Runx2 alleviates high glucose‐suppressed osteogenic differentiation via PI3K/AKT/GSK3β/β‐catenin pathway

Chen, Yang; Hu, Yun; Yang, Lan; Zhou, Jie; Tang, Yuying; Zheng, Leilei; Qin, Pu

doi:10.1002/cbin.10779

Cited by 45 publications

(33 citation statements)

References 31 publications

(34 reference statements)

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“…Hyperglycemia has been shown to suppress the PI3K/Akt/eNOS pathway in rat osteoblasts and therefore interfere with osteoblast transcription factors, such as RUNX2, critical for their differentiation and proliferation . In addition, hyperglycemia‐induced reactive oxygen species formation contributes to adipogenesis and inhibition of PI3K/Akt‐mediated osteogenic differentiation .…”

Section: Drugs and Bonementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Section: Drugs and Bonementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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“…Several interacting factors contribute to the risk of osteoporosis and fracture, including hormones, cytokines, transcription factors, and genetic variables. The differentiation of osteoblasts is regulated by many transcription factors, such as Runt-related transcription factor 2 (RUNX2), AMP-dependent transcription factor-4 (ATF4) [3], and osterix (OSX) [4], of which RUNX2 is considered to play a key role in the differentiation of osteoblasts [5]. The abnormal expression of osteoblast genes leads to bone dysplasia or bone formation disorder.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-505 is involved in the regulation of osteogenic differentiation of MC3T3-E1 cells partially by targeting RUNX2

Chen

Cai

et al. 2020

J Orthop Surg Res

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Objective: Evidence suggests that microRNAs (miRNAs) regulate the expression of genes involved in bone metabolism. This study aimed to investigate the role of miR-505 in the osteogenic differentiation of MC3T3-E1 cells. Methods: We performed miRNA sequencing to identify differentially expressed miRNAs between MC3T3-E1 cells treated with osteogenic induction medium (OIM) and control cells. Bioinformatics analysis was performed by using the TargetScan and miRDB databases. The expression of miR-505 in MC3T3-E1 cells was detected during osteogenic differentiation. After transfection with miR-505 mimic or miR-505 inhibitor, MC3T3-E1 cells were induced to differentiate into osteoblasts, and the expression of osteogenic differentiation markers (Runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OCN), and osterix (OSX)) was detected. Results: miR-505 was the most downregulated miRNA among the differentially expressed miRNAs. The RUNX2 gene was identified as a potential target of miR-505 using the target prediction program. miR-505 expression was downregulated during osteogenic differentiation of MC3T3-E1 cells. The expression of osteogenic marker genes was inhibited in MC3T3-E1 cells after transfection with miR-505. However, the expression of osteogenic marker genes was upregulated after transfection with miR-505 inhibitor.Conclusion: This study is the first to report miR-505 could bind to the RUNX2 gene and thus regulate partly the dysfunction of osteoblasts differentiation, which is expected to be targets for the treatment of osteoporosis.

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“…Insulin‐like growth factor 1 receptor (IGF1R) signaling is important for bone formation via endochondral ossification, osteoblast mediated bone mineralization leading to bone formation (Zhao et al, ; Zhang et al, ; Heilig et al, ). The phosphatidylinositol 3‐kinase/Akt (PI3K/Akt) signaling pathway is involved in osteoblast proliferation and differentiation (Guenou et al, ; Chen et al, ). Signaling through IGF1R in bone marrow stromal cells during differentiation is regulated by PI3K/Akt which inhibits apoptosis in osteoblasts (Youssef and Han, ).…”

Section: Introductionmentioning

confidence: 99%

Calycosin stimulates the osteogenic differentiation of rat calvarial osteoblasts by activating the IGF1R/PI3K/Akt signaling pathway

Fang

Xue

Zhao

et al. 2019

Cell Biology International

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Calycosin has been reported to have a strong osteogenic activity and a positive correlation with anti‐osteoporosis effects. However, its precise mechanism of action remains unclear. Since insulin‐like growth factor 1 receptor (IGF1R) signaling and phosphatidylinositol 3‐kinase/Akt (PI3K/Akt) signaling have been shown to play a pivotal role in regulating osteogenesis, we hypothesized that the osteogenic activity of calycosin is mediated by these signaling pathways. Rat calvarial osteoblasts (ROBs) were cultured in osteogenic medium containing calycosin with or without GSK1904529A (GSK) or LY294002 (LY) (inhibitors of IGF1R and PI3K, respectively). The effects on cell proliferation, alkaline phosphatase (ALP) activity, calcified nodules, mRNA or protein expression of osteogenic genes [alkaline phosphatase (Alpl), collagen type I (Col1a1), runt‐related transcription factor 2 (Runx2), Osterix, and bone morphogenetic protein 2 (Bmp2)], and phosphorylation of IGF1R and Akt were examined. The present results showed that calycosin enhanced cell proliferation, ALP activity and Alizarin Red‐S staining in a dose‐dependent manner in the range of 10−8–10−6 M, while an inhibitory effect was observed at 10−5 M. Treatment at the optimal concentration (10−6 M, a physiologically achievable concentration) increased mRNA levels of osteogenic genes and phosphorylation of IGF1R and Akt. Furthermore, treatment with GSK or LY partly reversed the effects of calycosin on ROBs, as indicated by the decreases in calycosin‐induced ALP activity, calcified nodules and osteogenic gene expression. These results suggest that the osteogenic effect of calycosin partly involves the IGF1R/PI3K/Akt signaling pathway.

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Runx2 alleviates high glucose‐suppressed osteogenic differentiation via PI3K/AKT/GSK3β/β‐catenin pathway

Cited by 45 publications

References 31 publications

Diabetes pharmacotherapy and effects on the musculoskeletal system

Diabetes pharmacotherapy and effects on the musculoskeletal system

MicroRNA-505 is involved in the regulation of osteogenic differentiation of MC3T3-E1 cells partially by targeting RUNX2

Calycosin stimulates the osteogenic differentiation of rat calvarial osteoblasts by activating the IGF1R/PI3K/Akt signaling pathway

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