Phosphoinositide 3-Kinase (PI3K) Activation is Differentially Regulated during Osteogenesis induced by TGF-β1 and BMP-2/BMP-7

Yamashita, Haruto; Ochiai, Hirokazu; Saito, Akiko; Shintani, Seikou; Azuma, Toshifumi

doi:10.2485/jhtb.23.9

Cited by 2 publications

(2 citation statements)

References 31 publications

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“…These data confirm the correlation between the levels of RANKL and transforming growth factor-β 1 revealed by us. Glucocorticoids stimulate apoptosis of osteoblasts, inhibit their proliferation and differentiation depending on the dose, duration and stage of cellular differentiation (Yamashita et al, 2014). Apparently, the level of transforming growth factor-β 1 in the blood serum of animals of the group with the experimental violation of bone tissue remodeling by glucocorticoids is due both to its dysregulatory role in the stages of osteoblast and osteoclast differentiation and to the action of dexamethasone.…”

Section: Discussionmentioning

confidence: 99%

Violations of cell-molecular mechanisms of bone remodeling under influence of glucocorticoids

Pavlov

Babenko

Kumetchko

et al. 2018

Regul. Mech. Biosyst.

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The fact is disturbance of the processes of bone tissue remodeling leads to a change in the balance between synthesis and resorption of bone and the development of osteoporosis. The most common cause of secondary osteoporosis is the use of glucocorticoid therapy. The aim of this study is to investigate the cellular-molecular mechanisms of disturbance of the processes of bone remodeling regulation, reflected by hormones and intercellular mediators (for example parathyroid hormone, calcitonin, RANKL, osteoprotegerin, P-selectin, interleukin-17, transforming growth factor-β1, adiponectin and visfatin) on the background experimental glucocorticoid osteoporosis. The experimental study carried out in two groups of white female rats. Disturbance of bone tissue remodeling was verified by histological examination of the femoral head, vertebrae of the thoracic and lumbar spine of rats and the measurement of bone density. The study of the levels of hormones and intercellular mediators in the blood serum of animals was carried out by the method of enzyme immunoassay. The bone mineral density of the experimental group was reduced compared to the bone mineral density of the control group. The study of the histostructure of the femoral head and vertebrae in rats of the experimental group in comparison with the animals of the control group revealed changes in the structural organization of bone tissue, confirmed by histomorphometry, indicating inhibition of the processes of osteosynthesis. The article analyzes the nature of the involvement of hormones and cytokines in pathogenetic mechanisms of development of bone tissue disorders. The levels of cytokines RANKL, osteoprotegerin, interleukin-17 and calcitonin in the blood serum of animals of the group with the violation of bone tissue remodeling by glucocorticoids were higher than in intact animals. Serum levels of P-selectin, parathyroid hormone, transforming growth factor-β1, adiponectin and visfatin were lower than similar levels in animals from the control group. The use of glucocorticoids increases the expression of RANKL and inhibits the synthesis of osteoprotegerin, resulting in stimulation of bone resorption. The effect of glucocorticoids in the experimental model is realized by changing the production of the studied hormones, cytokines and adhesion molecules. These changes stimulate the apoptosis of osteoblasts and inhibit their proliferation and differentiation, which is another mechanism of bone loss. Correlations found during the study reflect the relationship in the system of regulation of bone tissue remodeling under the influence of glucocorticoids. A complex system for regulating bone remodeling, which includes many regulatory pathways and their interactions, requires further study.

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Section: Discussionmentioning

confidence: 99%

Violations of cell-molecular mechanisms of bone remodeling under influence of glucocorticoids

Pavlov

Babenko

Kumetchko

et al. 2018

Regul. Mech. Biosyst.

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“…19) We previously reported that the phosphatidylinositide 3-kinase (PI3K)/Akt/mTOR/p70S6K pathway plays pivotal roles in the regulation of osteogenic differentiation by transforming growth factor-1 (TGF-1) 20) . We also reported that an experimental model that repeated or highdose administration of TGF-1 inhibited osteoblast differentiation of HPDL cells by decreasing insulin-like growth factor-1 (IGF-1) expression and subsequently downregulating PI3K/Akt signaling 21,22) , but Dex combined with BMP2/7 promotes osteoblast differentiation independently of IGF-1 expression unlike TGF-1 23) . …”

Section: Introductionmentioning

confidence: 99%

Synergistic and Mutual Antagonistic Regulations of Wnt Inhibitors Play an Important Role in Osteoblast Differentiation of Human Periodontal Ligament Cells

Tsukinowa

Onodera

Yoshizawa

et al. 2015

J. Hard Tissue Biology.

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Recent studies have suggested that a balance between Wnt and bone morphogenetic protein (BMP) output may be a key factor for regulatory networks involved in bone regeneration. Here we report that Wnt inhibitors coordinately regulate osteoblastic differentiation induced by BMPs of human periodontal ligament cell. Human periodontal ligament (HPDL) cells were stimulated with BMP2/7, Dexamethasone (Dex), or a combination of these reagents. After treatment, we analyzed the phosphorylated Smad1/5 and osteoblast differentiation markers. Specific antagonists such as Dickkopfs (Dkk1, Dkk2) , secreted Frizzled-related proteins (SFRP1,SFRP2), and sclerostin(SOST) which are believed to play important roles in osteoblast differentiations were also examined by quantitative RT-PCR. BMP2/7 treatment increased ALP activity modestly, and the combination of BMP2/7 with Dex greatly enhanced ALP activity. SOST expression increased sharply following BMP2/7 treatment; however, adding BMP2/7 and Dex drastically reversed this increase in SOST. BMP2/7 and Dex treatment synergistically decreased DKK2 and sFRP2 expression. In contrast, BMP2/7 and Dex had a significant inductive effect on DKK1 and sFRP1 expression. BMP2/7 treatment resulted in Smad1/5 phosphorylation, but adding Dex did not induce p-Smad1/5. However, BMP2/7-induced Smad1/5 phosphorylation was inhibited in the combined treatment group. These opposite trends support the previous reports showing mutual antagonism between DKK1 and DKK2 or sFRP1 and sFRP2. In conclusion, wellbalanced Wnt inhibitors may be crucial for bone tissue homeostasis.

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Phosphoinositide 3-Kinase (PI3K) Activation is Differentially Regulated during Osteogenesis induced by TGF-β1 and BMP-2/BMP-7

Cited by 2 publications

References 31 publications

Violations of cell-molecular mechanisms of bone remodeling under influence of glucocorticoids

Violations of cell-molecular mechanisms of bone remodeling under influence of glucocorticoids

Synergistic and Mutual Antagonistic Regulations of Wnt Inhibitors Play an Important Role in Osteoblast Differentiation of Human Periodontal Ligament Cells

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