Browsing by Author "Xie, Yixia"

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    Body Weight Influences Musculoskeletal Adaptation to Long-Term Voluntary Wheel Running During Aging
    (Oxford University Press, 2022-12-20) Kitase, Yukiko; Julian, Vallejo; Xie, Yixia; Dallas, Mark; Dallas, Sarah; Johnson, Mark; Wacker, Michael; Bonewald, Lynda; Anatomy, Cell Biology and Physiology, School of Medicine
    Frailty is a key hallmark of aging and exercise has been shown to delay aging effects. This study was initiated based on the hypothesis that voluntary wheel running (VWR) starting at 12 mo until 18 or 22 mo of age would benefit the female murine musculoskeletal system. Based on the final body weight, the mice were separated into high (HBW) and low body weight (LBW) subgroups. Beneficial effects of VWR were observed on soleus muscle mass and contractile force at both ages, although HBW led to greater increases at 22 mo. VWR increased fiber cross-sectional area by 20%, leading to more type I and fewer IIA fibers in soleus. HBW mice were resistant to age-related decline in Extensor digitorum longus (EDL) mass and contractile force. EDL in 18 mo HBW also showed 15% higher contractile force following VWR while muscle from 18 & 22 mo LBW responded to VWR with greater osteocyte protective factor secretion. Skeletal adaptation to VWR was also dependent on body weight, with HBW showing higher femoral cortical thickness and area under sedentary conditions. VWR maintained osteocyte dendrite number in HBW. VWR increased periosteal and endosteal circumferences in HBW, suggesting compensation for loss of material strength. Consistent with this, VWR maintained higher bone mechanical properties in 18mo LBW. In summary, VWR alters musculoskeletal parameters depending on body weight with HBW contributing to more muscle mass and strength to prevent sarcopenia while bone retains better mechanical properties in LBW but HBW contributes structural modification to prevent osteopenia.
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    Body weight influences musculoskeletal adaptation to long-term voluntary wheel running during aging in female mice
    (Impact Journals, 2022) Kitase, Yukiko; Vallejo, Julian A.; Dallas, Sarah L.; Xie, Yixia; Dallas, Mark; Tiede-Lewis, LeAnn; Moore, David; Meljanac, Anthony; Kumar, Corrine; Zhao, Carrie; Rosser, Jennifer; Brotto, Marco; Johnson, Mark L.; Liu, Ziyue; Wacker, Michael J.; Bonewald, Lynda; Anatomy, Cell Biology and Physiology, School of Medicine
    Frailty is the hallmark of aging that can be delayed with exercise. The present studies were initiated based on the hypothesis that long-term voluntary wheel running (VWR) in female mice from 12 to 18 or 22 months of age would have beneficial effects on the musculoskeletal system. Mice were separated into high (HBW) and low (LBW) body weight based on final body weights upon termination of experiments. Bone marrow fat was significantly higher in HBW than LBW under sedentary conditions, but not with VWR. HBW was more protective for soleus size and function than LBW under sedentary conditions, however VWR increased soleus size and function regardless of body weight. VWR plus HBW was more protective against muscle loss with aging. Similar effects of VWR plus HBW were observed with the extensor digitorum longus, EDL, however, LBW with VWR was beneficial in improving EDL fatigue resistance in 18 mo mice and was more beneficial with regards to muscle production of bone protective factors. VWR plus HBW maintained bone in aged animals. In summary, HBW had a more beneficial effect on muscle and bone with aging especially in combination with exercise. These effects were independent of bone marrow fat, suggesting that intrinsic musculoskeletal adaptions were responsible for these beneficial effects.
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    Degeneration of the osteocyte network in the C57BL/6 mouse model of aging
    (Impact Journals, 2017-10-26) Tiede-Lewis, LeAnn M.; Xie, Yixia; Hulbert, Molly A.; Campos, Richard; Dallas, Mark R.; Dusevich, Vladimir; Bonewald, Lynda F.; Dallas, Sarah L.; Anatomy and Cell Biology, School of Medicine
    Age-related bone loss and associated fracture risk are major problems in musculoskeletal health. Osteocytes have emerged as key regulators of bone mass and as a therapeutic target for preventing bone loss. As aging is associated with changes in the osteocyte lacunocanalicular system, we focused on the responsible cellular mechanisms in osteocytes. Bone phenotypic analysis was performed in young-(5mo) and aged-(22mo) C57BL/6 mice and changes in bone structure/geometry correlated with alterations in osteocyte parameters determined using novel multiplexed-3D-confocal imaging techniques. Age-related bone changes analogous to those in humans were observed, including increased cortical diameter, decreased cortical thickness, reduced trabecular BV/TV and cortical porosities. This was associated with a dramatic reduction in osteocyte dendrite number and cell density, particularly in females, where osteocyte dendricity decreased linearly from 5, 12, 18 to 22mo and correlated significantly with cortical bone parameters. Reduced dendricity preceded decreased osteocyte number, suggesting dendrite loss may trigger loss of viability. Age-related degeneration of osteocyte networks may impair bone anabolic responses to loading and gender differences in osteocyte cell body and lacunar fluid volumes we observed in aged mice may lead to gender-related differences in mechanosensitivity. Therapies to preserve osteocyte dendricity and viability may be beneficial for bone health in aging.
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    A Novel Osteogenic Cell Line that Differentiates into GFP‐Tagged Osteocytes and forms Mineral with a Bone‐like Lacunocanalicular Structure
    (Wiley, 2019) Wang, Kun; Le, Lisa; Chun, Brad M.; Tiede-Lewis, LeAnn M.; Shiflett, Lora A.; Prideaux, Matthew; Campos, Richard S.; Veno, Patricia A.; Xie, Yixia; Dusevich, Vladimir; Bonewald, Lynda F.; Dallas, Sarah L.; Anatomy and Cell Biology, IU School of Medicine
    Osteocytes, the most abundant cells in bone, were once thought to be inactive but are now known to have multifunctional roles in bone, including in mechanotransduction, regulation of osteoblast and osteoclast function and phosphate homeostasis. Because osteocytes are embedded in a mineralized matrix and are challenging to study, there is a need for new tools and cell models to understand their biology. We have generated two clonal osteogenic cell lines, OmGFP66 and OmGFP10, by immortalization of primary bone cells from mice expressing a membrane‐targeted GFP driven by the Dmp1‐promoter. One of these clones, OmGFP66, has unique properties compared to previous osteogenic and osteocyte cell models and forms 3‐dimensional mineralized bone‐like structures, containing highly dendritic GFP‐positive osteocytes, embedded in clearly defined lacunae. Confocal and electron microscopy showed that structurally and morphologically, these bone‐like structures resemble bone in vivo, even mimicking the lacunocanalicular ultrastructure and 3D spacing of in vivo osteocytes. In osteogenic conditions, OmGFP66 cells express alkaline phosphatase, produce a mineralized type‐I‐collagen matrix and constitutively express the early osteocyte marker, E11/gp38. With differentiation they express osteocyte markers, Dmp1, Phex, Mepe, Fgf23 and the mature osteocyte marker, Sost. They also express RankL, Opg and Hif1α, and show expected osteocyte responses to PTH, including downregulation of Sost, Dmp1 and Opg and upregulation of RankL and E11/gp38. Live‐cell imaging revealed the dynamic process by which OmGFP66 bone‐like structures form, the motile properties of embedding osteocytes and the integration of osteocyte differentiation with mineralization. The OmGFP10 clone showed an osteocyte gene expression profile similar to OmGFP66, but formed less organized bone nodule‐like mineral, similar to other osteogenic cell models. Not only do these cell lines provide useful new tools for mechanistic and dynamic studies of osteocyte differentiation, function and biomineralization, but OmGFP66 cells have the unique property of modeling osteocytes in their natural bone microenvironment.
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    Osteocyte RANKL Drives Bone Resorption in Mouse Ligature‐Induced Periodontitis
    (Oxford University Press, 2023) Kittaka, Mizuho; Yoshimoto, Tetsuya; Levitan, Marcus E.; Urata, Rina; Choi, Roy B.; Teno, Yayoi; Xie, Yixia; Kitase, Yukiko; Prideaux, Matthew; Dallas, Sarah L.; Robling, Alexander G.; Ueki, Yasuyoshi; Biomedical and Applied Sciences, School of Dentistry
    Mouse ligature-induced periodontitis (LIP) has been used to study bone loss in periodontitis. However, the role of osteocytes in LIP remains unclear. Furthermore, there is no consensus on the choice of alveolar bone parameters and time points to evaluate LIP. Here, we investigated the dynamics of changes in osteoclastogenesis and bone volume (BV) loss in LIP over 14 days. Time-course analysis revealed that osteoclast induction peaked on days 3 and 5, followed by the peak of BV loss on day 7. Notably, BV was restored by day 14. The bone formation phase after the bone resorption phase was suggested to be responsible for the recovery of bone loss. Electron microscopy identified bacteria in the osteocyte lacunar space beyond the periodontal ligament (PDL) tissue. We investigated how osteocytes affect bone resorption of LIP and found that mice lacking receptor activator of NF-κB ligand (RANKL), predominantly in osteocytes, protected against bone loss in LIP, whereas recombination activating 1 (RAG1)-deficient mice failed to resist it. These results indicate that T/B cells are dispensable for osteoclast induction in LIP and that RANKL from osteocytes and mature osteoblasts regulates bone resorption by LIP. Remarkably, mice lacking the myeloid differentiation primary response gene 88 (MYD88) did not show protection against LIP-induced bone loss. Instead, osteocytic cells expressed nucleotide-binding oligomerization domain containing 1 (NOD1), and primary osteocytes induced significantly higher Rankl than primary osteoblasts when stimulated with a NOD1 agonist. Taken together, LIP induced both bone resorption and bone formation in a stage-dependent manner, suggesting that the selection of time points is critical for quantifying bone loss in mouse LIP. Pathogenetically, the current study suggests that bacterial activation of osteocytes via NOD1 is involved in the mechanism of osteoclastogenesis in LIP. The NOD1-RANKL axis in osteocytes may be a therapeutic target for bone resorption in periodontitis.