34 results on '"Murugesh, Deepa"'
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2. Differential bone adaptation to mechanical unloading and reloading in young, old, and osteocyte deficient mice
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Cunningham, Hailey C., Orr, Sophie, Murugesh, Deepa K., Hsia, Allison W., Osipov, Benjamin, Go, Lauren, Wu, Po Hung, Wong, Alice, Loots, Gabriela G., Kazakia, Galateia J., and Christiansen, Blaine A.
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- 2023
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3. Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects
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Loots, Gabriela G., Robling, Alexander G., Chang, Jiun C., Murugesh, Deepa K., Bajwa, Jamila, Carlisle, Cameron, Manilay, Jennifer O., Wong, Alice, Yellowley, Clare E., and Genetos, Damian C.
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- 2018
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4. Manipulation of the Gut Microbiome Alters Acetaminophen Biodisposition in Mice
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Malfatti, Michael A., Kuhn, Edward A., Murugesh, Deepa K., Mendez, Melanie E., Hum, Nicholas, Thissen, James B., Jaing, Crystal J., and Loots, Gabriela G.
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- 2020
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5. Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation
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Robling, Alexander G., Kang, Kyung Shin, Bullock, Whitney A., Foster, William H., Murugesh, Deepa, Loots, Gabriela G., and Genetos, Damian C.
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- 2016
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6. Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells
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Collette, Nicole M., Yee, Cristal S., Hum, Nicholas R., Murugesh, Deepa K., Christiansen, Blaine A., Xie, LiQin, Economides, Aris N., Manilay, Jennifer O., Robling, Alexander G., and Loots, Gabriela G.
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- 2016
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7. Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model
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Yee, Cristal S., Xie, LiQin, Hatsell, Sarah, Hum, Nicholas, Murugesh, Deepa, Economides, Aris N., Loots, Gabriela G., and Collette, Nicole M.
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- 2016
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8. Antibiotic Treatment Prior to Injury Abrogates the Detrimental Effects of LPS in STR/ort Mice Susceptible to Osteoarthritis Development.
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Mendez, Melanie E, Murugesh, Deepa K, Christiansen, Blaine A, and Loots, Gabriela G
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LIPOPOLYSACCHARIDES ,ANTERIOR cruciate ligament ,OSTEOARTHRITIS ,ARTICULAR cartilage ,WOUNDS & injuries ,RHEUMATOID arthritis - Abstract
Post traumatic osteoarthritis (PTOA) is a form of secondary osteoarthritis (OA) that develops in ~50% of cases of severe articular joint injuries and leads to chronic and progressive degradation of articular cartilage and other joint tissues. PTOA progression can be exacerbated by repeated injury and systemic inflammation. Few studies have examined approaches for blunting or slowing down PTOA progression with emphasis on systemic inflammation; most arthritis studies focused on the immune system have been in the context of rheumatoid arthritis. To examine how the gut microbiome affects systemic inflammation during PTOA development, we used a chronic antibiotic treatment regimen starting at weaning for 6 weeks before anterior cruciate ligament (ACL) rupture in STR/ort mice combined with lipopolysaccharide (LPS)‐induced systemic inflammation. STR/ort mice develop spontaneous OA as well as a more severe PTOA phenotype than C57Bl/6J mice. By 6 weeks post injury, histological examination showed a more robust cartilage staining in the antibiotic‐treated (AB) STR/ort mice than in the untreated STR/ort controls. Furthermore, we also examined the effects of AB treatment on systemic inflammation and found that the effects of LPS administration before injury are also blunted by AB treatment in STR/ort mice. The AB‐ or AB+LPS‐treated STR/ort injured joints more closely resembled the C57Bl/6J VEH OA phenotypes than the vehicle‐ or LPS‐treated STR/ort, suggesting that antibiotic treatment has the potential to slow disease progression and should be further explored therapeutically as prophylactic post injury. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Degradation‐Resistant Hypoxia Inducible Factor‐2α in Murine Osteocytes Promotes a High Bone Mass Phenotype.
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Mendoza, Sarah V., Murugesh, Deepa K., Christiansen, Blaine A., Genetos, Zoe O., Loots, Gabriela G., Genetos, Damian C., and Yellowley, Clare E.
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OSTEOCYTES ,HYPOXIA-inducible factors ,PHENOTYPES ,HYPOXEMIA ,PROTEOLYSIS ,HOMEOSTASIS - Abstract
Molecular oxygen levels vary during development and disease. Adaptations to decreased oxygen bioavailability (hypoxia) are mediated by hypoxia‐inducible factor (HIF) transcription factors. HIFs are composed of an oxygen‐dependent α subunit (HIF‐α), of which there are two transcriptionally active isoforms (HIF‐1α and HIF‐2α), and a constitutively expressed β subunit (HIFβ). Under normoxic conditions, HIF‐α is hydroxylated via prolyl hydroxylase domain (PHD) proteins and targeted for degradation via Von Hippel‐Lindau (VHL). Under hypoxic conditions, hydroxylation via PHD is inhibited, allowing for HIF‐α stabilization and induction of target transcriptional changes. Our previous studies showed that Vhl deletion in osteocytes (Dmp1‐cre; Vhlf/f) resulted in HIF‐α stabilization and generation of a high bone mass (HBM) phenotype. The skeletal impact of HIF‐1α accumulation has been well characterized; however, the unique skeletal impacts of HIF‐2α remain understudied. Because osteocytes orchestrate skeletal development and homeostasis, we investigated the role of osteocytic HIF‐α isoforms in driving HBM phenotypes via osteocyte‐specific loss‐of‐function and gain‐of‐function HIF‐1α and HIF‐2α mutations in C57BL/6 female mice. Deletion of Hif1a or Hif2a in osteocytes showed no effect on skeletal microarchitecture. Constitutively stable, degradation‐resistant HIF‐2α (HIF‐2α cDR), but not HIF‐1α cDR, generated dramatic increases in bone mass, enhanced osteoclast activity, and expansion of metaphyseal marrow stromal tissue at the expense of hematopoietic tissue. Our studies reveal a novel influence of osteocytic HIF‐2α in driving HBM phenotypes that can potentially be harnessed pharmacologically to improve bone mass and reduce fracture risk. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Global molecular changes in a tibial compression induced ACL rupture model of post‐traumatic osteoarthritis
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Chang, Jiun C., Sebastian, Aimy, Murugesh, Deepa K., Hatsell, Sarah, Economides, Aris N., Christiansen, Blaine A., and Loots, Gabriela G.
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- 2017
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11. TGF-β regulates sclerostin expression via the ECR5 enhancer
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Loots, Gabriela G., Keller, Hansjoerg, Leupin, Olivier, Murugesh, Deepa, Collette, Nicole M., and Genetos, Damian C.
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- 2012
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12. Selective Erythroid Replacement in Murine β-Thalassemia Using Fetal Hematopoietic Stem Cells
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Bethel, Colin A., Murugesh, Deepa, Harrison, Michael R., Mohandas, Narla, and Rubin, Edward M.
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- 1993
13. Single-cell RNA-Seq reveals changes in immune landscape in post-traumatic osteoarthritis.
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Sebastian, Aimy, Hum, Nicholas R., McCool, Jillian L., Wilson, Stephen P., Murugesh, Deepa K., Martin, Kelly A., Rios-Arce, Naiomy Deliz, Amiri, Beheshta, Christiansen, Blaine A., and Loots, Gabriela G.
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CELL death ,KILLER cells ,ANTERIOR cruciate ligament ,LANDSCAPE changes ,KNEE joint ,ANTERIOR cruciate ligament injuries ,OSTEOARTHRITIS - Abstract
Osteoarthritis (OA) is the most common joint disease, affecting over 300 million people world-wide. Accumulating evidence attests to the important roles of the immune system in OA pathogenesis. Understanding the role of various immune cells in joint degeneration or joint repair after injury is vital for improving therapeutic strategies for treating OA. Post-traumatic osteoarthritis (PTOA) develops in ~50% of individuals who have experienced an articular trauma like an anterior cruciate ligament (ACL) rupture. Here, using the high resolution of single-cell RNA sequencing, we delineated the temporal dynamics of immune cell accumulation in the mouse knee joint after ACL rupture. Our study identified multiple immune cell types in the joint including neutrophils, monocytes, macrophages, B cells, T cells, NK cells and dendritic cells. Monocytes and macrophage populations showed the most dramatic changes after injury. Further characterization of monocytes and macrophages reveled 9 major subtypes with unique transcriptomics signatures, including a tissue resident Lyve1
hi Folr2hi macrophage population and Trem2hi Fcrls+ recruited macrophages, both showing enrichment for phagocytic genes and growth factors such as Igf1, Pdgfa and Pdgfc. We also identified several genes induced or repressed after ACL injury in a cell type-specific manner. This study provides new insight into PTOA-associated changes in the immune microenvironment and highlights macrophage subtypes that may play a role in joint repair after injury. [ABSTRACT FROM AUTHOR]- Published
- 2022
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14. Genetic evidence that SOST inhibits WNT signaling in the limb
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Collette, Nicole M., Genetos, Damian C., Murugesh, Deepa, Harland, Richard M., and Loots, Gabriela G.
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Biological sciences - Abstract
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.03.021 Byline: Nicole M. Collette (a)(b), Damian C. Genetos (c), Deepa Murugesh (a)(b), Richard M. Harland (b), Gabriela G. Loots (a)(b) Keywords: WNT signaling; SOST; Sclerostin; Shh; Limb formation Abstract: SOST is a negative regulator of bone formation, and mutations in human SOST are responsible for sclerosteosis. In addition to high bone mass, sclerosteosis patients occasionally display hand defects, suggesting that SOST may function embryonically. Here we report that overexpression of SOST leads to loss of posterior structures of the zeugopod and autopod by perturbing anterior-posterior and proximal-distal signaling centers in the developing limb. Mutant mice that overexpress SOST in combination with Grem1 and Lrp6 mutations display more severe limb defects than single mutants alone, while Sost.sup.- .sup./ .sup.- significantly rescues the Lrp6.sup.- .sup./ .sup.- skeletal phenotype, signifying that SOST gain-of-function impairs limb patterning by inhibiting the WNT signaling through LRP5/6. Author Affiliation: (a) Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94550, USA (b) Department of Molecular and Cell Biology, Division of Genetics, Genomics, and Development, and Center for Integrative Genomics, University of California, Berkeley, CA 94720-3204, USA (c) Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA Article History: Received 19 June 2009; Revised 18 March 2010; Accepted 22 March 2010
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- 2010
15. Preexisting Type 1 Diabetes Mellitus Blunts the Development of Posttraumatic Osteoarthritis.
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Rios‐Arce, Naiomy D, Murugesh, Deepa K, Hum, Nicholas R, Sebastian, Aimy, Jbeily, Elias H, Christiansen, Blaine A, and Loots, Gabriela G
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TYPE 1 diabetes ,HYPERGLYCEMIA ,OSTEOARTHRITIS ,ARTICULAR cartilage - Abstract
Type 1 diabetes mellitus (T1DM) affects 9.5% of the population. T1DM is characterized by severe insulin deficiency that causes hyperglycemia and leads to several systemic effects. T1DM has been suggested as a risk factor for articular cartilage damage and loss, which could expedite the development of osteoarthritis (OA). OA represents a major public health challenge by affecting 300 million people globally, yet very little is known about the correlation between T1DM and OA. In addition, current studies that have looked at the interaction between diabetes mellitus and OA have reported conflicting results with some suggesting a positive correlation whereas others did not. In this study, we aimed to evaluate whether T1DM exacerbates the development of spontaneous OA or accelerates the progression of posttraumatic osteoarthritis (PTOA) after joint injury. Histological evaluation of T1DM and control joints determined that T1DM mice displayed cartilage degeneration measurements consistent with mild OA phenotypes. RNA sequencing analyses identified significantly upregulated genes in T1DM corresponding to matrix‐degrading enzymes known to promote cartilage matrix degradation, suggesting a role of these enzymes in OA development. Next, we assessed whether preexisting T1DM influences PTOA development subsequent to trauma. At 6 weeks post‐injury, T1DM injured joints displayed significantly less cartilage damage and joint degeneration than injured non‐diabetic joints, suggesting a significant delay in PTOA disease progression. At the single‐cell resolution, we identified increased number of cells expressing the chondrocyte markers Col2a1, Acan, and Cytl1 in the T1DM injured group. Our findings demonstrate that T1DM can be a risk factor for OA but not for PTOA. This study provides the first account of single‐cell resolution related to T1DM and the risk for OA and PTOA. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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16. Long-term administration of AMD3100, an antagonist of SDF-1/CXCR4 signaling, alters fracture repair
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Toupadakis, Chrisoula A., Wong, Alice, Genetos, Damian C., Chung, Dai-Jung, Murugesh, Deepa, Anderson, Matthew J., Loots, Gabriela G., Christiansen, Blaine A., Kapatkin, Amy S., and Yellowley, Clare E.
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- 2012
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17. LPS‐Induced Inflammation Prior to Injury Exacerbates the Development of Post‐Traumatic Osteoarthritis in Mice.
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Mendez, Melanie E, Sebastian, Aimy, Murugesh, Deepa K, Hum, Nicholas R, McCool, Jillian L, Hsia, Allison W, Christiansen, Blaine A, and Loots, Gabriela G
- Abstract
Osteoarthritis (OA) is a debilitating and painful disease characterized by the progressive loss of articular cartilage. Post‐traumatic osteoarthritis (PTOA) is an injury‐induced type of OA that persists in an asymptomatic phase for years before it becomes diagnosed in ~50% of injured individuals. Although PTOA is not classified as an inflammatory disease, it has been suggested that inflammation could be a major driver of PTOA development. Here we examined whether a state of systemic inflammation induced by lipopolysaccharide (LPS) administration 5‐days before injury would modulate PTOA outcomes. RNA‐seq analysis at 1‐day post‐injury followed by micro‐computed tomography (μCT) and histology characterization at 6 weeks post‐injury revealed that LPS administration causes more severe PTOA phenotypes. These phenotypes included significantly higher loss of cartilage and subchondral bone volume. Gene expression analysis showed that LPS alone induced a large cohort of inflammatory genes previously shown to be elevated in synovial M1 macrophages of rheumatoid arthritis (RA) patients, suggesting that systemic LPS produces synovitis. This synovitis was sufficient to promote PTOA in MRL/MpJ mice, a strain previously shown to be resistant to PTOA. The synovium of LPS‐treated injured joints displayed an increase in cellularity, and immunohistological examination confirmed that this increase was in part attributable to an elevation in type 1 macrophages. LPS induced the expression of Tlr7 and Tlr8 in both injured and uninjured joints, genes known to be elevated in RA. We conclude that inflammation before injury is an important risk factor for the development of PTOA and that correlating patient serum endotoxin levels or their state of systemic inflammation with PTOA progression may help develop new, effective treatments to lower the rate of PTOA in injured individuals. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]
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- 2020
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18. Conditional Deletion of Sost in MSC‐Derived Lineages Identifies Specific Cell‐Type Contributions to Bone Mass and B‐Cell Development.
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Yee, Cristal S, Manilay, Jennifer O, Chang, Jiun C, Hum, Nicholas R, Murugesh, Deepa K, Bajwa, Jamila, Mendez, Melanie E, Economides, Aris E, Horan, Daniel J, Robling, Alexander G, and Loots, Gabriela G
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Sclerostin (Sost) is a negative regulator of bone formation and blocking its function via antibodies has shown great therapeutic promise by increasing both bone mass in humans and animal models. Sclerostin deletion in Sost KO mice (Sost−/−) causes high bone mass (HBM) similar to sclerosteosis patients. Sost−/− mice have been shown to display an up to 300% increase in bone volume/total volume (BV/TV), relative to age‐matched controls. It has been postulated that the main source of skeletal sclerostin is the osteocyte. To understand the cell‐type specific contributions to the HBM phenotype described in Sost−/− mice, as well as to address the endocrine and paracrine mode of action of sclerostin, we examined the skeletal phenotypes of conditional Sost loss‐of‐function (SostiCOIN/iCOIN) mice with specific deletions in (1) the limb mesenchyme (Prx1‐Cre; targets osteoprogenitors and their progeny); (2) midstage osteoblasts and their progenitors (Col1‐Cre); (3) mature osteocytes (Dmp1‐Cre); and (4) hypertrophic chondrocytes and their progenitors (ColX‐Cre). All conditional alleles resulted in significant increases in bone mass in trabecular bone in both the femur and lumbar vertebrae, but only Prx1‐Cre deletion fully recapitulated the amplitude of the HBM phenotype in the appendicular skeleton and the B‐cell defect described in the global KO. Despite WT expression of Sost in the axial skeleton of Prx1‐Cre deleted mice, these mice also had a significant increase in bone mass in the vertebrae, but the sclerostin released in circulation by the axial skeleton did not affect bone parameters in the appendicular skeleton. Also, both Col1 and Dmp1 deletion resulted in a similar 80% significant increase in trabecular bone mass, but only Col1 and Prx1 deletion resulted in a significant increase in cortical thickness. We conclude that several cell types within the Prx1‐osteoprogenitor‐derived lineages contribute significant amounts of sclerostin protein to the paracrine pool of Sost in bone. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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19. SOST/Sclerostin Improves Posttraumatic Osteoarthritis and Inhibits MMP2/3 Expression After Injury.
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Chang, Jiun C., Christiansen, Blaine A., Murugesh, Deepa K., Sebastian, Aimy, Hum, Nicholas R., Collette, Nicole M., Hatsell, Sarah, Economides, Aris N., Blanchette, Craig D., and Loots, Gabriela G.
- Abstract
ABSTRACT: Patients with anterior cruciate ligament (ACL) rupture are two times as likely to develop posttraumatic osteoarthritis (PTOA). Annually, there are ∼900,000 knee injuries in the United States, which account for ∼12% of all osteoarthritis (OA) cases. PTOA leads to reduced physical activity, deconditioning of the musculoskeletal system, and in severe cases requires joint replacement to restore function. Therefore, treatments that would prevent cartilage degradation post‐injury would provide attractive alternatives to surgery. Sclerostin (Sost), a Wnt antagonist and a potent negative regulator of bone formation, has recently been implicated in regulating chondrocyte function in OA. To determine whether elevated levels of Sost play a protective role in PTOA, we examined the progression of OA using a noninvasive tibial compression overload model in SOST transgenic (SOST
TG ) and knockout (Sost‐/‐ ) mice. Here we report that SOSTTG mice develop moderate OA and display significantly less advanced PTOA phenotype at 16 weeks post‐injury compared with wild‐type (WT) controls and Sost‐/‐ . In addition, SOSTTG built ∼50% and ∼65% less osteophyte volume than WT and Sost‐/‐ , respectively. Quantification of metalloproteinase (MMP) activity showed that SOSTTG had ∼2‐fold less MMP activation than WT or Sost‐/‐ , and this was supported by a significant reduction in MMP2/3 protein levels, suggesting that elevated levels of SOST inhibit the activity of proteolytic enzymes known to degrade articular cartilage matrix. Furthermore, intra‐articular administration of recombinant Sost protein, immediately post‐injury, also significantly decreased MMP activity levels relative to PBS‐treated controls, and Sost activation in response to injury was TNFα and NF‐κB dependent. These results provide in vivo evidence that sclerostin functions as a protective molecule immediately after joint injury to prevent cartilage degradation. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. [ABSTRACT FROM AUTHOR]- Published
- 2018
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20. Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts.
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Sebastian, Aimy, Hum, Nicholas R., Murugesh, Deepa K., Hatsell, Sarah, Economides, Aris N., and Loots, Gabriela G.
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WNT proteins ,MEMBRANE proteins ,BIOLOGICAL membranes ,JAK-STAT pathway ,CELLULAR signal transduction - Abstract
Wnt3a is a major regulator of bone metabolism however, very few of its target genes are known in bone. Wnt3a preferentially signals through transmembrane receptors Frizzled and co-receptors Lrp5/6 to activate the canonical signaling pathway. Previous studies have shown that the canonical Wnt co-receptors Lrp5 and Lrp6 also play an essential role in normal postnatal bone homeostasis, yet, very little is known about specific contributions by these co-receptors in Wnt3a-dependent signaling. We used high-throughput sequencing technology to identify target genes regulated by Wnt3a in osteoblasts and to elucidate the role of Lrp5 and Lrp6 in mediating Wnt3a signaling. Our study identified 782 genes regulated by Wnt3a in primary calvarial osteoblasts. Wnt3a up-regulated the expression of several key regulators of osteoblast proliferation/ early stages of differentiation while inhibiting genes expressed in later stages of osteoblastogenesis. We also found that Lrp6 is the key mediator of Wnt3a signaling in osteoblasts and Lrp5 played a less significant role in mediating Wnt3a signaling. [ABSTRACT FROM AUTHOR]
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- 2017
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21. Correction: Selective Erythroid Replacement in Murine |beta-Thalassemia Using Fetal Hematopoietic Stem Cells
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Bethel, Colin A., Murugesh, Deepa, Harrison, Michael R., Mohandas, Narla, and Rubin, Edward M.
- Published
- 1994
22. Global Gene Expression Analysis of Murine Limb Development.
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Taher, Leila, Collette, Nicole M., Murugesh, Deepa, Maxwell, Evan, Ovcharenko, Ivan, and Loots, Gabriela G.
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TRANSCRIPTION factors ,GENETIC regulation ,HEREDITY ,MORPHOGENESIS ,MORPHOLOGY ,NERVOUS system - Abstract
Detailed information about stage-specific changes in gene expression is crucial for understanding the gene regulatory networks underlying development and the various signal transduction pathways contributing to morphogenesis. Here we describe the global gene expression dynamics during early murine limb development, when cartilage, tendons, muscle, joints, vasculature and nerves are specified and the musculoskeletal system of limbs is established. We used whole-genome microarrays to identify genes with differential expression at 5 stages of limb development (E9.5 to 13.5), during fore- and hind-limb patterning. We found that the onset of limb formation is characterized by an up-regulation of transcription factors, which is followed by a massive activation of genes during E10.5 and E11.5 which levels off at later time points. Among the 3520 genes identified as significantly up-regulated in the limb, we find ∼30% to be novel, dramatically expanding the repertoire of candidate genes likely to function in the limb. Hierarchical and stage-specific clustering identified expression profiles that are likely to correlate with functional programs during limb development and further characterization of these transcripts will provide new insights into specific tissue patterning processes. Here, we provide for the first time a comprehensive analysis of developmentally regulated genes during murine limb development, and provide some novel insights into the expression dynamics governing limb morphogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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23. Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice.
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Donham, Cristine, Chicana, Betsabel, Robling, Alexander G., Mohamed, Asmaa, Elizaldi, Sonny, Chi, Michael, Freeman, Brian, Millan, Alberto, Murugesh, Deepa K., Hum, Nicholas R., Sebastian, Aimy, Loots, Gabriela G., and Manilay, Jennifer O.
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BONE marrow ,SCLEROSTIN ,OSTEITIS ,EXTRAMEDULLARY hematopoiesis ,HEMATOPOIETIC stem cells ,HEMATOPOIESIS - Abstract
Romosozumab, a humanized monoclonal antibody specific for sclerostin (SOST), has been approved for treatment of postmenopausal women with osteoporosis at a high risk for fracture. Previous work in sclerostin global knockout (Sost
−/− ) mice indicated alterations in immune cell development in the bone marrow (BM), which could be a possible side effect in romosozumab-treated patients. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young mice receiving sclerostin antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term Sost deficiency on wild-type (WT) long-term hematopoietic stem cells transplanted into older cohorts of Sost−/− mice. Our analyses revealed an increased frequency of granulocytes in the BM of Scl-Ab-treated mice and WT→Sost−/− chimeras, indicating myeloid-biased differentiation in Sost-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNFα, IL-1α, and MCP-1 in Sost−/− BM serum. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of Sost−/− mice. Taken together, our current study indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM. [ABSTRACT FROM AUTHOR]- Published
- 2021
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24. Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes.
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Sebastian, Aimy, McCool, Jillian L., Hum, Nicholas R., Murugesh, Deepa K., Wilson, Stephen P., Christiansen, Blaine A., and Loots, Gabriela G.
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CARTILAGE ,ARTICULAR cartilage ,JOINTS (Anatomy) ,CONNECTIVE tissues ,RNA sequencing ,HETEROGENEITY ,EXTRACELLULAR matrix ,CARTILAGE cells - Abstract
Articular cartilage is a connective tissue lining the surfaces of synovial joints. When the cartilage severely wears down, it leads to osteoarthritis (OA), a debilitating disease that affects millions of people globally. The articular cartilage is composed of a dense extracellular matrix (ECM) with a sparse distribution of chondrocytes with varying morphology and potentially different functions. Elucidating the molecular and functional profiles of various chondrocyte subtypes and understanding the interplay between these chondrocyte subtypes and other cell types in the joint will greatly expand our understanding of joint biology and OA pathology. Although recent advances in high-throughput OMICS technologies have enabled molecular-level characterization of tissues and organs at an unprecedented resolution, thorough molecular profiling of articular chondrocytes has not yet been undertaken, which may be in part due to the technical difficulties in isolating chondrocytes from dense cartilage ECM. In this study, we profiled articular cartilage from healthy and injured mouse knee joints at a single-cell resolution and identified nine chondrocyte subtypes with distinct molecular profiles and injury-induced early molecular changes in these chondrocytes. We also compared mouse chondrocyte subpopulations to human chondrocytes and evaluated the extent of molecular similarity between mice and humans. This work expands our view of chondrocyte heterogeneity and rapid molecular changes in chondrocyte populations in response to joint trauma and highlights potential mechanisms that trigger cartilage degeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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25. Diabetes Promotes Mild Osteoarthritis in The Streptozotocin‐ Induced Diabetic Mouse Model.
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Rios Arce, Naiomy, Murugesh, Deepa, Hum, Nicholas, Sebastian, Aimy, Jbeily, Elias, Christiansen, Blaine, and Loots, Gabriela
- Abstract
R2490 --> Osteoarthritis (OA) is a degenerative joint disease that affects millions of people worldwide. In the United States alone OA affects more than 30 million adults. Several risk factors for OA are well studied, still, there are no therapies to prevent OA. Diabetes mellitus has emerged as a possible risk factor for OA. However, the current literature shows inconsistent results and most of these studies do not address the molecular changes associated with this effect. In addition, most of these studies do not account for changes in body mass index, a well‐known risk factor for OA. In the present study, we first aimed to determine if diabetes is indeed a risk factor for OA, independently of body mass index. Next, we examined diabetes‐related molecular changes in the mouse cartilage knee joints that could contribute to OA. We hypothesized that diabetes would promote OA. Sixteen weeks old streptozotocin‐induced diabetic male mice were assessed for OA and molecular changes in the knee cartilage joint. Cartilage degeneration measurements of the knee joint show a mild OA phenotype in the diabetic group, characterized by proteoglycan loss, when compared to the control group, suggesting that diabetes can moderately promote OA. However, diabetes does not intensify post‐traumatic osteoarthritis induced by a non‐invasive tibial compression injury model. Changes in cartilage knee joint gene expression by RNA sequencing (RNAseq) identified 519 up regulated genes and 645 down regulated genes differentially regulated between diabetic and non‐diabetic animals. This includes known regulators of cartilage and bone remodeling genes such as Col11a2, Col27a1, Mmp28, Adam33, Bglap, Ctsk and Acp5. Our findings suggest that diabetes can be a risk factor for OA, and we identified differential expression of genes that might contribute to the enhanced OA phenotype observed in the diabetic group. This study provides the first account of cartilage knee joint gene expression changes related to diabetes and the risk of OA. Understanding the relationship between diabetes and OA and the molecular changes associated with this can lead to the development of new therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. Antibiotic Treatment Prior to Injury Improves Post-Traumatic Osteoarthritis Outcomes in Mice.
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Mendez, Melanie E., Murugesh, Deepa K., Sebastian, Aimy, Hum, Nicholas R., McCloy, Summer A., Kuhn, Edward A., Christiansen, Blaine A., and Loots, Gabriela G.
- Subjects
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ANTERIOR cruciate ligament injuries , *ARTICULAR cartilage , *OSTEOARTHRITIS , *GUT microbiome , *WNT signal transduction , *CARTILAGE - Abstract
Osteoarthritis (OA) is a painful and debilitating disease characterized by the chronic and progressive degradation of articular cartilage. Post-traumatic OA (PTOA) is a secondary form of OA that develops in ~50% of cases of severe articular injury. Inflammation and re-occurring injury have been implicated as contributing to the progression of PTOA after the initial injury. However, there is very little known about external factors prior to injury that could affect the risk of PTOA development. To examine how the gut microbiome affects PTOA development we used a chronic antibiotic treatment regimen starting at weaning for six weeks prior to ACL rupture, in mice. A six-weeks post-injury histological examination showed more robust cartilage staining on the antibiotic (AB)-treated mice than the untreated controls (VEH), suggesting slower disease progression in AB cohorts. Injured joints also showed an increase in the presence of anti-inflammatory M2 macrophages in the AB group. Molecularly, the phenotype correlated with a significantly lower expression of inflammatory genes Tlr5, Ccl8, Cxcl13, and Foxo6 in the injured joints of AB-treated animals. Our results indicate that a reduced state of inflammation at the time of injury and a lower expression of Wnt signaling modulatory protein, Rspo1, caused by AB treatment can slow down or improve PTOA outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
27. Global Gene Expression Analysis Identifies Age-Related Differences in Knee Joint Transcriptome during the Development of Post-Traumatic Osteoarthritis in Mice.
- Author
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Sebastian, Aimy, Murugesh, Deepa K., Mendez, Melanie E., Hum, Nicholas R., Rios-Arce, Naiomy D., McCool, Jillian L., Christiansen, Blaine A., and Loots, Gabriela G.
- Subjects
- *
GENE expression , *OSTEOARTHRITIS , *MICE , *BONE metabolism , *AGE groups , *KNEE , *CARTILAGE cells - Abstract
Aging and injury are two major risk factors for osteoarthritis (OA). Yet, very little is known about how aging and injury interact and contribute to OA pathogenesis. In the present study, we examined age- and injury-related molecular changes in mouse knee joints that could contribute to OA. Using RNA-seq, first we profiled the knee joint transcriptome of 10-week-old, 62-week-old, and 95-week-old mice and found that the expression of several inflammatory-response related genes increased as a result of aging, whereas the expression of several genes involved in cartilage metabolism decreased with age. To determine how aging impacts post-traumatic arthritis (PTOA) development, the right knee joints of 10-week-old and 62-week-old mice were injured using a non-invasive tibial compression injury model and injury-induced structural and molecular changes were assessed. At six-week post-injury, 62-week-old mice displayed significantly more cartilage degeneration and osteophyte formation compared with young mice. Although both age groups elicited similar transcriptional responses to injury, 62-week-old mice had higher activation of inflammatory cytokines than 10-week-old mice, whereas cartilage/bone metabolism genes had higher expression in 10-week-old mice, suggesting that the differential expression of these genes might contribute to the differences in PTOA severity observed between these age groups. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
28. Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression.
- Author
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Sebastian, Aimy, Chang, Jiun C., Mendez, Melanie E., Murugesh, Deepa K., Hatsell, Sarah, Economides, Aris N., Christiansen, Blaine A., and Loots, Gabriela G.
- Subjects
ANTERIOR cruciate ligament ,OSTEOARTHRITIS ,GENE expression ,RNA sequencing ,CYTOKINES ,ENZYMES - Abstract
Anterior cruciate ligament (ACL) injuries often result in post-traumatic osteoarthritis (PTOA). To better understand the molecular mechanisms behind PTOA development following ACL injury, we profiled ACL injury-induced transcriptional changes in knee joints of three mouse strains with varying susceptibility to OA: STR/ort (highly susceptible), C57BL/6J (moderately susceptible) and super-healer MRL/MpJ (not susceptible). Right knee joints of the mice were injured using a non-invasive tibial compression injury model and global gene expression was quantified before and at 1-day, 1-week, and 2-weeks post-injury using RNA-seq. Following injury, injured and uninjured joints of STR/ort and injured C57BL/6J joints displayed significant cartilage degeneration while MRL/MpJ had little cartilage damage. Gene expression analysis suggested that prolonged inflammation and elevated catabolic activity in STR/ort injured joints, compared to the other two strains may be responsible for the severe PTOA phenotype observed in this strain. MRL/MpJ had the lowest expression values for several inflammatory cytokines and catabolic enzymes activated in response to ACL injury. Furthermore, we identified several genes highly expressed in MRL/MpJ compared to the other two strains including B4galnt2 and Tpsab1 which may contribute to enhanced healing in the MRL/MpJ. Overall, this study has increased our knowledge of early molecular changes associated with PTOA development. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
29. HIGH EFFICIENCY GENETIC MODIFICATION OF UNSTIMULATED PRIMARY CD8+ AND CD34+ CELLS USING ADENO-ASSOCIATED VIRUS PLASMID LIPOSOME COMPLEXES.
- Author
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Lebkowski, Jane S., Brunette, Elisa, Kilinski, Lydia, Murugesh, Deepa, Berson, Amy E., Philip, Mohan, Okarma, Thomas B., and Philip, Ramila
- Published
- 1994
- Full Text
- View/download PDF
30. Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner.
- Author
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Collette, Nicole M., Yee, Cristal S., Murugesh, Deepa, Sebastian, Aimy, Taher, Leila, Gale, Nicholas W., Economides, Aris N., Harland, Richard M., and Loots, Gabriela G.
- Subjects
- *
LIFE sciences , *WNT genes , *CELLULAR signal transduction , *HOMEOSTASIS , *BONE diseases , *DEVELOPMENTAL biology - Abstract
Abstract: WNT signaling is critical in most aspects of skeletal development and homeostasis, and antagonists of WNT signaling are emerging as key regulatory proteins with great promise as therapeutic agents for bone disorders. Here we show that Sost and its paralog Sostdc1 emerged through ancestral genome duplication and their expression patterns have diverged to delineate non-overlapping domains in most organ systems including musculoskeletal, cardiovascular, nervous, digestive, reproductive and respiratory. In the developing limb, Sost and Sostdc1 display dynamic expression patterns with Sost being restricted to the distal ectoderm and Sostdc1 to the proximal ectoderm and the mesenchyme. While Sostdc1 −/− mice lack any obvious limb or skeletal defects, Sost −/− mice recapitulate the hand defects described for Sclerosteosis patients. However, elevated WNT signaling in Sost −/− ; Sostdc1 −/− mice causes misregulation of SHH signaling, ectopic activation of Sox9 in the digit 1 field and preaxial polydactyly in a Gli1- and Gli3-dependent manner. In addition, we show that the syndactyly documented in Sclerosteosis is present in both Sost −/− and Sost −/− ; Sostdc1 −/− mice, and is driven by misregulation of Fgf8 in the AER, a region lacking Sost and Sostdc1 expression. This study highlights the complexity of WNT signaling in skeletal biology and disease and emphasizes how redundant mechanism and non-cell autonomous effects can synergize to unveil new intricate phenotypes caused by elevated WNT signaling. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
31. Sostdc1 Regulates NK Cell Maturation and Cytotoxicity.
- Author
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Millan, Alberto J., Elizaldi, Sonny R., Lee, Eric M., Aceves, Jeffrey O., Murugesh, Deepa, Loots, Gabriela G., and Manilay, Jennifer O.
- Subjects
- *
KILLER cells , *CELL physiology , *CELLULAR control mechanisms , *CELL-mediated cytotoxicity , *CELL growth - Abstract
NK cells are innate-like lymphocytes that eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified roles for sclerostin domain--containing-1 (Sostdc1) in NK cell development and function. Sostdc1-knockout (Sostdc1-/-) mice display a progressive accumulation of transitional NK cells (tNKs) (CD27+CD11b+) with age, indicating a partial developmental block. The NK cell Ly49 repertoire in Sostdc1-/- mice is also changed. Lower frequencies of Sostdc1-/- splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I+, G2+, H+, and D+ populations were universally decreased at the most mature (CD272CD11b+) stage. We hypothesized that the Ly49 repertoire in Sostdc1-/- mice would correlate with NK killing ability and observed that Sostdc1-/- NK cells are hyporesponsive against MHC class I--deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-g expression to controls. Consistent with Sostdc1's known role in Wnt signaling regulation, Tcf7 and Lef1 levels were higher in Sostdc1-/- NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1-/- immature NK and tNK cells, but Eomes and Tbx21 expression was unaffected. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both nonhematopoietic and hematopoietic sources. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation and cytotoxicity, and identify potential NK cell niches. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
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32. Global gene expression analysis identifies Mef2c as a potential player in Wnt16-mediated transcriptional regulation.
- Author
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Sebastian, Aimy, Hum, Nicholas R., Morfin, Cesar, Murugesh, Deepa K., and Loots, Gabriela G.
- Subjects
- *
WNT genes , *GENE expression , *GENETIC transcription regulation , *BONE resorption , *GENE targeting , *HOMEOSTASIS - Abstract
Abstract Wnt16 is a major Wnt ligand involved in the regulation of postnatal bone homeostasis. Previous studies have shown that Wnt16 promotes bone formation and inhibits bone resorption, suggesting that this molecule could be targeted for therapeutic interventions to treat bone thinning disorders such as osteoporosis. However, the molecular mechanisms by which Wnt16 regulates bone metabolism is not yet fully understood. To better understand the molecular mechanisms by which Wnt16 promotes bone formation and to identify the target genes regulated by Wnt16 in osteoblasts, we treated calvarial osteoblasts purified from C57Bl / 6 mice with recombinant Wnt16 and profiled the gene expression changes by RNA-seq at 24 h post-treatment. We also compared gene expression profiles of Wnt16-treated osteoblasts to canonical Wnt3a- and non-canonical Wnt5a-treated osteoblasts. This study identified 576 genes differentially expressed in Wnt16-treated osteoblasts compared to sham-treated controls; these included several members of Wnt pathway ( Wnt2b , Wnt7b , Wnt11 , Axin2 , Sfrp2 , Sfrp4 , Fzd5 etc.) and TGF-β/BMP signaling pathway ( Bmp7 , Inhba , Inhbb , Tgfb2 etc.). Wnt16 also regulated a large number of genes with known bone phenotypes. We also found that about 37% (215/576) of the Wnt16 targets overlapped with Wnt3a targets and ~15% (86/576) overlapped with Wnt5a targets, suggesting that Wnt16 activates both canonical and non-canonical Wnt signaling targets in osteoblasts. Transcription factor binding motif enrichment analysis in the promoter regions of Wnt16 targets identified noncanonical Wnt/JNK pathway activated transcription factors Fosl2 and Fosl1 as two of the most significantly enriched transcription factors associated with genes activated by Wnt16 while Mef2c was the most significantly enriched transcription factor associated with genes repressed by Wnt16. We also found that a large number of Mef2c targets overlapped with genes down-regulated by Wnt16 and Mef2c itself was transcriptionally repressed by Wnt16 suggesting that Mef2c plays a role in Wnt16-mediated transcriptional regulation. Highlights • Wnt16 regulated the expression of 576 genes in osteoblasts. • Wnt16 targets overlapped with both Wnt3a and Wnt5a targets. • Genes repressed by Wnt16 showed enrichment for Mef2c binding motifs. • Wnt16 transcriptionally suppressed Mef2c. • A large number of Mef2c targets overlapped with genes down-regulated by Wnt16. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
33. Preaxial polydactyly caused by hyperactive WNT signaling in Sclerostin/Sostdc1 double knockouts
- Author
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Collette, Nicole M., Yee, Cristal, Murugesh, Deepa, Harland, Richard, and Loots, Gabriela
- Published
- 2011
- Full Text
- View/download PDF
34. Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline.
- Author
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Lau EY, Negrete OA, Bennett WFD, Bennion BJ, Borucki M, Bourguet F, Epstein A, Franco M, Harmon B, He S, Jones D, Kim H, Kirshner D, Lao V, Lo J, McLoughlin K, Mosesso R, Murugesh DK, Saada EA, Segelke B, Stefan MA, Stevenson GA, Torres MW, Weilhammer DR, Wong S, Yang Y, Zemla A, Zhang X, Zhu F, Allen JE, and Lightstone FC
- Abstract
A rapid response is necessary to contain emergent biological outbreaks before they can become pandemics. The novel coronavirus (SARS-CoV-2) that causes COVID-19 was first reported in December of 2019 in Wuhan, China and reached most corners of the globe in less than two months. In just over a year since the initial infections, COVID-19 infected almost 100 million people worldwide. Although similar to SARS-CoV and MERS-CoV, SARS-CoV-2 has resisted treatments that are effective against other coronaviruses. Crystal structures of two SARS-CoV-2 proteins, spike protein and main protease, have been reported and can serve as targets for studies in neutralizing this threat. We have employed molecular docking, molecular dynamics simulations, and machine learning to identify from a library of 26 million molecules possible candidate compounds that may attenuate or neutralize the effects of this virus. The viability of selected candidate compounds against SARS-CoV-2 was determined experimentally by biolayer interferometry and FRET-based activity protein assays along with virus-based assays. In the pseudovirus assay, imatinib and lapatinib had IC
50 values below 10 μM, while candesartan cilexetil had an IC50 value of approximately 67 µM against Mpro in a FRET-based activity assay. Comparatively, candesartan cilexetil had the highest selectivity index of all compounds tested as its half-maximal cytotoxicity concentration 50 (CC50 ) value was the only one greater than the limit of the assay (>100 μM)., Competing Interests: Authors OAN, BH, RM, EAS, and MAS were employed by Sandia National Laboratories. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lau, Negrete, Bennett, Bennion, Borucki, Bourguet, Epstein, Franco, Harmon, He, Jones, Kim, Kirshner, Lao, Lo, McLoughlin, Mosesso, Murugesh, Saada, Segelke, Stefan, Stevenson, Torres, Weilhammer, Wong, Yang, Zemla, Zhang, Zhu, Allen and Lightstone.)- Published
- 2021
- Full Text
- View/download PDF
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