Glycogen Synthase Kinase-3 Beta (GSK3β) as a Potential Drug Target in Regulating Osteoclastogenesis: An Updated Review on Current Evidence

Abstract

Glycogen synthase kinase 3-beta (GSK3β) is a highly conserved protein kinase originally involved in glucose metabolism, insulin activity, and energy homeostasis. Recent scientific evidence demonstrated the significant role of GSK3β in regulating bone remodelling through involvement in multiple signalling networks. Specifically, the inhibition of GSK3β enhances the conversion of osteoclast progenitors into mature osteoclasts. GSK3β is recognised as a pivotal regulator for the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), nuclear factor-kappa B (NF-κB), nuclear factor-erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1), canonical Wnt/beta (β)-catenin, and protein kinase C (PKC) signalling pathways during osteoclastogenesis. Conversely, the inhibition of GSK3β has been shown to prevent bone loss in animal models with complex physiology, suggesting that the role of GSK3β may be more significant in bone formation than bone resorption. Divergent findings have been reported regarding the efficacy of GSK3β inhibitors as bone-protecting agents. Some studies demonstrated that GSK3β inhibitors reduced osteoclast formation, while one study indicated an increase in osteoclast formation in RANKL-stimulated bone marrow macrophages (BMMs). Given the discrepancies observed in the accumulated evidence, further research is warranted, particularly regarding the use of GSK3β silencing or overexpression models. Such efforts will provide valuable insights into the direct impact of GSK3β on osteoclastogenesis and bone resorption.

Local re-activation of osteoclast differentiation as a novel therapeutic strategy for osteonecrosis of the jaw

“…In literature there are three publications directly or indirectly suggesting three different approaches aimed to potentiate osteoclast differentiation or mitigate bisphosphonates activity, that might be further developed in order to locally target BRONJ. They are respectively based on the inhibition of Glycogen synthase kinase-3 beta (GSK3β) ( 6 ), geranyl-geraniol (GG) administration ( 7 ) or local use of magnesium (Mg) ( 8 – 10 ). GSK3β is a highly conserved serine/threonine kinase active in different signal transduction pathways.…”

“…GSK3β is a highly conserved serine/threonine kinase active in different signal transduction pathways. Several studies, that were summarized and discussed in a recent review ( 6 ), evidenced that inhibition of GSK3β, obtained by phosphorylation or down-regulation, in the presence of the cytokines macrophage colony- stimulating factor (M-CSF) and nuclear factor Kappa B ligand (RANKL) favors in vitro differentiation of osteoclast precursors into osteoclasts. Although the target of these studies was the comprehension of the role of GSK3β in bone remodeling with regards to its role in osteoporosis, these observations suggest that GSK3β inhibition, obtained for instance by using lithium chloride (LiCl), might be an interesting putative target also for the therapy of ONJ.…”