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Full-Text Articles in Orthopedics
Glut1 Is Redundant In Hypoxic And Glycolytic Nucleus Pulposus Cells Of The Intervertebral Disc, Shira N. Johnston, Elizabeth S. Silagi, Vedavathi Madhu, Duc H. Nguyen, Irving M. Shapiro, Makarand V. Risbud
Glut1 Is Redundant In Hypoxic And Glycolytic Nucleus Pulposus Cells Of The Intervertebral Disc, Shira N. Johnston, Elizabeth S. Silagi, Vedavathi Madhu, Duc H. Nguyen, Irving M. Shapiro, Makarand V. Risbud
Department of Orthopaedic Surgery Faculty Papers
Glycolysis is central to homeostasis of nucleus pulposus (NP) cells in the avascular intervertebral disc. Since the glucose transporter, GLUT1, is a highly enriched phenotypic marker of NP cells, we hypothesized that it is vital for the development and postnatal maintenance of the disc. Surprisingly, primary NP cells treated with 2 well-characterized GLUT1 inhibitors maintained normal rates of glycolysis and ATP production, indicating intrinsic compensatory mechanisms. We showed in vitro that NP cells mitigated GLUT1 loss by rewiring glucose import through GLUT3. Of note, we demonstrated that substrates, such as glutamine and palmitate, did not compensate for glucose restriction resulting …
Abcc6 Null Mice-A Model For Mineralization Disorder Pxe Shows Vertebral Osteopenia Without Enhanced Intervertebral Disc Calcification With Aging, Paige K Boneski, Vedavathi Madhu, Ryan Tomlinson, Irving Shapiro, Koen Van De Wetering, Makarand V Risbud
Abcc6 Null Mice-A Model For Mineralization Disorder Pxe Shows Vertebral Osteopenia Without Enhanced Intervertebral Disc Calcification With Aging, Paige K Boneski, Vedavathi Madhu, Ryan Tomlinson, Irving Shapiro, Koen Van De Wetering, Makarand V Risbud
Department of Orthopaedic Surgery Faculty Papers
Chronic low back pain is a highly prevalent health condition intricately linked to intervertebral disc degeneration. One of the prominent features of disc degeneration that is commonly observed with aging is dystrophic calcification. ATP-binding cassette sub-family C member 6 (ABCC6), a presumed ATP efflux transporter, is a key regulator of systemic levels of the mineralization inhibitor pyrophosphate (PPi). Mutations in ABCC6 result in pseudoxanthoma elasticum (PXE), a progressive human metabolic disorder characterized by mineralization of the skin and elastic tissues. The implications of ABCC6 loss-of-function on pathological mineralization of structures in the spine, however, are unknown. Using the Abcc6 -/- …
Genetic Murine Models Of Spinal Development And Degeneration Provide Valuable Insights Into Intervertebral Disc Pathobiology., J. Melrose, S. Tessier, M. V. Risbud
Genetic Murine Models Of Spinal Development And Degeneration Provide Valuable Insights Into Intervertebral Disc Pathobiology., J. Melrose, S. Tessier, M. V. Risbud
Department of Orthopaedic Surgery Faculty Papers
Disc degeneration and associated back and neck pain elicits a substantial burden on healthcare systems and the individuals affected, necessitating the development of novel therapeutic strategies. This goal can only be achieved by a better understanding of intervertebral disc development, homeostasis and pathogenesis. A number of genetic and in-bred murine models are reviewed to underscore the importance of the mouse as an animal model of choice for the assessment of intervertebral disc pathobiology. Appraisals of the differences between mouse and human musculoskeletal systems and proteoglycan structures are also included. A number of important target pathways and molecules have been identified, …
Cox-2 Expression Mediated By Calcium-Tonebp Signaling Axis Under Hyperosmotic Conditions Serves Osmoprotective Function In Nucleus Pulposus Cells., Hyowon Choi, Weera Chaiyamongkol, Alexandra C. Doolittle, Zariel I. Johnson, Shilpa S. Gogate, Zachary R. Schoepflin, Irving M. Shapiro, Makarand V. Risbud
Cox-2 Expression Mediated By Calcium-Tonebp Signaling Axis Under Hyperosmotic Conditions Serves Osmoprotective Function In Nucleus Pulposus Cells., Hyowon Choi, Weera Chaiyamongkol, Alexandra C. Doolittle, Zariel I. Johnson, Shilpa S. Gogate, Zachary R. Schoepflin, Irving M. Shapiro, Makarand V. Risbud
Department of Orthopaedic Surgery Faculty Papers
The nucleus pulposus (NP) of intervertebral discs experiences dynamic changes in tissue osmolarity because of diurnal loading of the spine. TonEBP/NFAT5 is a transcription factor that is critical in osmoregulation as well as survival of NP cells in the hyperosmotic milieu. The goal of this study was to investigate whether cyclooxygenase-2 (COX-2) expression is osmoresponsive and dependent on TonEBP, and whether it serves an osmoprotective role. NP cells up-regulated COX-2 expression in hyperosmotic media. The induction of COX-2 depended on elevation of intracellular calcium levels and p38 MAPK pathway, but independent of calcineurin signaling as well as MEK/ERK and JNK …
Lack Of Evidence For Involvement Of Tonebp And Hyperosmotic Stimulus In Induction Of Autophagy In The Nucleus Pulposus., Chao Liu, Hyowon Choi, Zariel I. Johnson, Jiwei Tian, Irving Shapiro, Makarand V Risbud
Lack Of Evidence For Involvement Of Tonebp And Hyperosmotic Stimulus In Induction Of Autophagy In The Nucleus Pulposus., Chao Liu, Hyowon Choi, Zariel I. Johnson, Jiwei Tian, Irving Shapiro, Makarand V Risbud
Department of Orthopaedic Surgery Faculty Papers
Nucleus pulposus (NP) cells reside in a physiologically hyperosmotic environment within the intervertebral disc. TonEBP/NFAT5 is an osmo-sensitive transcription factor that controls expression of genes critical for cell survival under hyperosmotic conditions. A recent report on NP and studies of other cell types have shown that hyperosmolarity triggers autophagy. However, little is known whether such autophagy induction occurs through TonEBP. The goal of this study was to investigate the role of TonEBP in hyperosmolarity-dependent autophagy in NP. Loss-of-function studies showed that autophagy in NP cells was not TonEBP-dependent; hyperosmolarity did not upregulate autophagy as previously reported. NP tissue of haploinsufficient …
Rna Sequencing Reveals A Role Of Tonebp Transcription Factor In Regulation Of Pro-Inflammatory Genes In Response To Hyperosmolarity In Healthy Nucleus Pulposus Cells: A Homeostatic Response?, Zariel I. Johnson, Irving M. Shapiro, Makarand V. Risbud
Rna Sequencing Reveals A Role Of Tonebp Transcription Factor In Regulation Of Pro-Inflammatory Genes In Response To Hyperosmolarity In Healthy Nucleus Pulposus Cells: A Homeostatic Response?, Zariel I. Johnson, Irving M. Shapiro, Makarand V. Risbud
Department of Orthopaedic Surgery Faculty Papers
Transcription factor tonicity-responsive enhancer-binding protein (TonEBP/NFAT5) is critical for osmo-adaptation and extracellular matrix homeostasis of nucleus pulposus (NP) cells in their hypertonic tissue niche. Recent studies implicate TonEBP signaling in inflammatory disease and rheumatoid arthritis pathogenesis. However, broader functions of TonEBP in the disc remain unknown. RNA sequencing was performed on NP cells with TonEBP knockdown under hypertonic conditions. 1140 TonEBP-dependent genes were identified and categorized using Ingenuity Pathway Analysis. Bioinformatic analysis showed enrichment of matrix homeostasis and cytokine/chemokine signaling pathways. C-C motif chemokine ligand 2 (CCL2), interleukin 6 (IL6), tumor necrosis factor (TNF), and nitric oxide synthase 2 (NOS2) …