HIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/β-catenin-dependent mechanism.

Hdl Handle:
http://hdl.handle.net/10147/264783
Title:
HIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/β-catenin-dependent mechanism.
Authors:
Butler, Joseph S; Dunning, Eilis C; Murray, David W; Doran, Peter P; O'Byrne, John M
Affiliation:
Clinical Research Centre, UCD School of Medicine & Medical Science, Mater Misericordiae University Hospital, Dublin, Ireland; Department of Trauma & Orthopaedic Surgery, Royal College of Surgeons in Ireland, Cappagh National Orthopaedic Hospital, Dublin, Ireland. josephsbutler@hotmail.com.
Citation:
HIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/β-catenin-dependent mechanism. 2013, 31 (2):218-26 J. Orthop. Res.
Journal:
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
Issue Date:
Feb-2013
URI:
http://hdl.handle.net/10147/264783
DOI:
10.1002/jor.22196
PubMed ID:
23281130
Abstract:
HIV infection is associated with metabolic bone disease resulting in bone demineralization and reduced bone mass. The molecular mechanisms driving this disease process have yet to be elucidated. Wnt/β-catenin signaling plays a key role in bone development and remodeling. We attempted to determine the effects of the HIV-1 protein, gp120, on Wnt/β-catenin signaling at an intracellular and transcriptional level in primary human osteoblasts (HOBs). This work, inclusive of experimental controls, was part of a greater project assessing the effects of a variety of different agents on Wnt/β-catenin signaling (BMC Musculoskelet Disord 2010;11:210).We examined the phenotypic effects of silencing and overexpressing the Wnt antagonist, Dickkopf-1 (Dkk1) in HOBs treated with gp120. HOBs exposed to gp120 displayed a significant reduction in alkaline phosphatase activity (ALP) activity and cell proliferation and increased cellular apoptosis over a 48 h time course. Immunocytochemistry demonstrated a significant reduction in intracytosolic and intranuclear β-catenin in response to HIV-1 protein exposure. These changes were associated with a reduction of TCF/LEF-mediated transcription, the transcriptional outcome of canonical Wnt β-catenin signaling. Silencing Dkk1 expression in HOBs exposed to gp120 resulted in increased ALP activity and cell proliferation, and decreased cellular apoptosis relative to scrambled control. Dkk1 overexpression exacerbated the inhibitory effect of gp120 on HOB function, with decreases in ALP activity and cell proliferation and increased cellular apoptosis relative to vector control. Wnt/β-catenin signaling plays a key regulatory role in HIV-associated bone loss, with Dkk1, aputative central mediator in this degenerative process. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 218-226, 2013.
Item Type:
Article
Language:
en
ISSN:
1554-527X

Full metadata record

DC FieldValue Language
dc.contributor.authorButler, Joseph Sen_GB
dc.contributor.authorDunning, Eilis Cen_GB
dc.contributor.authorMurray, David Wen_GB
dc.contributor.authorDoran, Peter Pen_GB
dc.contributor.authorO'Byrne, John Men_GB
dc.date.accessioned2013-01-09T16:28:47Z-
dc.date.available2013-01-09T16:28:47Z-
dc.date.issued2013-02-
dc.identifier.citationHIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/β-catenin-dependent mechanism. 2013, 31 (2):218-26 J. Orthop. Res.en_GB
dc.identifier.issn1554-527X-
dc.identifier.pmid23281130-
dc.identifier.doi10.1002/jor.22196-
dc.identifier.urihttp://hdl.handle.net/10147/264783-
dc.description.abstractHIV infection is associated with metabolic bone disease resulting in bone demineralization and reduced bone mass. The molecular mechanisms driving this disease process have yet to be elucidated. Wnt/β-catenin signaling plays a key role in bone development and remodeling. We attempted to determine the effects of the HIV-1 protein, gp120, on Wnt/β-catenin signaling at an intracellular and transcriptional level in primary human osteoblasts (HOBs). This work, inclusive of experimental controls, was part of a greater project assessing the effects of a variety of different agents on Wnt/β-catenin signaling (BMC Musculoskelet Disord 2010;11:210).We examined the phenotypic effects of silencing and overexpressing the Wnt antagonist, Dickkopf-1 (Dkk1) in HOBs treated with gp120. HOBs exposed to gp120 displayed a significant reduction in alkaline phosphatase activity (ALP) activity and cell proliferation and increased cellular apoptosis over a 48 h time course. Immunocytochemistry demonstrated a significant reduction in intracytosolic and intranuclear β-catenin in response to HIV-1 protein exposure. These changes were associated with a reduction of TCF/LEF-mediated transcription, the transcriptional outcome of canonical Wnt β-catenin signaling. Silencing Dkk1 expression in HOBs exposed to gp120 resulted in increased ALP activity and cell proliferation, and decreased cellular apoptosis relative to scrambled control. Dkk1 overexpression exacerbated the inhibitory effect of gp120 on HOB function, with decreases in ALP activity and cell proliferation and increased cellular apoptosis relative to vector control. Wnt/β-catenin signaling plays a key regulatory role in HIV-associated bone loss, with Dkk1, aputative central mediator in this degenerative process. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 218-226, 2013.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Journal of orthopaedic research : official publication of the Orthopaedic Research Societyen_GB
dc.titleHIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/β-catenin-dependent mechanism.en_GB
dc.typeArticleen
dc.contributor.departmentClinical Research Centre, UCD School of Medicine & Medical Science, Mater Misericordiae University Hospital, Dublin, Ireland; Department of Trauma & Orthopaedic Surgery, Royal College of Surgeons in Ireland, Cappagh National Orthopaedic Hospital, Dublin, Ireland. josephsbutler@hotmail.com.en_GB
dc.identifier.journalJournal of orthopaedic research : official publication of the Orthopaedic Research Societyen_GB
dc.description.provinceLeinsteren

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