A Review on the Crosstalk between Insulin and Wnt/β-Catenin Signalling for Bone Health

Abstract

A positive association between insulin resistance and osteoporosis has been widely established. However, crosstalk between the signalling molecules in insulin and Wingless (Wnt)/beta-(β-)catenin transduction cascades orchestrating bone homeostasis remains not well understood. The current review aims to collate the existing evidence, reporting (a) the expression of insulin signalling molecules involved in bone-related disorders and (b) the expression of Wnt/β-catenin signalling molecules involved in governing insulin homeostasis. The downstream effector molecule, glycogen synthase kinase-3 beta (GSK3β), has been identified to be a point of convergence linking the two signal transduction networks. This review highlights that GSK3β may be a drug target in the development of novel anabolic agents and the potential use of GSK3β inhibitors to treat bone-related disorders.

Keywords: GSK3β; bone loss; glycogen synthase kinase-3 beta; type 1 diabetes mellitus; type 2 diabetes mellitus.

Figure 1

Framework of literature search.

Figure 2

The insulin and IGF-1 signalling pathway. Abbreviations: Akt, protein kinase B; GSK3β, glycogen synthase kinase-3 beta; IGF-1, insulin-like growth factor-1; IGFBP, insulin-like growth factor binding protein; IRS, insulin receptor substrate; p-Akt, phosphorylated protein kinase B; PDK1, phosphoinositide-dependent kinase-1; p-glycogen synthase, phosphorylated glycogen synthase; p-GSK3β, phosphorylated glycogen synthase kinase-3 beta; PI3K, phosphoinositide-3-kinases; p-IGF-1R, phosphorylated insulin-like growth factor-1 receptor; p-insulin receptor, phosphorylated insulin receptor; PIP₂, phosphatidylinositol-4,5-biphosphate; PIP₃, phosphatidylinositol-3,4,5-triphosphate.

Figure 3

The Wnt/β-catenin signalling pathway. Abbreviations: Axin, axis inhibition protein; APC, adenomatosis polyposis coli; CK1α, casein kinase 1α; DKK1, Dickkopf-related protein 1; DKK2, Dickkopf-related protein 2; Dsh, phosphoprotein Dishevelled; GSK3β, glycogen synthase kinase-3 beta; LEF, lymphoid enhancing factor; LRP4/5/6, lipoprotein receptor-related protein 4/5/6; p-β-catenin, phosphorylated β-catenin; p-GSK3β, phosphorylated glycogen synthase kinase-3 beta; sFRP-1, secreted frizzled-related protein-1; TCF, T-cell factor.

Figure 4

The crosstalk between insulin/IGF-1 and Wnt/β-catenin signalling molecules during insulin deficiency, insulin resistance, oestrogen deficiency, or subjected to mechanical loading. Arrow pointing upward (↑) indicates an increase in expression, arrow pointing downward (↓) indicates a decrease in expression, whereas the arrow pointing both sides (↔) indicates no change in expression. Abbreviations: Akt, protein kinase B; APC, adenomatosis polyposis coli; Axin, axis inhibition protein; c-Fos, Fos proto-oncogene; CK1α, casein kinase 1α; DKK1/2, Dickkopf-related protein 1 or 2; Dsh, phosphoprotein Dishevelled; GSK3β, glycogen synthase kinase-3 beta; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; IGFBP6, insulin-like growth factor binding protein 6; IRS, insulin receptor substrate; LEF, lymphoid enhancing factor; LRP4/5/6, lipoprotein receptor-related protein 4/5/6; NFATc1, nuclear factor of activated T cells cytoplasmic 1; NF-κB, nuclear factor-kappa B; OPG, osteoprotegerin; p-Akt, phosphorylated protein kinase B; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphoinositide-3-kinases; p-glycogen synthase, phosphorylated glycogen synthase; p-GSK3β, phosphorylated glycogen synthase kinase-3 beta; p-IGF-1R, phosphorylated insulin-like growth factor-1 receptor; p-insulin receptor, phosphorylated insulin receptor; PIP₂, phosphatidylinositol-4,5-biphosphate; PIP₃, phosphatidylinositol-3,4,5-triphosphate; RANK, receptor activator of nuclear factor-kappa B; RANKL, receptor activator of nuclear factor-kappa B ligand; sFRP-1, secreted frizzled-related protein-1; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TCF, T-cell factor; TRAF6, tumour necrosis factor receptor-associated factor 6; Wnt, Wingless ligand.