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Osteoarthritis Cartilage. 2016 Sep;24(9):1613-21. doi: 10.1016/j.joca.2016.04.010. Epub 2016 Apr 12.

Direct in vivo evidence of activated macrophages in human osteoarthritis.

Author information

Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA; Department of Medicine, Duke University School of Medicine, Durham, NC, USA. Electronic address:
Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
Division of Nuclear Medicine, Department of Radiology, Duke University School of Medicine, Durham, NC, USA.
Department of Radiology, The Medical Physics Program and Nuclear Medicine, Duke University School of Medicine, Durham, NC, USA.
Department of Chemistry, Purdue University, West Lafayette, IN, USA.
Eli Lilly and Company, Indianapolis, IN, USA.



Through binding to folate receptor-β (FR-β), the new (99m)Tc-EC20 (Etarfolatide) imaging technique detects activated but not resting macrophages in vivo. The goal of this study was to investigate macrophage-related inflammation in osteoarthritis (OA).


Twenty-five individuals (50 knees) with symptomatic OA of at least one knee underwent SPECT-CT imaging of both knees and planar imaging of the whole body after injection of Etarfolatide. Scans and knee radiographs were scored blinded to clinical information including knee and other joint site pain severity. Measures of association controlled for age, gender, body mass index (BMI) and employed repeated measures to adjust for correlation between knees.


Activated macrophages were present in the majority (76%) of knees. The quantity of knee-related macrophages was significantly associated with knee pain severity (R = 0.60, P < 0.0001) and radiographic knee OA severity including joint space narrowing (R = 0.68, P = 0.007), and osteophyte (R = 0.66, P = 0.001). Macrophages were also localized to joints commonly affected by OA including hand finger joints (12%), thumb bases (28%), shoulders (26%), great toes (18%) and ankles (12%). The presence of joint pain at fingers, wrists, ankles and great toes was significantly positively associated with presence of activated macrophages at these sites (P < 0.0001-0.04).


This study provides the first direct in vivo evidence for macrophage involvement in OA in a substantial proportion of human knees. The association of quantity of activated macrophages with radiographic knee OA severity and joint symptoms suggests that drugs targeting macrophages and macrophage-associated inflammatory pathways may have the potential to be both symptom and structure modifying.



Inflammation; Joint pain; Knee; Macrophage; Osteoarthritis

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

All authors met all criteria for authorship in the ICMJE Recommendations. Virginia B Kraus designed the study and supervised all aspects of the study conduct, interpretation and reporting. Gary McDaniel, PAC served as the study coordinator under the supervision of Dr. Kraus for all aspects of the study. Janet L Huebner assisted with study logistics and performed, sample handling and study monitoring. Thomas Stabler coordinated and performed all sample management. Carl F Pieper provided statistical support for the project. Steven Shipes served as the study coordinator for all radiological procedures and performed all the Etarfolatide imaging studies. Neil A. Petry actively participated in the imaging protocol design, IND preparation, study management and manuscript preparation and review process. He was also responsible for the procurement, compounding, quality control and dispensing of 99mTc–Etarfolatide imaging agent administration to subjects enrolled in this study. Philip S Low assisted with study design and interpretation. Dr. Low is the inventor of EC20 (Etarfolatide). Jiayin Shen performed the immunohistochemical staining for the synovial fluid samples and was an employee of Endocyte. Peter Mitchell, contributor to the study concept and design, and Terry A McNearney, contributor to the study design and logistics, are employees of Eli Lilly and Co.

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