Browsing by Author "John, Sutha K."

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    Single-Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model
    (Wiley Blackwell (John Wiley & Sons), 2015-07) Wright, Laura E.; Buijs, Jeroen T.; Kim, Hun-Soo; Coats, Laura E.; Scheidler, Anne M.; John, Sutha K.; She, Yun; Murthy, Sreemala; Ma, Ning; Chin-Sinex, Helen J.; Bellido, Teresita M.; Bateman, Ted A.; Mendonca, Marc S.; Mohammad, Khalid S.; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Increased fracture risk is commonly reported in cancer patients receiving radiotherapy, particularly at sites within the field of treatment. The direct and systemic effects of ionizing radiation on bone at a therapeutic dose are not well-characterized in clinically relevant animal models. Using 20-week-old male C57Bl/6 mice, effects of irradiation (right hindlimb; 2 Gy) on bone volume and microarchitecture were evaluated prospectively by microcomputed tomography and histomorphometry and compared to contralateral-shielded bone (left hindlimb) and non-irradiated control bone. One week postirradiation, trabecular bone volume declined in irradiated tibias (-22%; p < 0.0001) and femurs (-14%; p = 0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibias (-17%; p = 0.003), and no loss was detected at the femur. Osteoclast number, apoptotic osteocyte number, and marrow adiposity were increased in irradiated bone relative to contralateral and non-irradiated bone, whereas osteoblast number was unchanged. Despite no change in osteoblast number 1 week postirradiation, dynamic bone formation indices revealed a reduction in mineralized bone surface and a concomitant increase in unmineralized osteoid surface area in irradiated bone relative to contralateral and non-irradiated control bone. Further, dose-dependent and time-dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast-like MC3T3 cells were relatively radioresistant, whereas calvarial osteocyte and osteocyte-like MLO-Y4 cell apoptosis was induced as early as 48 hours postirradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation, and coculture of irradiated RAW264.7 cells with MLO-Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multifaceted nature of radiation-induced bone loss by demonstrating direct and systemic effects on bone and its many cell types using clinically relevant doses; they have important implications for bone health in patients treated with radiation therapy.
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    The effect of Abi3 locus deletion on the progression of Alzheimer's disease-related pathologies
    (Frontiers Media, 2023-02-21) Karahan, Hande; Smith, Daniel C.; Kim, Byungwook; McCord, Brianne; Mantor, Jordan; John, Sutha K.; Al-Amin, Md Mamun; Dabin, Luke C.; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
    Human genetics studies of Alzheimer’s disease (AD) have identified the ABI3 gene as a candidate risk gene for AD. Because ABI3 is highly expressed in microglia, the brain’s immune cells, it was suggested that ABI3 might impact AD pathogenesis by regulating the immune response. Recent studies suggest that microglia have multifaceted roles in AD. Their immune response and phagocytosis functions can have beneficial effects in the early stages of AD by clearing up amyloid-beta (Aβ) plaques. However, they can be harmful at later stages due to their continuous inflammatory response. Therefore, it is important to understand the role of genes in microglia functions and their impact on AD pathologies along the progression of the disease. To determine the role of ABI3 at the early stage of amyloid pathology, we crossed Abi3 knock-out mice with the 5XFAD Aβ-amyloidosis mouse model and aged them until 4.5-month-old. Here, we demonstrate that deletion of the Abi3 locus increased Aβ plaque deposition, while there was no significant change in microgliosis and astrogliosis. Transcriptomic analysis indicates alterations in the expression of immune genes, such as Tyrobp, Fcer1g, and C1qa. In addition to the transcriptomic changes, we found elevated cytokine protein levels in Abi3 knock-out mouse brains, strengthening the role of ABI3 in neuroinflammation. These findings suggest that loss of ABI3 function may exacerbate AD progression by increasing Aβ accumulation and inflammation starting from earlier stages of the pathology.