Browsing by Subject "Bone morphogenetic proteins"

Now showing 1 - 5 of 5
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    Application of Salubrinal for Bone Fracture Healing
    (Office of the Vice Chancellor for Research, 2014-04-11) Yokota, Hiroki; Lin, Chien-Chi
    The long-term objective of this project is to commercialize a novel synthetic chemical agent, salubrinal, for treatment of bone growth and fracture healing. Bone morphogenetic proteins (BMPs) are clinically administered as growth stimulators for bone fracture healing. However, BMPs are not only expensive, but also stimulate ectopic bone formation and potentially induce cancer. A synthetic chemical agent that permits facile storage and administration could reduce costs, and provide longer shelf-life, and better bone healing outcomes. Currently, no synthetic chemical agents as a stimulator of fracture healing are clinically available. The research team recently identified “salubrinal,” a synthetic chemical agent, as a potential therapeutic stimulator of bone growth and fracture healing. An invention disclosure and a U.S. patent were filed. In this FORCES project, we are examining efficacy of salubrinal using a mouse model of closed tibia fracture. The results strongly indicate that salubrinal can accelerate bone fracture healing.
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    BMP Pathway and Reactive Retinal Gliosis
    (2013-03-06) Dharmarajan, Subramanian; Belecky-Adams, Teri; Skalnik, David Gordon; Zhang, Xin; Atkinson, Simon
    Reactive gliosis is known to have a beneficial and a degenerative effect following injury to neurons. Although many factors have been implicated in reactive gliosis, their role in regulating this change is still unclear. We investigated the role of bone morphogenetic proteins in reactive gliosis in vivo and in vitro. In vivo, IHC analysis indicated reactive gliosis in the 6 week Ins2Akita mouse and WPK rat retinas. Expression of BMP7 was upregulated in these models, leading to an increase in the phosphorylation of downstream SMAD1. In vitro, treatment of murine retinal astrocyte cells with a strong oxidizing agent such as sodium peroxynitrite regulated RNA levels of various markers, including GFAP, CSPGs, MMPs and TIMPs. BMP7 treatment also regulated RNA levels to a similar extent, suggesting reactive gliosis. Treatment with high glucose DMEM and BMP4, however, did not elicit increase in levels to a similar degree. Increase in SMAD levels and downstream targets of SMAD signaling such as ID1, ID3 and MSX2 was also observed following treatment with sodium peroxynitrite in vitro and in the 6 week Ins2Akita mouse retinas in vivo. These data concur with previously established data which show an increase in BMP7 levels following injury. It also demonstrates a role for BMP7 in gliosis following disease. Further, it suggests SMAD signaling to play a role in initiating reactivity in astrocytes as well as in remodeling the extracellular matrix following injury and in a disease condition.
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    Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis
    (SpringerNature, 2016-06-30) Han, Peidong; Bloomekatz, Joshua; Ren, Jie; Zhang, Ruilin; Grinstein, Jonathan D.; Zhao, Long; Burns, C. Geoffrey; Burns, Caroline E.; Anderson, Ryan M.; Chi, Neil C.; Department of Pediatrics, IU School of Medicine
    Many organs are composed of complex tissue walls that are structurally organized to optimize organ function. In particular, the ventricular myocardial wall of the heart comprises an outer compact layer that concentrically encircles the ridge-like inner trabecular layer. Although disruption in the morphogenesis of this myocardial wall can lead to various forms of congenital heart disease and non-compaction cardiomyopathies, it remains unclear how embryonic cardiomyocytes assemble to form ventricular wall layers of appropriate spatial dimensions and myocardial mass. Here we use advanced genetic and imaging tools in zebrafish to reveal an interplay between myocardial Notch and Erbb2 signalling that directs the spatial allocation of myocardial cells to their proper morphological positions in the ventricular wall. Although previous studies have shown that endocardial Notch signalling non-cell-autonomously promotes myocardial trabeculation through Erbb2 and bone morphogenetic protein (BMP) signalling, we discover that distinct ventricular cardiomyocyte clusters exhibit myocardial Notch activity that cell-autonomously inhibits Erbb2 signalling and prevents cardiomyocyte sprouting and trabeculation. Myocardial-specific Notch inactivation leads to ventricles of reduced size and increased wall thickness because of excessive trabeculae, whereas widespread myocardial Notch activity results in ventricles of increased size with a single-cell-thick wall but no trabeculae. Notably, this myocardial Notch signalling is activated non-cell-autonomously by neighbouring Erbb2-activated cardiomyocytes that sprout and form nascent trabeculae. Thus, these findings support an interactive cellular feedback process that guides the assembly of cardiomyocytes to morphologically create the ventricular myocardial wall and more broadly provide insight into the cellular dynamics of how diverse cell lineages organize to create form.
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    Differential involvement of Wnt signaling in Bmp regulation of cancellous versus periosteal bone growth
    (Springer Nature, 2017-06-06) He, Guangxu; Shi, Yu; Lim, Joohyun; Bellido, Teresita; Ni, Jiangdong; Long, Fanxin; Anatomy and Cell Biology, School of Medicine
    Bone morphogenetic proteins (Bmp) are well-known to induce bone formation following chondrogenesis, but the direct role of Bmp signaling in the osteoblast lineage is not completely understood. We have recently shown that deletion of the receptor Bmpr1a in the osteoblast lineage with Dmp1-Cre reduces osteoblast activity in general but stimulates proliferation of preosteoblasts specifically in the cancellous bone region, resulting in diminished periosteal bone growth juxtaposed with excessive cancellous bone formation. Because expression of sclerostin (SOST), a secreted Wnt antagonist, is notably reduced in the Bmpr1a-deficient osteocytes, we have genetically tested the hypothesis that increased Wnt signaling might mediate the increase in cancellous bone formation in response to Bmpr1a deletion. Forced expression of human SOST from a Dmp1 promoter fragment partially rescues preosteoblast hyperproliferation and cancellous bone overgrowth in the Bmpr1a mutant mice, demonstrating functional interaction between Bmp and Wnt signaling in the cancellous bone compartment. To test whether increased Wnt signaling can compensate for the defect in periosteal growth caused by Bmpr1a deletion, we have generated compound mutants harboring a hyperactive mutation (A214V) in the Wnt receptor Lrp5. However, the mutant Lrp5 does not restore periosteal bone growth in the Bmpr1a-deficient mice. Thus, Bmp signaling restricts cancellous bone accrual partly through induction of SOST that limits preosteoblast proliferation, but promotes periosteal bone growth apparently independently of Wnt activation.
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    Role of TGF-β Activated Kinase 1(TAK1) in Chick Retinal Development
    (Office of the Vice Chancellor for Research, 2014-04-11) Ravi, Vagisha; Belecky-Adams, Teri
    Bone morphogenetic proteins (BMPs) play a critical role in vertebrate eye development by regulating cell fate processes in the retina through canonical SMAD and non-canonical MAPK pathways. TGF-β Activated Kinase 1(TAK1) is a MAPKKK that activates the MAPK cascade upon BMP activation. Dysregulation of TAK1 is associated with a variety of diseased states including cancer, but little is known about the role of TAK1 in development. Recent in vitro studies have indicated that TAK1 inhibits the G1-S phase Cyclin D, a process known to be critical to cell cycle exit. Although no studies have focused on the role of TAK1 in retinal development, many studies have indicated that BMPs as well as properly timed cell cycle exit are critical for the differentiation of specific cell types. In studies designed to test the hypothesis that TAK1 is an essential regulator of cell cycle exit in the chick embryonic retina, we have performed immunohistochemistry using an antibody that specifically detects the activated form of TAK1 (pTAK1) and shown the extensive localization of pTAK1 in a subset of differentiated cells and, more prominently, in the mitotic progenitor cells of the retina. Our preliminary studies, aimed at in vivo pharmacological inhibition of TAK1 activity using (5Z)-7-Oxozeaenol in the developing chick eye, show that TAK1 inhibition could lead to a range of developmental defects in the retina. While further studies focusing on molecular changes resulting from TAK1 inhibition and overexpression would shed more light on its functional role in the retina, our results suggest that TAK1 signaling is critical for normal eye development. The heavy localization of pTAK1 in mitotic progenitor cells especially, could be indicative of its role in cell cycle exit. Understanding the functional role of this protein in the context of eye development could aid in understanding the pathophysiology of diseased states associated with TAK1.