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OBJECTIVE: Musculoskeletal diseases such as osteoarthritis (OA) are leading causes of pain, physical inactivity and disability worldwide. Synovial fibroblasts (SFs) expressing fibroblast activation protein (FAP) are crucial for OA progression. Positron emission tomography (PET) with (68)Gallium-labelled FAP-inhibitors ((68) Ga-FAPI) visualizes FAP-positive activated fibroblasts. Here, we systematically analyze FAPI-uptake respecting OA and joint degeneration in a cohort of 268 patients. METHODS: (68) Ga-FAPI-PET-scans of 268 oncological patients were analyzed for increased joint-associated FAPI-uptake, quantified by maximal, mean standardized uptake values (SUVmax/mean) and target to blood ratios (TBR) and compared with computed tomography-based OA-classification according to Kellgren and Lawrence. FAP-expression of SF from OA and rheumatoid arthritis (RA) (15 OA- and 26 RA-patients) were analyzed by single-cell cytometry by time of flight (cyTOF). RESULTS: 148 of 268 patients (55.2%) showed increased joint-associated FAPI-uptake (average SUVmax/mean of 3.25 ± 1.28/ 1.94 ± 0.70). The most frequent FAPI-positive joints were acromioclavicular and shoulder joints followed by sternoclavicular, lumbar facet and hip joints. FAPI-uptake was frequently asymmetric whereas OA-scoring displayed a symmetric allocation of degenerative changes suggesting discordance between FAPI-uptake and OA-scoring. Only in end-stage-OA (grade 4 according to Kellgren and Lawrence) FAPI-uptake was concordantly and significantly elevated. Abundant FAP-positive fibroblasts in end-stage-OA were confirmed by CyTOF. CONCLUSION: FAPI-uptake in joints is frequent and can occur in presence as well as in absence of joint degeneration. We suggest that FAPI-PET/CT complements conventional musculoskeletal imaging by providing information on synovial activity, the exact triggers of which remain to be elucidated.
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