Browsing by Author "Li, Jiliang"
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Item Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats(MDPI, 2012-12-05) Zhang, Qing; Miller, Christopher; Bible, Jesse; Li, Jiliang; Xu, Xiaoqing; Mehta, Nozer; Gilligan, James; Vignery, Agnès; Scholz, Jodi A Carlson; Biology, School of ScienceMechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture.Item Author Correction: Inhibitory effects of dopamine receptor D1 agonist on mammary tumor and bone metastasis(Springer Nature, 2022-11-03) Minami, Kazumasa; Liu, Shengzhi; Liu, Yang; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Li, Bai‑Yan; Matsuura, Nariaki; Koizumi, Masahiko; Yin, Yukun; Gan, Liangying; Xu, Aihua; Li, Jiliang; Nakshatri, Harikrishna; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyThis corrects the article "Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis" in volume 7, 45686. doi: 10.1038/srep45686Item Author Correction: Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice(Springer Nature, 2021-05-10) Yin, Yukun; Corry, Kylie A.; Loughran, John P.; Li, Jiliang; Biology, School of ScienceCorrection to: Scientific Reports https://doi.org/10.1038/s41598-019-57185-1, published online 15 January 2020Item The Axolotl Fibula as a Model for the Induction of Regeneration across Large Segment Defects in Long Bones of the Extremities(Public Library of Science, 2015) Chen, Xiaoping; Song, Fengyu; Jhamb, Deepali; Li, Jiliang; Bottino, Marco C.; Palakal, Mathew J.; Stocum, David L.; Department of Biology, School of ScienceWe tested the ability of the axolotl (Ambystoma mexicanum) fibula to regenerate across segment defects of different size in the absence of intervention or after implant of a unique 8-braid pig small intestine submucosa (SIS) scaffold, with or without incorporated growth factor combinations or tissue protein extract. Fractures and defects of 10% and 20% of the total limb length regenerated well without any intervention, but 40% and 50% defects failed to regenerate after either simple removal of bone or implanting SIS scaffold alone. By contrast, scaffold soaked in the growth factor combination BMP-4/HGF or in protein extract of intact limb tissue promoted partial or extensive induction of cartilage and bone across 50% segment defects in 30%-33% of cases. These results show that BMP-4/HGF and intact tissue protein extract can promote the events required to induce cartilage and bone formation across a segment defect larger than critical size and that the long bones of axolotl limbs are an inexpensive model to screen soluble factors and natural and synthetic scaffolds for their efficacy in stimulating this process.Item Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia(2006-05) Iwata, Ken; Li, Jiliang; Follet, Helene; Phipps, Roger J; Burr, David B.Recent studies demonstrate that bisphosphonates suppress bone resorption by leading to apoptosis of the osteoclast and inhibiting the differentiation to mature osteoclasts. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized that bisphosphonates inhibit osteoblast apoptosis and stimulate osteoblast proliferation and differentiation in vitro, leading to increased bone formation. The purpose of this study was to investigate the effect of bisphosphonates on bone formation. We administered risedronate at 0.05, 0.5 or 5.0 μg/kg/day or alendronate at 0.1, 1.0 or 10 μg/kg/day subcutaneously for 17 days to 6-month-old female Sprague–Dawley rats. Control rats were given a daily subcutaneous injection of saline. Following sacrifice, the femoral and tibial mid-diaphyses were harvested and mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) were measured on periosteal and endocortical surfaces. In the femur, periosteal MAR was significantly lower in all treatment groups (22–29% for risedronate, 26–36% for alendronate) than in control. In the tibia, periosteal MAR and BFR of all treatment groups were significantly lower (41–50% for risedronate, 43–52% for alendronate) than in the control group. Because the periosteal surfaces of these bones are only undergoing bone formation in modeling mode, our results show that bisphosphonates suppress bone formation independently of bone resorption. Because this effect is seen on periosteal MAR rather than on periosteal MS/BS, we hypothesize that bisphosphonates affect the activity of individual osteoblasts at the cell level. This may help to explain the reason that the anabolic effects of teriparatide are blunted when administered concurrently with or following a course of bisphosphonates in humans.Item Bone Metabolism: The Role of STAT3 and Reactive Oxygen Species(2013-08-14) Newnum, America Bethanne; Li, Jiliang; Marrs, James; Ji, Julie; Atkinson, SimonSignal Transducers and Activators of Transcription 3 (STAT3), a transcription factor expressed in many cell types, including osteoblasts and osteoclasts, is emerging as a key regulator of bone mass and strength. STAT3 mutations cause a rare human immunodeficiency disease characterized by extremely elevated levels of IgE in serum that have associated craniofacial and skeletal features, such as reduced bone mineral density and recurrent pathological fractures. Our microarray data and immunohistochemical staining using a normal rat model have shown that STAT3 mRNA and protein levels markedly increase in response to mechanical loading. In addition, as indicated by STAT3 phosphorylation in MC3T3-E1 osteoblastic cells, STAT3 activity significantly increases in response to 30 to 90 minutes fluid shear stress. In order to further study the role that STAT3 plays in bone responsiveness to loading, tissue-selective STAT3 knockout (KO) mice, in which inactivation of STAT3 occurs in osteoblasts, were generated by breeding the transgenic mice in which Cre recombinase cDNA was cloned downstream of a 3.6 or 2.3 kb fragment of the rat Col1a1 promoter (Col3.6-Cre and Col2.3-Cre, respectively) with a strain of floxed mice in which the two loxP sites flank exons 18-20 of the STAT3 gene were used. Mice engineered with bone selective inactivation of STAT3 in osteoblasts exhibited significantly lower bone mineral density (7-12%, p<0.05) and reduced ultimate force (21-34%, p<0.01) compared to their age-matched littermate controls. The right ulnae of 16-week-old bone specific STAT3 KO mice and the age-matched control mice were loaded with peak forces of 2.5 N and 2.75 N for female and male mice, respectively, at 2 Hz, 120 cycles/day for 3 consecutive days. Mice with inactivation of STAT3 specific in bone were significantly less responsive to mechanical loading than the control mice as indicated by decreased relative mineralizing surface (rMS/BS, 47-59%, p<0.05) and relative bone formation rate (rBFR/BS, 64-75%, p<0.001). Bone responsiveness was equally decreased in mice in which STAT3 is inactivated either in early osteoblasts (Col3.6-Cre) or in mature osteoblasts (Col2.3-Cre). Accumulating evidence indicates that bone metabolism is significantly affected by activities in mitochondria. For instance, although STAT3 is reported to be involved in bone formation and resorption through regulation of nuclear genes, inactivation of STAT3 is shown to disrupt mitochondrial activities and result in an increased level of reactive oxygen species (ROS). Inactivation of STAT3 suppressed load-driven mitochondrial activity, which led to an elevated level of ROS in cultured primary osteoblasts. Oxidative stress induced by administration of buthionine sulfoximine (BSO) significantly inhibits load-induced bone formation in wild type mice. Taken together, the results support the notion that the loss-of-function mutation of STAT3 in osteoblasts and osteocytes diminishes load-driven bone formation and impairs the regulation of oxidative stress in mitochondria.Item Characterization and Assessment of Lung and Bone Marrow Derived Endothelial Cells and their Bone Regenerative Potential(2021-12) Valuch, Conner R.; Li, Jiliang; Kacena, Melissa; Marrs, JamesFracture repair is costly and difficult to treat. One of the main causations of nonunion is a lack of essential blood supply. The needed blood is supplied by the growth of new blood vessels, a process known as angiogenesis, that invade the damaged tissue early in the healing process. We proposed using bone tissue engineering as an effective therapy. This therapy uses stem cells to aid in tissue regeneration. Endothelial progenitor cells (EPCs) were selected due to their ability to form tube-like networks in vitro. EPCs were isolated from murine bone marrow and lung tissue. We tested EPC’s tube forming, proliferative, and wound migration ability in vitro. To test their ability in vivo we created a femoral fracture in young and old mice. EPCs were seeded to the fracture site upon a collagen scaffold. The in vitro studies displayed that the bone marrow and lung-derived endothelial cells presented EPC traits. In the mouse fracture model bone marrow, endothelial cells did not significantly improve the healing process. In the future, we want to improve our cell extraction and purification method, as well as test a new stem cell delivery biomaterial. We also want to select and use a growth factor (GF) that can help to promote bone regeneration in tandem with the EPCs.Item Characterization and assessment of lung and bone marrow derived endothelial cells and their bone regenerative potential(Frontiers, 2022) de Lima Perini, Mariana Moraes; Valuch, Conner R.; Dadwal, Ushashi C.; Awosanya, Olatundun D.; Mostardo, Sarah L.; Blosser, Rachel J.; Knox, Adam M.; McGuire, Anthony C.; Battina, Hanisha L.; Nazzal, Murad; Kacena, Melissa A.; Li, Jiliang; Biology, School of ScienceAngiogenesis is important for successful fracture repair. Aging negatively affects the number and activity of endothelial cells (ECs) and subsequently leads to impaired bone healing. We previously showed that implantation of lung-derived endothelial cells (LECs) improved fracture healing in rats. In this study, we characterized and compared neonatal lung and bone marrow-derived endothelial cells (neonatal LECs and neonatal BMECs) and further asses3sed if implantation of neonatal BMECs could enhance bone healing in both young and aged mice. We assessed neonatal EC tube formation, proliferation, and wound migration ability in vitro in ECs isolated from the bone marrow and lungs of neonatal mice. The in vitro studies demonstrated that both neonatal LECs and neonatal BMECs exhibited EC traits. To test the function of neonatal ECs in vivo, we created a femoral fracture in young and aged mice and implanted a collagen sponge to deliver neonatal BMECs at the fracture site. In the mouse fracture model, endochondral ossification was delayed in aged control mice compared to young controls. Neonatal BMECs significantly improved endochondral bone formation only in aged mice. These data suggest BMECs have potential to enhance aged bone healing. Compared to LECs, BMECs are more feasible for translational cell therapy and clinical applications in bone repair. Future studies are needed to examine the fate and function of BMECs implanted into the fracture sites.Item Characterizing Femoral Structure of the Ts66Yah Mouse Model of Down Syndrome(2023-08) Sloan, Kourtney; Roper, Randall J.; Li, Jiliang; McNulty, Margaret A.; Picard, Christine J.Down syndrome (DS) is caused by the partial or complete trisomy of human chromosome 21 (Hsa21) and can result in skeletal deficits, including lower bone mineral density (BMD) and increased risk of fracture and osteoporosis or osteopenia earlier than the general population. Mouse models of DS have been developed to understand the genetic mechanisms resulting in these phenotypes, but models differ due to the complex genetic nature of DS and differing genome structures between humans and mice. Ts65Dn mice have been a popular model of DS as they contain ~50% of Hsa21 orthologous genes on a freely segregating minichromosome, but there is speculation that the phenotypes are exaggerated by non-Hsa21 orthologous trisomic genes also present. To address this issue, the Ts66Yah mouse model was developed to remove the non-Hsa21 orthologous trisomic genes. In this study, male and female Ts66Yah mouse femurs were evaluated during bone accrual and peak bone mass to investigate structural differences using micro-computed tomography. Additionally, the role of trisomic Dyrk1a, a Hsa21 gene previously linked to bone deficits in Ts65Dn mice, was evaluated through genetic and pharmacological means in Ts66Yah femurs at postnatal day 36. Ts66Yah mice were found to have little or no trabecular deficits at any age evaluated, but sex-dependent cortical deficits were present at all ages investigated. Reducing Dyrk1a copy number in Ts66Yah mice significantly improved cortical deficits but did not return cortical bone to euploid levels. Pharmacological treatment with DYRK1A inhibitor L21 was confounded by multiple variables, making it difficult to draw conclusions about DYRK1A inhibition in this manner. Overall, these results indicate trabecular deficits associated with Ts65Dn mice may be due to the non-Hsa21 orthologous trisomic genes, and more Hsa21 orthologous trisomic genes are necessary to produce trabecular deficits in DS model mice. As more mouse models of DS are developed, multiple models need to be assessed to accurately define DS-associated phenotypes and test potential treatments.Item CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners(Elsevier, 2021-11-06) Liu, Zhiyuan; Wang, Huihui; Hou, Yongyong; Yang, Yang; Jia, Jingkun; Wu, Jinzhi; Zuo, Zhuo; Gao, Tianchang; Ren, Suping; Bian, Yiying; Liu, Shengnan; Fu, Jingqi; Sun, Yongxin; Li, Jiliang; Yamamoto, Masayuki; Zhang, Qiang; Xu, Yuanyuan; Pi, Jingbo; Biology, School of ScienceFine-tuning of osteoclast differentiation (OD) and bone remodeling is crucial for bone homeostasis. Dissecting the mechanisms regulating osteoclastogenesis is fundamental to understanding the pathogenesis of various bone disorders including osteoporosis and arthritis. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), which belongs to the CNC-bZIP family of transcription factors, orchestrates a variety of physiological processes and stress responses. While Nfe2l1 gene may be transcribed into multiple alternatively spliced isoforms, the biological function of the different isoforms of NFE2L1 in bone metabolism, osteoclastogenesis in particular, has not been reported. Here we demonstrate that knockout of all isoforms of Nfe2l1 transcripts specifically in the myeloid lineage in mice [Nfe2l1(M)-KO] results in increased activity of osteoclasts, decreased bone mass and worsening of osteoporosis induced by ovariectomy and aging. In comparison, LysM-Cre-mediated Nfe2l1 deletion has no significant effect on the osteoblast and osteocytes. Mechanistic investigations using bone marrow cells and RAW 264.7 cells revealed that deficiency of Nfe2l1 leads to accelerated and elevated OD, which is attributed, at least in part, to enhanced accumulation of ROS in the early stage of OD and expression of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1α (Nfatc1/α). In addition, NFE2L1 regulates the transcription of multiple antioxidant genes and Nfatc1/α and OD in an isoform-specific manner. While long isoforms of NFE2L1 function as accelerators of induction of Nfatc1/α and antioxidant genes and OD, the short isoform NFE2L1-453 serves as a brake that keeps the long isoforms’ accelerator effects in check. These findings provide a novel insight into the regulatory roles of NFE2L1 in osteoclastogenesis and highlight that NFE2L1 is essential in regulating bone remodeling and thus may be a valuable therapeutic target for bone disorders.