Abnormal subchondral bone remodeling featured by overactivated osteoclastogenesis leads to articular cartilage degeneration and osteoarthritis (OA) progression, but the mechanism is unclear. We used lymphocyte cytosolic protein 1 ( Lcp1 ) knockout mice to suppress subchondral osteoclasts in a mice OA model with anterior cruciate ligament transection (ACLT), and Lcp1 −/− mice showed decreased bone remodeling in subchondral bone and retarded cartilage degeneration. For mechanisms, the activated osteoclasts in subchondral bone induced type-H vessels and elevated oxygen concentration, which ubiquitylated hypoxia-inducible factor 1 alpha subunit (HIF-1α) in chondrocytes and led to cartilage degeneration. Lcp1 knockout impeded angiogenesis, which maintained hypoxia environment in joints and delayed the OA progression. Stabilization of HIF-1α delayed cartilage degeneration, and knockdown of Hif1a abolished the protective effects of Lcp1 knockout. Last, we showed that Oroxylin A, an Lcp1- encoded protein l -plastin (LPL) inhibitor, could alleviate OA progression. In conclusion, maintaining hypoxic environment is an attractive strategy for OA treatment.

BackgroundConventional short‐axis PET typically utilizes multi‐bed multi‐pass acquisition to produce quantitative whole‐body dynamic images and cannot record all the uptake information simultaneously, resulting in errors when fitting the time‐activity curves (TACs) and calculating radiation doses.PurposeThe aim of this study is to evaluate the 13N‐ammonia biodistribution and the internal radiation doses using a 194 cm long total‐body PET/CT scanner (uEXPLORER), and make a comparison with the previous short‐axis PET results.MethodsTen subjects (age 40–74 years) received 13N‐NH3 injection (418.1‐670.81 MBq) and were under a dynamic scan for about 60 min with using a 3‐dimensional whole‐body protocol. ROIs were drawn visually on 11 major organs (brain, thyroid, gallbladder, heart wall, kidneys, liver, pancreas, spleen, lungs, bone marrow, and urinary bladder content) for each subject. TACs were generated using Pmod and the absorbed radiation doses were calculated using Olinda 2.2. To compare with the conventional PET/CT, five points were sampled on uEXPLORER's TACs to mimic the result of a short‐axis PET/CT (15 cm axial FOV, consisted of 9 or 10 bed positions). Then the TACs were obtained using the multi‐exponential fitting method, and the residence time and radiation dose were also calculated and compared with uEXPLORER.ResultsThe highest absorbed organ doses were the pancreas, thyroid, spleen, heart wall, and kidneys for the male. For the female, the first five highest absorbed organ dose coefficients were the pancreas, heart wall, spleen, lungs, and kidneys. The lowest absorbed dose was found in red marrow both for male and female. The simulated short‐axis PET can fit TACs well for the gradually‐changed uptake organs but typically underestimated for the rapid‐uptake organs during the first‐10 min, resulting in errors in the calculated radiation dose.ConclusionuEXPLORER PET/CT can measure 13N‐ammonia's TACs simultaneously in all organs of the whole body, which can provide more accurate biodistribution and radiation dose estimation compared with the conventional short‐axis scanners.

Background: 68Ga-labelled fibroblast activation protein inhibitors, such as [68Ga]Ga-DOTA-FAPI-04 and [68Ga]Ga-DOTA-FAPI-46, have been successfully applied in positron emission tomography imaging of various tumour types. To broaden the spectrum of applicable PET tracers for extended imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of two 11C-labelled FAP inhibitors, 11C-FAPI-01 and 11C-FAPI-02. Results: 11C-FAPI-01 and 11C-FAPI-02 were synthesized in over 15% radiochemical yields, with specific activities of 67 GBq/µmol and 34 GBq/µmol, respectively, at the end of synthesis and radiochemical purities greater than 99%. In U87MG tumour xenograft PET studies, the three tracers experienced higher specific uptake at the tumour site. However, because of significant differences in metabolism and clearance, [68Ga]Ga-DOTA-FAPI-04 experienced high uptake in the kidney, whereas 11C-FAPI-01 and 11C-FAPI-02 showed high uptake in the liver and intestine. Biodistribution studies revealed significant hepatobiliary excretion of 11C-FAPI-01 and 11C-FAPI-02. 11C-FAPI-02 showed higher specific tumour uptake in U87MG xenografts (1.71 ± 0.08% injected dose per gram of tissue [ID/g]) than 11C-FAPI-01 (1.34 ± 0.10%ID/g) and [68Ga]Ga-DOTA-FAPI-04 (1.29 ± 0.04%ID/g) after 30 min p.i. In orthotopic glioma models, the uptake values were 0.07 ± 0.03% ([68Ga]Ga-DOTA-FAPI-04) and 0.16 ± 0.03% (11C-FAPI-02), respectively. Conclusion: 11C-FAPI-01 and 11C-FAPI-02 are interesting candidates for translation to the clinic, taking advantage of the shorter half-life and physical imaging properties of C-11. The availability of 11C-FAPI-01 and 11C-FAPI-02 may allow extended PET studies of FAP-related diseases, such as cancer, arthritis, heart diseases, or pulmonary fibrosis.