RGD Reference Report - GSK-3ß inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation. - Rat Genome Database

RGD Reference Report - GSK-3ß inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation. - Rat Genome Database

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GSK-3ß inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation.
Authors:	Amirhosseini, Mehdi Madsen, Rune V Escott, K Jane Bostrom, Mathias P Ross, F Patrick Fahlgren, Anna
Citation:	Amirhosseini M, etal., J Cell Physiol. 2018 Mar;233(3):2398-2408. doi: 10.1002/jcp.26111. Epub 2017 Sep 28.
RGD ID:	13792731
Pubmed:	PMID:28731198 (View Abstract at PubMed)
PMCID:	PMC5705568 (View Article at PubMed Central)
DOI:	DOI:10.1002/jcp.26111 (Journal Full-text)
Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/ß-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/ß-catenin signaling by inhibiting glycogen synthase kinase-3ß (GSK-3ß) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation. We examined effects of GSK-3ß inhibition on regulation of RANKL and OPG in a rat model of mechanical instability-induced peri-implant osteolysis. The rats were treated daily with a GSK-3ß inhibitor, AR28 (20¿mg/kg bw), for up to 5 days. Bone tissue and blood serum were assessed by qRT-PCR, immunohistochemistry, and ELISA on days 3 and 5, and by micro-CT on day 5. After 3 days of treatment with AR28, mRNA levels of ß-catenin, Runx2, Osterix, Col1α1, and ALP were increased leading to higher osteoblast numbers compared to vehicle-treated animals. BMP-2 and Wnt16 mRNA levels were downregulated by mechanical instability and this was rescued by GSK-3ß inhibition. Osteoclast numbers were decreased significantly after 3 days of GSK-3ß inhibition, which correlated with enhanced OPG mRNA expression. This was accompanied by decreased serum levels of TRAP5b on days 3 and 5. Treatment with AR28 upregulated osteoblast differentiation, while osteoclastogenesis was blunted, leading to increased bone mass by day 5. These data suggest that GSK-3ß inactivation suppresses osteolysis through regulating both osteoblast and osteoclast differentiation in a rat model of instability-induced osteolysis.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Gsk3b	Rat	positive regulation of osteoclast differentiation		IMP			RGD
Gsk3b	Rat	regulation of osteoblast differentiation		IMP			RGD

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Genes (Rattus norvegicus)

Gsk3b (glycogen synthase kinase 3 beta)

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