Browsing by Author "Corry, Kylie A."

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    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 Science
    Correction to: Scientific Reports https://doi.org/10.1038/s41598-019-57185-1, published online 15 January 2020
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    Genome-wide Analysis Using ChIP-seq Reveals Novel Downstream Targets of Stat3
    (Office of the Vice Chancellor for Research, 2015-04-17) Corry, Kylie A.; Li, Jiliang
    Many cells are involved in the orchestra that is bone homeostasis--particularly osteoclasts and osteoblasts who mediate remodeling of bones. This creates a balance that must be kept in check, otherwise pathologies arise. The JAK-Stat signaling pathway is crucial to maintaining this balance. It has long been known that the transcription factor Stat3 has more profound effects on bone homeostasis than other members of the Stat family of proteins. Recently, a genetic condition called Job’s Syndrome has been specifically linked to point mutations in the STAT3 gene. These patients present with severe bone abnormalities including prominent foreheads, broad nasal bridges, and abnormal eye spacing. Therefore, our lab has extensively studied conditional knockouts of Stat3 in all three types of bones cells in mice and observed severe deficiencies in numerous parameters of normal bone phenotypes. Stat3 seems to play a principal role in the signaling that takes place upon mechanical loading of bone tissues and calling cells into action where they are needed. Furthermore, STAT3 has been found to be up-regulated in the early-response gene cluster following mechanical loading. Our current approach to studying Stat3’s effects on bone include employing available ChIP-seq data in order to elucidate the genome-wide binding patterns of Stat3. From the peak distribution, we can begin to uncover novel downstream effectors of Stat3 signaling that are responsible for the observed phenotypes in our mouse knockout model. A preliminary look at the ChIP-seq data reveals Wnt and Nrf2 signaling to be under the control of Stat3. In our further research we endeavor to experimentally confirm the ChIP-seq data for Stat3 with RNA-seq experiments in the hopes of finding potential therapeutic targets for bone pathologies.
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    Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice
    (Nature Research, 2020-01-15) Yin, Yukun; Corry, Kylie A.; Loughran, John P.; Li, Jiliang; Biology, School of Science
    Keap1 is a negative controller of the transcription factor Nrf2 for its activity. The Keap1/Nrf2 signaling pathway has been considered as a master regulator of cytoprotective genes, and exists in many cell types including osteoblasts and osteoclasts. Our previous study shows Nrf2 deletion decreases bone formation. Recent studies show hyperactivation of Nrf2 causes osteopenia in Keap1−/− mice, and Keap1−/− osteoblasts have significantly less proliferative potential than Keap1+/− osteoblasts. We aimed to examine if moderate Nrf2 activation by disruption of Keap1 impacts bone metabolism. We examined bone phenotype of Keap1 heterozygotic mice (Ht) in comparison with Keap1 wild type (WT) mice. Deletion or knockdown of Keap1 enhanced the gene expression of Nrf2, ALP and wnt5a in cultured primary osteoblasts compared to WT control. In male mice, compared with their age-matched littermate WT controls, Keap1 Ht mice showed significant increase in bone formation rate (+30.7%, P = 0.0029), but did not change the ultimate force (P < 0.01). The osteoclast cell numbers (−32.45%, P = 0.01) and surface (−32.58%, P = 0.03) were significantly reduced by Keap1 deficiency in male mice. Compared to male WT mice, serum bone resorption marker in male Keap1 Ht mice was significantly decreased. Our data suggest that moderate Nrf2 activation by disruption of Keap1 improved bone mass by regulating bone remodeling in male mice.
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    Novel insights into the mechanistic gene regulation of STAT3 in bone cells
    (2015-06-25) Corry, Kylie A.; Li, Jiliang; Bidwell, Joseph; Na, Sungsoo
    Many cells are involved in the orchestra that is bone homeostasis--particularly osteoclasts and osteoblasts, which mediate remodeling of bones. This creates a balance that must be kept in check, otherwise pathologies arise. The JAK-STAT signaling pathway is crucial to maintaining this balance. It has long been known that the transcription factor STAT3 has more profound effects on bone homeostasis than other members of the STAT family of proteins. Recently, a genetic condition called Job’s Syndrome has been specifically linked to point mutations in the Stat3 gene. These patients present with severe bone abnormalities, including prominent foreheads, broad nasal bridges, and abnormal eye spacing. For this reason, our lab has extensively studied conditional knockouts of Stat3 in all three types of bones cells in mice and observed severe deficiencies in numerous parameters of normal bone phenotypes. STAT3 seems to play a principal role in the signaling that takes place upon mechanical loading of bone tissues and calling cells into action where they are needed. Furthermore, STAT3 has been found to be up-regulated in the early-response gene cluster following mechanical loading. Our current approach to studying STAT3’s effects on bone includes both in vivo and in vitro comparisons of WT and KO STAT3 models. The conditional knock-out of STAT3 in 8-week old mice revealed significant phenotypic variations as compared to the WT controls, while no significant differences were observed in cKO newborn pups. We also looked at immortalized WT and STAT3 KO cell lines. The STAT3 KO cells had diminished proliferation rates and decreased differentiation capabilities. Furthermore, STAT3 KO cells showed significantly reduced mRNA levels of both Wnt3a and Wnt5a when exposed to fluid shear stress. By employing available ChIP-seq data, we were able to elucidate the genome-wide binding patterns of STAT3. From the peak distribution, we can begin to uncover novel downstream effectors of STAT3 signaling that are responsible for the observed phenotypes in our conditional knockout mouse model. A preliminary look at the ChIP-seq data reveals Wnt and Nrf2 signaling to be under the putative control of STAT3. In our further research, we endeavor to experimentally confirm the ChIP-seq data for STAT3 with RNA-seq experiments in the hopes of finding potential therapeutic targets for bone pathologies.
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    Stat3 in osteocytes mediates osteogenic response to loading
    (Elsevier, 2019-07-29) Corry, Kylie A.; Zhou, Hongkang; Brustovetsky, Tatiana; Himes, Evan R.; Bivi, Nicoletta; Horn, M. Ryne; Kitase, Yukiko; Wallace, Joseph M.; Bellido, Teresita; Brustovetsky, Nickolay; Li, Jiliang; Biology, School of Science
    Signal transducer and activator of transcription 3 (Stat3) is a member of the Stat family of proteins involved in signaling in many different cell types, including osteocytes. Osteocytes are considered major mechanosensing cells in bone due to their intricate dendritic networks able to sense changes in physical force and to orchestrate the response of osteoclasts and osteoblasts. We examined the role of Stat3 in osteocytes by generating mice lacking Stat3 in these cells using the Dmp-1(8kb)-Cre promoter (Stat3cKO mice). Compared to age-matched littermate controls, Stat3cKO mice of either sex (18 weeks old) exhibit reduced bone formation indices, decreased osteoblasts and increased osteoclasts, and altered material properties, without detectable changes in bone mineral density (BMD) or content of either trabecular or cortical bone. In addition, Stat3cKO mice of either sex show significantly decreased load-induced bone formation. Furthermore, pharmacologic inhibition of Stat3 in osteocytes in vitro with WP1066 blocked the increase in cytosolic calcium induced by ATP, a mediator of the cellular responses to sheer stress. WP1066 also increased reactive oxygen species (ROS) production in cultured MLO-Y4 osteocytes. These data demonstrate that Stat3 is a critical mediator of mechanical signals received by osteocytes and suggest that osteocytic Stat3 is a potential therapeutic target to stimulate bone anabolism.