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[18F]Sodium fluoride PET-MRI detects increased metabolic bone response to whole-joint loading stress in osteoarthritic knees

Watkins, L E; Haddock, B; MacKay, J W; Baker, J; Uhlrich, S D; Mazzoli, V; Gold, G E; Kogan, F
OBJECTIVE:F]NaF PET-MRI was used to study the acute joint response to exercise in OA knees, and compare relationships between regions of increased uptake after loading and structural OA progression two years later. METHODS:> 3) were identified and the presence of structural MRI features was noted. Five participants returned two years later to assess structural change on MRI. RESULTS:P < 0.001) that differed by bone region. CONCLUSION:There were regional differences in the acute bone metabolic response to exercise and areas of focally large changes in the metabolic bone response that might be representative of whole-joint dysfunction.
PMCID:9922526
PMID: 36031138
ISSN: 1522-9653
CID: 5579272

Assessment of quantitative [18F]Sodium fluoride PET measures of knee subchondral bone perfusion and mineralization in osteoarthritic and healthy subjects

Watkins, L; MacKay, J; Haddock, B; Mazzoli, V; Uhlrich, S; Gold, G; Kogan, F
OBJECTIVE:F]NaF uptake in subchondral bone of individuals with and without knee osteoarthritis (OA). METHODS:) were evaluated using the Hawkins 3-compartment model. Measures were compared between structurally normal-appearing bone regions and those with structural findings. RESULTS:, and extraction fraction were significantly different between Healthy subjects and subjects with OA. Between-group differences in metabolic parameters were observed both in regions where the OA group had degenerative changes as well as in regions that appeared structurally normal. CONCLUSIONS:F]NaF PET imaging can complement assessments of structural abnormalities observed on MRI.
PMCID:8159876
PMID: 33639259
ISSN: 1522-9653
CID: 5579182

Small molecule inhibitors of protein interaction with glycosaminoglycans (SMIGs), a novel class of bioactive agents with anti-inflammatory properties

Harris, Nicholas; Kogan, Faina Yurgenzon; Il'kova, Gabriela; Juhas, Stefan; Lahmy, Orly; Gregor, Yevgeniya I; Koppel, Juraj; Zhuk, Regina; Gregor, Paul
BACKGROUND: Small molecule inhibitors of biologically important protein-glycosaminoglycan (GAG) interactions have yet to be identified. METHODS: Compound libraries were screened in an assay of L-selectin-IgG binding to heparin (a species of heparan sulfate [HS-GAG]). Hits were validated, IC-50s established and direct binding of hits to HS-GAGs was investigated by incubating compounds alone with heparin. Selectivity of inhibitors was assessed in 11 different protein-GAG binding assays. Anti-inflammatory activity of selected compounds was evaluated in animal models. RESULTS: Screening identified a number of structurally-diverse planar aromatic cationic amines. Scaffolds similar to known GAG binders, chloroquine and tilorone, were also identified. Inhibitors displayed activity also against bovine kidney heparan sulfate. Direct binding of compounds to GAGs was verified by incubating compounds with heparin alone. Selectivity of inhibitors was demonstrated in a panel of 11 heparin binding proteins, including selectins, chemokines (IL-8, IP-10), Beta Amyloid and cytokines (VEGF, IL-6). A number of selected lead compounds showed dose-dependent efficacy in peritonitis, paw edema and delayed type hypersensitivity. CONCLUSIONS: A new class of compounds, SMIGs, inhibits protein-GAG interaction by direct binding to GAGs. Although their IC-50s were in the low micro-molar range, SMIGs binding to HS-GAGs appeared to be stable in physiological conditions, indicating high avidity binding. SMIGs may interfere with major checkpoints for inflammatory and autoimmune events. GENERAL SIGNIFICANCE: SMIGs are a class of structurally-diverse planar aromatic cationic amines that have an unusual mode of action - inhibiting protein-GAG interactions via direct and stable binding to GAGs. SMIGs may have therapeutic potential in inflammatory and autoimmune disorders.
PMID: 24060749
ISSN: 0006-3002
CID: 723612