GSK‐3β inhibition suppresses instability‐induced osteolysis by a dual action on osteoblast and osteoclast differentiation

Abstract

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/β-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/β-catenin signaling by inhibiting glycogen synthase kinase-3β (GSK-3β) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation. We examined effects of GSK-3β 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-3β 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 β-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-3β inhibition. Osteoclast numbers were decreased significantly after 3 days of GSK-3β 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-3β inactivation suppresses osteolysis through regulating both osteoblast and osteoclast differentiation in a rat model of instability-induced osteolysis.

Retracted: MicroRNA‐539 promotes osteoblast proliferation and differentiation and osteoclast apoptosis through the AXNA‐dependent Wnt signaling pathway in osteoporotic rats

“…With reference to a previous study, miRNAs have regulatory functions on multiple components of Wnt signaling pathway . Also, it has been indicated that the Wnt signaling pathway plays an important role in the regulation of both osteoblast and osteoclast differentiation . The crucial step of Wnt signaling pathway is the degradation of cytosolic β‐catenin by the APC/AXIN1 destruction complex, and Wnt signaling inhibits β‐catenin ubiquitination normally occurring within the complex, resulting in complex saturation through an accumulation of phospho‐β‐catenin .…”

The Effects of Biomaterial Implant Wear Debris on Osteoblasts

“…These results further implicate the GSK-3β/β-catenin signaling pathway as a mediator of Ti particle-induced osteolysis. A recent study showed that modulation of Wnt/β-catenin and BMP-2 signaling with GSK-3β inhibitor AR28 accelerated bone repair, up-regulated osteoblast differentiation, and attenuated osteoclastogenesis via an OPGassociated mechanism in a rat model of instability-induced osteolysis (Amirhosseini et al, 2017).…”

Development of an immunogenomic landscape for the competing endogenous RNAs network of peri-implantitis

“…It has been reported to play a role in regulating a variety of cellular responses, including cell growth, migration, tumorigenesis and cytokine production [26]. Amirhosseini et al reported that inhibition of GSK3B could regulate osteoblast and osteoclast differentiation to suppress instable-induced osteolysis and bone loss by activating Wnt /β-catenin signaling [27]. In addition, Jang et al demonstrated a novel role for GSK3B…”