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Full-Text Articles in Orthopedics
Increased Hif-2Α Activity In The Nucleus Pulposus Causes Intervertebral Disc Degeneration In The Aging Mouse Spine, Shira N Johnston, Maria Tsingas, Rahatul Ain, Ruteja A Barve, Makarand Risbud
Increased Hif-2Α Activity In The Nucleus Pulposus Causes Intervertebral Disc Degeneration In The Aging Mouse Spine, Shira N Johnston, Maria Tsingas, Rahatul Ain, Ruteja A Barve, Makarand Risbud
Department of Orthopaedic Surgery Faculty Papers
Hypoxia-inducible factors (HIFs) are essential to the homeostasis of hypoxic tissues. Although HIF-2α, is expressed in nucleus pulposus (NP) cells, consequences of elevated HIF-2 activity on disc health remains unknown. We expressed HIF-2α with proline to alanine substitutions (P405A; P531A) in the Oxygen-dependent degradation domain (HIF-2αdPA) in the NP tissue using an inducible, nucleus pulposus-specific K19CreERT allele to study HIF-2α function in the adult intervertebral disc. Expression of HIF-2α in NP impacted disc morphology, as evident from small but significantly higher scores of degeneration in NP of 24-month-old K19CreERT; HIF-2αdPA (K19-dPA) mice. Noteworthy, comparisons of grades …
A New Perspective On Intervertebral Disc Calcification-From Bench To Bedside, Emanuel Novais, Rajkishen Narayanan, Jose Canseco, Koen Van De Wetering, Christopher Kepler, Alan Hilibrand, Alex Vaccaro, Makarand Risbud
A New Perspective On Intervertebral Disc Calcification-From Bench To Bedside, Emanuel Novais, Rajkishen Narayanan, Jose Canseco, Koen Van De Wetering, Christopher Kepler, Alan Hilibrand, Alex Vaccaro, Makarand Risbud
Department of Orthopaedic Surgery Faculty Papers
Disc degeneration primarily contributes to chronic low back and neck pain. Consequently, there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis, ectopic calcification, herniation, or mixed phenotypes. Amongst these phenotypes, disc calcification is the least studied. Ectopic calcification, by definition, is the pathological mineralization of soft tissues, widely studied in the context of conditions that afflict vasculature, skin, and cartilage. Clinically, disc calcification is associated with poor surgical outcomes and back pain refractory to conservative treatment. It is frequently seen as a consequence of disc aging and progressive degeneration but exhibits unique molecular …
Loss Of Function Mutation In Ank Causes Aberrant Mineralization And Acquisition Of Osteoblast-Like-Phenotype By The Cells Of The Intervertebral Disc, Takashi Ohnishi, Victoria Tran, Kimheak Sao, Pranay Ramteke, William Querido, Ruteja A. Barve, Koen Van De Wetering, Makarand V. Risbud
Loss Of Function Mutation In Ank Causes Aberrant Mineralization And Acquisition Of Osteoblast-Like-Phenotype By The Cells Of The Intervertebral Disc, Takashi Ohnishi, Victoria Tran, Kimheak Sao, Pranay Ramteke, William Querido, Ruteja A. Barve, Koen Van De Wetering, Makarand V. Risbud
Department of Orthopaedic Surgery Faculty Papers
Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate efflux transporter, progressive ankylosis (ANK) is a regulator of extracellular inorganic pyrophosphate levels and plays an important role in tissue mineralization. However, the function of ANK in intervertebral disc has not been fully explored. Herein we analyzed the spinal phenotype of Ank mutant mice (ank/ank) with attenuated ANK function. Micro-computed tomography and histological analysis showed that loss of ANK function results in the aberrant annulus fibrosus mineralization and peripheral disc fusions with cranial to caudal progression in …
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 …
The Cgas-Sting Pathway Affects Vertebral Bone But Does Not Promote Intervertebral Disc Cell Senescence Or Degeneration, Olivia K. Ottone, C. James Kim, John A. Collins, Makarand V. Risbud
The Cgas-Sting Pathway Affects Vertebral Bone But Does Not Promote Intervertebral Disc Cell Senescence Or Degeneration, Olivia K. Ottone, C. James Kim, John A. Collins, Makarand V. Risbud
Department of Orthopaedic Surgery Faculty Papers
The DNA-sensing cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) and mediates type-I interferon inflammatory responses to foreign viral and bacterial DNA as well as self-DNA. Studies of the intervertebral disc in humans and mice demonstrate associations between aging, increased cell senescence, and disc degeneration. Herein we assessed the role of STING in SASP promotion in STING gain- (N153S) and loss-of-function mouse models. N153S mice evidenced elevated circulating levels of proinflammatory markers including IL-1β, IL-6, and TNF-α, showed elevated monocyte and macrophage abundance in the vertebral marrow, and exhibited a mild trabecular and cortical bone phenotype in caudal vertebrae. Interestingly, …
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 …
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) …