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Article ; Online: The cytoskeleton and connected elements in bone cell mechano-transduction.

Gould, Nicole R / Torre, Olivia M / Leser, Jenna M / Stains, Joseph P

2021 Volume 149, Page(s) 115971

Abstract: Bone is a mechano-responsive tissue that adapts to changes in its mechanical environment. Increases in strain lead to increased bone mass acquisition, whereas decreases in strain lead to a loss of bone mass. Given that mechanical stress is a regulator of ...

Abstract	Bone is a mechano-responsive tissue that adapts to changes in its mechanical environment. Increases in strain lead to increased bone mass acquisition, whereas decreases in strain lead to a loss of bone mass. Given that mechanical stress is a regulator of bone mass and quality, it is important to understand how bone cells sense and transduce these mechanical cues into biological changes to identify druggable targets that can be exploited to restore bone cell mechano-sensitivity or to mimic mechanical load. Many studies have identified individual cytoskeletal components - microtubules, actin, and intermediate filaments - as mechano-sensors in bone. However, given the high interconnectedness and interaction between individual cytoskeletal components, and that they can assemble into multiple discreet cellular structures, it is likely that the cytoskeleton as a whole, rather than one specific component, is necessary for proper bone cell mechano-transduction. This review will examine the role of each cytoskeletal element in bone cell mechano-transduction and will present a unified view of how these elements interact and work together to create a mechano-sensor that is necessary to control bone formation following mechanical stress.
MeSH term(s)	Actin Cytoskeleton ; Actins ; Cytoskeleton ; Intermediate Filaments ; Microtubules ; Osteocytes
Chemical Substances	Actins
Language	English
Publishing date	2021-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	632515-4
ISSN	1873-2763 ; 8756-3282
ISSN (online)	1873-2763
ISSN	8756-3282
DOI	10.1016/j.bone.2021.115971
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Article ; Online: Osteoblast-lineage calcium/calmodulin-dependent kinase 2 delta and gamma regulates bone mass and quality.

Leser, Jenna M / Torre, Olivia M / Gould, Nicole R / Guo, Qiaoyue / Buck, Heather V / Kodama, Joe / Otsuru, Satoru / Stains, Joseph P

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 47, Page(s) e2304492120

Abstract: Bone regulates its mass and quality in response to diverse mechanical, hormonal, and local signals. The bone anabolic or catabolic responses to these signals are often received by osteocytes, which then coordinate the activity of osteoblasts and ... ...

Abstract	Bone regulates its mass and quality in response to diverse mechanical, hormonal, and local signals. The bone anabolic or catabolic responses to these signals are often received by osteocytes, which then coordinate the activity of osteoblasts and osteoclasts on bone surfaces. We previously established that calcium/calmodulin-dependent kinase 2 (CaMKII) is required for osteocytes to respond to some bone anabolic cues in vitro. However, a role for CaMKII in bone physiology in vivo is largely undescribed. Here, we show that conditional codeletion of the most abundant isoforms of CaMKII (delta and gamma) in mature osteoblasts and osteocytes [Ocn-cre:
MeSH term(s)	Mice ; Animals ; Calcium/metabolism ; Calmodulin/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Osteoblasts/metabolism ; Osteocytes/metabolism ; Phosphates/metabolism ; Hypophosphatemia
Chemical Substances	Calcium (SY7Q814VUP) ; Calmodulin ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17) ; Phosphates ; Camk2g protein, mouse (EC 2.7.11.17)
Language	English
Publishing date	2023-11-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2304492120
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Article ; Online: Aging, Osteo-Sarcopenia, and Musculoskeletal Mechano-Transduction.

Leser, Jenna M / Harriot, Anicca / Buck, Heather V / Ward, Christopher W / Stains, Joseph P

Frontiers in rehabilitation sciences

2021 Volume 2

Abstract: The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, ... ...

Abstract	The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, falls, low-energy fractures, and increased risk of co-morbid disease that leads to musculoskeletal frailty. The biology of osteo-sarcopenia is most understood in the context of systemic neuro-endocrine and immune/inflammatory alterations that drive inflammation, oxidative stress, reduced autophagy, and cellular senescence in the bone and muscle. Here we integrate these concepts to our growing understanding of how bone and muscle senses, responds and adapts to mechanical load. We propose that age-related alterations in cytoskeletal mechanics alter load-sensing and mechano-transduction in bone osteocytes and muscle fibers which underscores osteo-sarcopenia. Lastly, we examine the evidence for exercise as an effective countermeasure to osteo-sarcopenia.
Language	English
Publishing date	2021-12-06
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-6861
ISSN (online)	2673-6861
DOI	10.3389/fresc.2021.782848
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Article ; Online: In vitro

Gould, Nicole R / Leser, Jenna M / Torre, Olivia M / Khairallah, Ramzi J / Ward, Christopher W / Stains, Joseph P

Bio-protocol

2021 Volume 11, Issue 23, Page(s) e4251

Abstract: Bone is a dynamic tissue that adapts to changes in its mechanical environment. Mechanical stimuli pressurize interstitial fluid in the lacunar-canalicular system within the bone matrix, causing fluid shear stress (FSS) across bone embedded, mechano- ... ...

Abstract	Bone is a dynamic tissue that adapts to changes in its mechanical environment. Mechanical stimuli pressurize interstitial fluid in the lacunar-canalicular system within the bone matrix, causing fluid shear stress (FSS) across bone embedded, mechano-sensitive osteocytes. Therefore, modeling this mechanical stimulus
Language	English
Publishing date	2021-12-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.4251
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Article ; Online: Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease.

Kulkarni, Subhash / Saha, Monalee / Slosberg, Jared / Singh, Alpana / Nagaraj, Sushma / Becker, Laren / Zhang, Chengxiu / Bukowski, Alicia / Wang, Zhuolun / Liu, Guosheng / Leser, Jenna M / Kumar, Mithra / Bakhshi, Shriya / Anderson, Matthew J / Lewandoski, Mark / Vincent, Elizabeth / Goff, Loyal A / Pasricha, Pankaj Jay

eLife

2023 Volume 12

Abstract: The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating ... ...

Abstract	The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.
MeSH term(s)	Adult ; Humans ; Glial Cell Line-Derived Neurotrophic Factor ; Enteric Nervous System ; Gastrointestinal Motility ; Gene Expression Profiling ; Mesoderm
Chemical Substances	Glial Cell Line-Derived Neurotrophic Factor
Language	English
Publishing date	2023-12-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.88051
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Article: Connexin43 regulates osteoprotegerin expression via ERK1/2 -dependent recruitment of Sp1

Gupta, Aditi / Leser, Jenna M / Gould, Nicole R / Buo, Atum M / Moorer, Megan C / Stains, Joseph P

Biochemical and biophysical research communications. 2019 Feb. 12, v. 509, no. 3

2019

Abstract: In bone, connexin43 expression in cells of the osteoblast lineage plays an important role in restraining osteoclastogenesis and bone resorption. While there is a consensus around the notion that the anti-osteoclastogenic factor, osteoprotegerin, is a ... ...

Abstract	In bone, connexin43 expression in cells of the osteoblast lineage plays an important role in restraining osteoclastogenesis and bone resorption. While there is a consensus around the notion that the anti-osteoclastogenic factor, osteoprotegerin, is a driver of this effect, how connexin43 regulates osteoprotegerin gene expression is unclear. Here, we show that loss of connexin43 decreased osteoprotegerin gene expression and reduced ERK1/2 activation. Conversely, overexpression of connexin43 increased osteoprotegerin expression and enhanced ERK1/2 activation. This increase in phospho-ERK1/2 is required for connexin43 to induce transcription from the osteoprotegerin proximal promoter. Connexin43 increased promoter activity via a specific 200 base pair region of the osteoprotegerin promoter located at −1486 to −1286 with respect to the transcriptional start site, a region which includes four Sp1 binding elements. Further, activation of this promoter region required an intact functional connexin43, as hypomorphic or dominant negative connexin43 mutant constructs, including one with increased hemichannel activity, were unable to stimulate osteoprotegerin expression as strongly as wild type connexin43. Using chromatin immunoprecipitations, we show that connexin43 expression enhanced the recruitment of Sp1, but not Runx2, to the osteoprotegerin proximal promoter. In total, these data show that connexin43-dependent gap junctional communication among osteoblast cells permits efficient ERK1/2 activation. ERK1/2 signaling promotes the recruitment of the potent transcriptional activator, Sp1, to the osteoprotegerin proximal promoter, resulting in robust transcription of anti-osteoclastogenic factor, osteoprotegerin.
Keywords	bone resorption ; chromatin ; gene expression ; mutants ; osteoblasts ; precipitin tests ; promoter regions ; transactivators ; transcription (genetics)
Language	English
Dates of publication	2019-0212
Size	p. 728-733.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2018.12.173
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Article ; Online: TRPV4 calcium influx controls sclerostin protein loss independent of purinergic calcium oscillations.

Williams, Katrina M / Leser, Jenna M / Gould, Nicole R / Joca, Humberto C / Lyons, James S / Khairallah, Ramzi J / Ward, Christopher W / Stains, Joseph P

Bone

2020 Volume 136, Page(s) 115356

Abstract: Skeletal remodeling is driven in part by the osteocyte's ability to respond to its mechanical environment by regulating the abundance of sclerostin, a negative regulator of bone mass. We have recently shown that the osteocyte responds to fluid shear ... ...

Abstract	Skeletal remodeling is driven in part by the osteocyte's ability to respond to its mechanical environment by regulating the abundance of sclerostin, a negative regulator of bone mass. We have recently shown that the osteocyte responds to fluid shear stress via the microtubule network-dependent activation of NADPH oxidase 2 (NOX2)-generated reactive oxygen species and subsequent opening of TRPV4 cation channels, leading to calcium influx, activation of CaMKII, and rapid sclerostin protein downregulation. In addition to the initial calcium influx, purinergic receptor signaling and calcium oscillations occur in response to mechanical load and prior to rapid sclerostin protein loss. However, the independent contributions of TRPV4-mediated calcium influx and purinergic calcium oscillations to the rapid sclerostin protein downregulation remain unclear. Here, we showed that NOX2 and TRPV4-dependent calcium influx is required for calcium oscillations, and that TRPV4 activation is both necessary and sufficient for sclerostin degradation. In contrast, calcium oscillations are neither necessary nor sufficient to acutely decrease sclerostin protein abundance. However, blocking oscillations with apyrase prevented fluid shear stress induced changes in osterix (Sp7), osteoprotegerin (Tnfrsf11b), and sclerostin (Sost) gene expression. In total, these data provide key mechanistic insights into the way bone cells translate mechanical cues to target a key effector of bone formation, sclerostin.
MeSH term(s)	Calcium/metabolism ; Calcium Signaling ; Osteocytes/metabolism ; Stress, Mechanical ; TRPV Cation Channels/metabolism
Chemical Substances	TRPV Cation Channels ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2020-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	632515-4
ISSN	1873-2763 ; 8756-3282
ISSN (online)	1873-2763
ISSN	8756-3282
DOI	10.1016/j.bone.2020.115356
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Article ; Online: Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein.

Gould, Nicole R / Williams, Katrina M / Joca, Humberto C / Torre, Olivia M / Lyons, James S / Leser, Jenna M / Srikanth, Manasa P / Hughes, Marcus / Khairallah, Ramzi J / Feldman, Ricardo A / Ward, Christopher W / Stains, Joseph P

eLife

2021 Volume 10

Abstract: The downregulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of ... ...

Abstract	The downregulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Bone Morphogenetic Proteins/metabolism ; Bone and Bones/metabolism ; Cell Line ; Cues ; Down-Regulation/drug effects ; Female ; Gaucher Disease/metabolism ; Genetic Markers ; Humans ; Lysosomes/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Osteocytes/metabolism ; Osteogenesis/drug effects ; Parathyroid Hormone/metabolism ; Parathyroid Hormone/pharmacology ; Rats ; Signal Transduction/drug effects
Chemical Substances	Adaptor Proteins, Signal Transducing ; Bone Morphogenetic Proteins ; Genetic Markers ; Parathyroid Hormone ; SOST protein, human ; Sost protein, mouse ; Sost protein, rat
Language	English
Publishing date	2021-03-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.64393
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Article ; Online: Connexin43 regulates osteoprotegerin expression via ERK1/2 -dependent recruitment of Sp1.

Gupta, Aditi / Leser, Jenna M / Gould, Nicole R / Buo, Atum M / Moorer, Megan C / Stains, Joseph P

Biochemical and biophysical research communications

2019 Volume 509, Issue 3, Page(s) 728–733

Abstract	In bone, connexin43 expression in cells of the osteoblast lineage plays an important role in restraining osteoclastogenesis and bone resorption. While there is a consensus around the notion that the anti-osteoclastogenic factor, osteoprotegerin, is a driver of this effect, how connexin43 regulates osteoprotegerin gene expression is unclear. Here, we show that loss of connexin43 decreased osteoprotegerin gene expression and reduced ERK1/2 activation. Conversely, overexpression of connexin43 increased osteoprotegerin expression and enhanced ERK1/2 activation. This increase in phospho-ERK1/2 is required for connexin43 to induce transcription from the osteoprotegerin proximal promoter. Connexin43 increased promoter activity via a specific 200 base pair region of the osteoprotegerin promoter located at -1486 to -1286 with respect to the transcriptional start site, a region which includes four Sp1 binding elements. Further, activation of this promoter region required an intact functional connexin43, as hypomorphic or dominant negative connexin43 mutant constructs, including one with increased hemichannel activity, were unable to stimulate osteoprotegerin expression as strongly as wild type connexin43. Using chromatin immunoprecipitations, we show that connexin43 expression enhanced the recruitment of Sp1, but not Runx2, to the osteoprotegerin proximal promoter. In total, these data show that connexin43-dependent gap junctional communication among osteoblast cells permits efficient ERK1/2 activation. ERK1/2 signaling promotes the recruitment of the potent transcriptional activator, Sp1, to the osteoprotegerin proximal promoter, resulting in robust transcription of anti-osteoclastogenic factor, osteoprotegerin.
MeSH term(s)	Animals ; Cells, Cultured ; Connexin 43/metabolism ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Osteoblasts/cytology ; Osteoblasts/metabolism ; Osteoprotegerin/genetics ; Promoter Regions, Genetic ; Sp1 Transcription Factor/metabolism ; Transcriptional Activation
Chemical Substances	Connexin 43 ; Osteoprotegerin ; Sp1 Transcription Factor ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
Language	English
Publishing date	2019-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2018.12.173
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