Browsing by Author "Li, Jie"
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Item Effects of knee loading on obesity‐related nonalcoholic fatty liver disease in an ovariectomized mouse model with high fat diet(Wiley, 2018) Tan, Nian; Li, Xinle; Zhai, Lidong; Liu, Daquan; Li, Jie; Yokota, Hiroki; Zhang, Ping; Anatomy and Cell Biology, School of MedicineAim Hormonal and nutritional disorders are the main causes of obesity and nonalcoholic fatty liver disease, especially in the elderly and postmenopausal women. Although physical activity may alleviate these disorders, the elderly may often have difficulty in conducting physical exercise. The purpose of this study was to investigate the therapeutic effect of knee loading, a new form of physical stimulation, on the symptom of obesity and fatty liver. Methods Using ovariectomized mice with high fat diet, we evaluated the effect of knee loading that applies gentle cyclic loads to the knee. Female C57BL/6 mice were divided into five groups: control (SCD), high fat diet (HF), HF with loading (HF+L), HF with ovariectomy (HF+OVX), and HF+OVX with loading (HF+OVX+L). Except for SCD, mice underwent sham operation or ovariectomy and maintained on high fat diet. After 6 weeks, the mice in HF+L and HF+OVX+L were treated with 6‐week knee loading. Results Compared to the obesity groups (HF and HF+OVX), knee loading significantly decreased a gain in body weight, liver weight, and white adipose tissue (all P<0.01). It also reduced the lipid level in the serum (P<0.01) and histological severity of hepatic steatosis (P<0.01). Furthermore, knee loading downregulated biomarkers related to the endoplasmic reticulum stress (GRP78, p‐eIF2α and ATF4) and altered biomarkers in autophagy (LC3 and p62). Conclusions Knee loading suppressed obesity‐associated metabolic alterations and hepatic steatosis, the effect with knee loading might be associated with suppression of the ER stress and promotion of autophagy.Item eIF2α signaling regulates autophagy of osteoblasts and the development of osteoclasts in OVX mice(Springer Nature, 2019-12-09) Li, Jie; Li, Xinle; Liu, Daquan; Hamamura, Kazunori; Wan, Qiaoqiao; Na, Sungsoo; Yokota, Hiroki; Zhang, Ping; Biomedical Engineering, School of Engineering and TechnologyBone loss in postmenopausal osteoporosis is induced chiefly by an imbalance of bone-forming osteoblasts and bone-resorbing osteoclasts. Salubrinal is a synthetic compound that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Phosphorylation of eIF2α alleviates endoplasmic reticulum (ER) stress, which may activate autophagy. We hypothesized that eIF2α signaling regulates bone homeostasis by promoting autophagy in osteoblasts and inhibiting osteoclast development. To test the hypothesis, we employed salubrinal to elevate the phosphorylation of eIF2α in an ovariectomized (OVX) mouse model and cell cultures. In the OVX model, salubrinal prevented abnormal expansion of rough ER and decreased the number of acidic vesiculars. It regulated ER stress-associated signaling molecules such as Bip, p-eIF2α, ATF4 and CHOP, and promoted autophagy of osteoblasts via regulation of eIF2α, Atg7, LC3, and p62. Salubrinal markedly alleviated OVX-induced symptoms such as reduction of bone mineral density and bone volume fraction. In primary bone-marrow-derived cells, salubrinal increased the differentiation of osteoblasts, and decreased the formation of osteoclasts by inhibiting nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Live cell imaging and RNA interference demonstrated that suppression of osteoclastogenesis is in part mediated by Rac1 GTPase. Collectively, this study demonstrates that ER stress-autophagy axis plays an important role in OVX mice. Bone-forming osteoblasts are restored by maintaining phosphorylation of eIF2α, and bone-resorbing osteoclasts are regulated by inhibiting NFATc1 and Rac1 GTPase.Item eIF2α signaling regulates ischemic osteonecrosis through endoplasmic reticulum stress(Nature Publishing Group, 2017-07-11) Liu, Daquan; Zhang, Yunlong; Li, Xinle; Li, Jie; Yang, Shuang; Xing, Xiaoxue; Fan, Guanwei; Yokota, Hiroki; Zhang, Ping; Biomedical Engineering, School of Engineering and TechnologyOsteonecrosis of the femoral head (ONFH) primarily results from ischemia/hypoxia to the femoral head, and one of the cellular manifestations is the endoplasmic reticulum (ER) stress. To understand possible linkage of ischemic osteonecrosis to the ER stress, a surgery-induced animal model was employed and salubrinal was administered to evaluate the role of ER stress. Salubrinal is a synthetic chemical that inhibits de-phosphorylation of eIF2α, and it can suppress cell death from the ER stress at a proper dose. The results indicated that the ER stress was associated with ONFH and salubrinal significantly improved ONFH-induced symptoms such as osteonecrosis, bone loss, reduction in vessel perfusion, and excessive osteoclastogenesis in the femoral head. Salubrinal also protected osteoblast development by upregulating the levels of ATF4, ALP and RUNX2, and it stimulated angiogenesis of endothelial cells through elevating ATF4 and VEGF. Collectively, the results support the notion that the ER stress is an important pathological outcome in the surgery-induced ONFH model, and salubrinal improves ONFH symptoms by enhancing angiogenesis and bone healing via suppressing the ER stress.Item Histological Tracking into the Third Dimension: Evolution of Early Tumorigenesis in VHL Kidney(Codon, 2021-09-10) Mubarak, Mayyan; Al-Gharaibeh, Nayef; Sommaruga, Samuel; Li, Jie; Vortmeyer, Alexander Oliver; Pathology and Laboratory Medicine, School of MedicineUsing a novel three-dimensional (3D) approach, we tracked histological changes to elucidate the earliest stages of renal clear cell neoplasia in normal kidney tissue of patients with von Hippel-Lindau (VHL) disease. Tissue blocks of interest were procured, serially sectioned, and 3D reconstruction of the entirety of pathologic events was performed. The results reveal an abundance of foci with aberrant clear cell proliferation that initially develop along the tubular lining, but have the potential to aggregate within individual tubules. This stage is followed by the extension of clear cell aggregates beyond the tubular basement membrane, which allows for the recruitment of angiogenesis derived from interstitial vasculature. The results suggest that the most frequent pathologic event in VHL kidneys is the presence of isolated or aggregated clear cells within the tubular epithelium, potentially developing further into a protracted process of neoplasia. The abundance of independent pathologic events in VHL kidneys confirms developmental mechanisms to precede tumor initiation. To our knowledge, this is the first report demonstrating that tracking of histologic changes in the 3rd dimension enables the confirmation of the sequence of events from the earliest pathologic change in the VHL kidney to the neoplastic stage. This approach is not only useful for visualization and quantification of pathologic changes but also for targeted sampling allowing selective analysis of the earliest stages of clear cell carcinogenesis.Item Knee loading inhibits osteoclast lineage in a mouse model of osteoarthritis(Nature Publishing Group, 2016) Li, Xinle; Yang, Jing; Liu, Daquan; Li, Jie; Niu, Kaijun; Feng, Shiqing; Yokota, Hiroki; Zhang, Ping; Department of Biomedical Engineering, School of Engineering and TechnologyOsteoarthritis (OA) is a whole joint disorder that involves cartilage degradation and periarticular bone response. Changes of cartilage and subchondral bone are associated with development and activity of osteoclasts from subchondral bone. Knee loading promotes bone formation, but its effects on OA have not been well investigated. Here, we hypothesized that knee loading regulates subchondral bone remodeling by suppressing osteoclast development, and prevents degradation of cartilage through crosstalk of bone-cartilage in osteoarthritic mice. Surgery-induced mouse model of OA was used. Two weeks application of daily dynamic knee loading significantly reduced OARSI scores and CC/TAC (calcified cartilage to total articular cartilage), but increased SBP (subchondral bone plate) and B.Ar/T.Ar (trabecular bone area to total tissue area). Bone resorption of osteoclasts from subchondral bone and the differentiation of osteoclasts from bone marrow-derived cells were completely suppressed by knee loading. The osteoclast activity was positively correlated with OARSI scores and negatively correlated with SBP and B.Ar/T.Ar. Furthermore, knee loading exerted protective effects by suppressing osteoclastogenesis through Wnt signaling. Overall, osteoclast lineage is the hyper responsiveness of knee loading in osteoarthritic mice. Mechanical stimulation prevents OA-induced cartilage degeneration through crosstalk with subchondral bone. Knee loading might be a new potential therapy for osteoarthritis patients.Item Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing(Elsevier, 2015-12) Liu, Daquan; Li, Xinle; Li, Jie; Yang, Jing; Yokota, Hiroki; Zhang, Ping; Department of Biomedical Engineering, School of Engineering and TechnologyOsteonecrosis of the femoral head is a serious orthopedic problem. Moderate loads with knee loading promote bone formation, but their effects on osteonecrosis have not been investigated. Using a rat model, we examined a hypothesis that knee loading enhances vessel remodeling and bone healing through the modulation of the fate of bone marrow-derived cells. In this study, osteonecrosis was induced by transecting the ligamentum teres followed by a tight ligature around the femoral neck. For knee loading, 5 N loads were laterally applied to the knee at 15 Hz for 5 min/day for 5 weeks. Changes in bone mineral density (BMD) and bone mineral content (BMC) of the femur were measured by pDEXA, and ink infusion was performed to evaluate vessel remodeling. Femoral heads were harvested for histomorphometry, and bone marrow-derived cells were isolated to examine osteoclast development and osteoblast differentiation. The results showed that osteonecrosis significantly induced bone loss, and knee loading stimulated both vessel remodeling and bone healing. The osteonecrosis group exhibited the lowest trabecular BV/TV (p b 0.001) in the femoral head, and lowest femoral BMD and BMC (both p b 0.01). However, knee loading increased trabecular BV/TV (p b 0.05) as well as BMD (pb 0.05) and BMC (p b 0.01). Osteonecrosis decreased the vessel volume (pb 0.001), vessel number (pb 0.001) and VEGF expression (p b 0.01), and knee loading increased them (pb 0.001, pb 0.001 and p b 0.01). Osteonecrosis activated osteoclast development, and knee loading reduced its formation, migration, adhesion and the level of “pit” formation (pb 0.001, pb 0.01, pb 0.001 and pb 0.001). Furthermore, knee loading significantly increased osteoblast differentiation and CFU-F (both p b 0.001). A significantly positive correlation was observed between vessel remodeling and bone healing (both p b 0.01). These results indicate that knee loading could be effective in repair osteonecrosis of the femoral head in a rat model. This effect might be attributed to promoting vessel remodeling, suppressing osteoclast development, and increasing osteoblast and fibroblast differentiation. In summary, the current study suggests that knee loading might potentially be employed as a non-invasive therapy for osteonecrosis of the femoral head.Item Mechanical loading attenuates breast cancer-associated bone metastasis in obese mice by regulating the bone marrow microenvironment(Wiley, 2021) Huang, Menglu; Liu, Hong; Zhu, Lei; Li, Xinle; Li, Jie; Yang, Shuang; Liu, Daquan; Song, Xiaomeng; Yokota, Hiroki; Zhang, Ping; Biomedical Engineering, School of Engineering and TechnologyBreast cancer, a common malignancy for women, preferentially metastasizes to bone and obesity elevates the chance of its progression. While mechanical loading can suppress obesity and tumor-driven osteolysis, its effect on bone-metastasized obese mice has not been investigated. Here, we hypothesized that mechanical loading can lessen obesity-associated bone degradation in tumor-invaded bone by regulating the fate of bone marrow-derived cells. In this study, the effects of mechanical loading in obese mice were evaluated through X-ray imaging, histology, cytology, and molecular analyses. Tumor inoculation to the tibia elevated body fat composition, osteolytic lesions, and tibia destruction, and these pathologic changes were stimulated by the high-fat diet (HFD). However, mechanical loading markedly reduced these changes. It suppressed osteoclastogenesis by downregulating receptor activator of nuclear factor Kappa-B ligand and cathepsin K and promoted osteogenesis, which was associated with the upregulation of OPG and downregulation of C/enhancer-binding protein alpha and proliferator-activated receptor gamma for adipogenic differentiation. Furthermore, it decreased the levels of tumorigenic genes such as Rac1, MMP9, and interleukin 1β. In summary, this study demonstrates that although a HFD aggravates bone metastases associated with breast cancer, mechanical loading significantly protected tumor-invaded bone by regulating the fate of bone marrow-derived cells. The current study suggests that mechanical loading can provide a noninvasive, palliative option for alleviating breast cancer-associated bone metastasis, in particular for obese patients.Item Mechanical Loading Mitigates Osteoarthritis Symptoms by Regulating the Inflammatory Microenvironment(SSRN, 2021-06-14) Zhang, Weiwei; Li, Xinle; Li, Jie; Wang, Xiaoyu; Liu, Daquan; Zhai, Lidong; Ding, Beibei; Li, Guang; Sun, Yuting; Yokota, Hiroki; Zhang, Ping; Biomedical Engineering, Purdue School of Engineering and TechnologyOsteoarthritis (OA) is one of the most common chronic diseases, in which inflammatory responses in the articular cavity induce chondrocyte apoptosis and cartilage degeneration. While mechanical loading is reported to mitigate synovial inflammation, the mechanism and pathways for the loading-driven improvement of OA symptoms remain unclear. In this research, we evaluated the loading effects on the M1/M2 polarization of synovial macrophages via performing molecular, cytology, and histology analyses. In the OA groups, the cell layer of the synovial lining was enlarged with an increase in cell density. Also, M1 macrophages were polarized and pro-inflammatory cytokines were increased. In contrast, in the OA group with mechanical loading cartilage degradation was reduced and synovial inflammation was alleviated. Notably, the polarization of M1 macrophages was diminished by mechanical loading, while that of M2 macrophages was increased. Furthermore, mechanical loading decreased the levels of pro-inflammatory cytokines such as IL-1β and TNF-α and suppressed PI3K/AKT/NF-κB signaling. Consistently, NF-κB inhibited decreased the polarization of M1 macrophages in RAW264.7 macrophages. Taken together, this study demonstrates that mechanical loading changes the ratio of M1 and M2 macrophage polarization via regulating PI3K/AKT/NF-κB signaling and provides chondroprotective effects in the mouse OA model.Item Mechanical loading stimulates bone angiogenesis through enhancing type H vessel formation and downregulating exosomal miR-214-3p from bone marrow-derived mesenchymal stem cells(Wiley, 2021) Wang, Xuetong; Li, Xinle; Li, Jie; Zhai, Lidong; Liu, Daquan; Abdurahman, Abdusami; Zhang, Yifan; Yokota, Hiroki; Zhang, Ping; Biomedical Engineering, School of Engineering and TechnologyExosomes are important transporters of miRNAs, which play varying roles in the healing of the bone fracture. Angiogenesis is one of such critical events in bone healing, and we previously reported the stimulatory effect of mechanical loading in vessel remodeling. Focusing on type H vessels and exosomal miR-214-3p, this study examined the mechanism of loading-driven angiogenesis. MiRNA sequencing and qRT-PCR revealed that miR-214-3p was increased in the exosomes of the bone-losing ovariectomized (OVX) mice, while it was significantly decreased by knee loading. Furthermore, compared to the OVX group, exosomes, derived from the loading group, promoted the angiogenesis of endothelial cells. In contrast, exosomes, which were transfected with miR-214-3p, decreased the angiogenic potential. Notably, knee loading significantly improved the microvascular volume, type H vessel formation, and bone mineral density and contents, as well as BV/TV, Tb.Th, Tb.N, and Tb.Sp. In cell cultures, the overexpression of miR-214-3p in endothelial cells reduced the tube formation and cell migration. Collectively, this study demonstrates that knee loading promotes angiogenesis by enhancing the formation of type H vessels and downregulating exosomal miR-214-3p.Item Notch signaling regulates adipose browning and energy metabolism(Nature Publishing Group, 2014-08) Bi, Pengpeng; Shan, Tizhong; Liu, Weiyi; Yue, Feng; Yang, Xin; Liang, Xin-Rong; Wang, Jinghua; Li, Jie; Carlesso, Nadia; Liu, Xiaoqi; Kuang, Shihuan; Department of Pediatrics, IU School of MedicineBeige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.