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

Wong, Sok Kuan; Mohamad, Nur-Vaizura; Jayusman, Putri Ayu; Ibrahim, Nurul ‘Izzah

doi:10.3390/ijms241512441

Cited by 7 publications

(4 citation statements)

References 55 publications

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“…These results highlight the complex connections between skeletal strength and metabolic disorders. 45 Li et al have reported the importance of the PPAR signalling pathway in bone development, demonstrating its influence on the fate of mesenchymal stem cells and the potential of this pathway as a therapeutic target in enhancing bone density. 46 Guo et al studied the AMPK signalling pathway and have reported its role in bone remodelling, emphasizing its capacity to suppress osteoclast activity and thus promote skeletal health.…”

Section: Discussionmentioning

confidence: 99%

“…These results highlight the complex connections between skeletal strength and metabolic disorders. 45 Li et al. have reported the importance of the PPAR signalling pathway in bone development, demonstrating its influence on the fate of mesenchymal stem cells and the potential of this pathway as a therapeutic target in enhancing bone density.…”

Section: Discussionmentioning

confidence: 99%

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Functions of Epimedin C in a zebrafish model of glucocorticoid‐induced osteoporosis

Zhou,

Lian,

Jia

et al. 2024

J Cellular Molecular Medi

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Epimedium is thought to enhance the integrity of tendons and bones, ease joint discomfort and rigidity and enhance kidney function. Although glucocorticoids are commonly used in clinical practice, the mechanism by which the active compound Epimedin C (EC) alleviates glucocorticoid‐induced osteoporosis (GIOP) is not well understood. The therapeutic potential of EC in treating GIOP was evaluated using alizarin red S staining, calcein immersion and fluorescence imaging, and bone mineralization, bone mass accumulation and bone density in zebrafish larvae were determined. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the key signalling pathways related to bone development were identified. A protein–protein interaction network (PPIN) was constructed to identify osteoclast characteristic genes and the findings were verified using real‐time quantitative PCR (RT‐qPCR). The bone tissue damage caused by prednisolone was reduced by EC. It also altered physiological processes, improved bone density, boosted mineralization and increased bone mass and activity. Subsequent empirical investigations showed that EC impacted the major signalling pathways involved in bone development, such as osteoclast differentiation, oestrogen, MAPK, insulin resistance, PPAR and AMPK signalling pathways. It also decreased the expression of genes typical of osteoclasts. The results of our study uncover a previously unknown function of EC in controlling bone formation and emphasize the potential of EC as a therapeutic target. The osteoprotective effect of EC indicates its potential as a cost‐effective strategy for treating GIOP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functions of Epimedin C in a zebrafish model of glucocorticoid‐induced osteoporosis

Zhou,

Lian,

Jia

et al. 2024

J Cellular Molecular Medi

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“…Phosphoinositide-dependent kinase 1 (PDK1) is the downstream serine/threonine protein kinase recruited by PIP 3 to phosphorylate and activate AKT. Following that, GSK3β is phosphorylated and inhibited, serving as a negative regulator to increase NFATc1 nuclear transportation and transcriptional activity [4,34].…”

Section: Pi3k/akt Signalling Pathwaymentioning

confidence: 99%

“…Eventually, activated IRS-1 recruits phosphatidylinositol-3-kinase (PI3K) to activate downstream molecular targets. The activation of protein kinase B (AKT) phosphorylates inhibits GSK3β to activate glycogen synthase, leading to production of glycogen [4]. Despite GSK3β traditionally acting as a negative regulator of glycogen synthesis, it has been identified as a central point of convergence for multiple intracellular signalling pathways involved in various physiological processes [5].…”

Section: Introductionmentioning

confidence: 99%

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

Wong

2024

Biomolecules

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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.

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Osteoking prevents bone loss and enhances osteoblastic bone formation by modulating the AGEs/IGF‐1/β‐catenin/OPG pathway in type 2 diabetic db/db mice

Yang,

Li,

Wang

et al. 2024

Cell Biology International

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Type 2 diabetic osteoporosis (T2DOP) is a skeletal metabolic syndrome characterized by impaired bone remodeling due to type 2 diabetes mellitus, and there are drawbacks in the present treatment. Osteoking (OK) is widely used for treating fractures and femoral head necrosis. However, OK is seldom reported in the field of T2DOP, and its role and mechanism of action need to be elucidated. Consequently, this study investigated whether OK improves bone remodeling and the mechanisms of diabetes‐induced injury. We used db/db mice as a T2DOP model and stimulated MC3T3‐E1 cells (osteoblast cell line) with high glucose (HG, 50 mM) and advanced glycation end products (AGEs, 100 µg/mL), respectively. The effect of OK on T2DOP was assessed using a combined 3‐point mechanical bending test, hematoxylin and eosin staining, and enzyme‐linked immunosorbent assay. The effect of OK on enhancing MC3T3‐E1 cell differentiation and mineralization under HG and AGEs conditions was assessed by an alkaline phosphatase activity assay and alizarin red S staining. The AGEs/insulin‐like growth factor‐1(IGF‐1)/β‐catenin/osteoprotegerin (OPG) pathway‐associated protein levels were assayed by western blot analysis and immunohistochemical staining. We found that OK reduced hyperglycemia, attenuated bone damage, repaired bone remodeling, increased tibial and femoral IGF‐1, β‐catenin, and OPG expression, and decreased receptor activator of nuclear kappa B ligand and receptor activator of nuclear kappa B expression in db/db mice. Moreover, OK promoted the differentiation and mineralization of MC3T3‐E1 cells under HG and AGEs conditions, respectively, and regulated the levels of AGEs/IGF‐1/β‐catenin/OPG pathway‐associated proteins. In conclusion, our results suggest that OK may lower blood glucose, alleviate bone damage, and attenuate T2DOP, in part through activation of the AGEs/IGF‐1/β‐catenin/OPG pathway.

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

Cited by 7 publications

References 55 publications

Functions of Epimedin C in a zebrafish model of glucocorticoid‐induced osteoporosis

Functions of Epimedin C in a zebrafish model of glucocorticoid‐induced osteoporosis

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

Osteoking prevents bone loss and enhances osteoblastic bone formation by modulating the AGEs/IGF‐1/β‐catenin/OPG pathway in type 2 diabetic db/db mice

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