 contrast agent in 12 rats, we detected a significant decrease of T1 on injured knees in all cartilage plates at 48 h (-15%, 95%-confidence interval (CI) = [-18%,-11%]) while no change was observed in the controls (-2%, 95%-CI = [-5%,+1%]). CONCLUSIONS: This study provides the first in vivo evidence that hyaluronan-related inflammatory response in cartilage after injury is a common finding. Beyond P15-1, we have demonstrated that molecular imaging can provide a versatile technology to investigate and phenotype PTOA pathogenesis, as well as study therapeutic interventions.
OBJECTIVE: One driving factor in the progression to posttraumatic osteoarthritis (PTOA) is the perpetuation of the inflammatory response to injury into chronic inflammation. Molecular imaging offers many opportunities to complement the sensitivity of current imaging modalities with molecular specificity. The goal of this study was to develop and characterize agents to image hyaluronan (HA)-mediated inflammatory signaling. DESIGN: We developed optical (Cy5.5-P15-1) and magnetic resonance contrast agents (Gd-DOTA-P15-1) based in a hyaluronan-binding peptide (P15-1) that has shown anti-inflammatory effects on human chondrocytes, and validated them in vitro and in vivo in two animal models of PTOA. RESULTS: In vitro studies with a near infrared (NIR) Cy5.5-P15-1 imaging agent showed a fast and stable localization of Cy5.5-P15-1 on chondrocytes, but not in synovial cells. In vivo NIR showed significantly higher retention of imaging agent in PTOA knees between 12 and 72 h (n = 8, Cohen's d > 2 after 24 h). NIR fluorescence accumulation correlated with histologic severity in cartilage and meniscus (ρ between 0.37 and 0.57, P < 0.001). By using in vivo magnetic resonance imaging with a Gd-DOTA-P15-1 contrast agent in 12 rats, we detected a significant decrease of T1 on injured knees in all cartilage plates at 48 h (-15%, 95%-confidence interval (CI) = [-18%,-11%]) while no change was observed in the controls (-2%, 95%-CI = [-5%,+1%]). CONCLUSIONS: This study provides the first in vivo evidence that hyaluronan-related inflammatory response in cartilage after injury is a common finding. Beyond P15-1, we have demonstrated that molecular imaging can provide a versatile technology to investigate and phenotype PTOA pathogenesis, as well as study therapeutic interventions.
Authors: R B Frobell; H P Roos; E M Roos; M-P Hellio Le Graverand; R Buck; J Tamez-Pena; S Totterman; T Boegard; L S Lohmander Journal: Osteoarthritis Cartilage Date: 2008-02-21 Impact factor: 6.576
Authors: Cornelia Tolg; Sara R Hamilton; Ewa Zalinska; Lori McCulloch; Ripal Amin; Natalia Akentieva; Francoise Winnik; Rashmin Savani; Darius J Bagli; Len G Luyt; Mary K Cowman; Jim B McCarthy; Eva A Turley Journal: Am J Pathol Date: 2012-08-11 Impact factor: 4.307