Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling

Kawamura, Naohiro; Kugimiya, Fumitaka; Oshima, Yasushi; Ohba, Shinsuke; Ikeda, Toshiyuki; Saito, Taku; Shinoda, Yusuke; Kawasaki, Yosuke; Ogata, Naoshi; Hoshi, Kazuto; Akiyama, Tsuyoshi; Chen, William S.; Hay, Nissim; Tobe, Kazuyuki; Kadowaki, Takashi; Azuma, Yoshiaki; Tanaka, Sakae; Nakamura, Kozo; Chung, Ung Il; Kawaguchi, Hiroshi

doi:10.1371/journal.pone.0001058

Cited by 223 publications

(223 citation statements)

References 39 publications

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“…These findings are consistent with those from studies of other cell types demonstrating the critical role of PI 3-kinase/Akt in the regulation of proinflammatory cytokines and the production of some MMPs (45)(46)(47)(48), as well as with other studies in which activation of the PI 3-kinase/Akt pathway was essential in up-regulating proinflammatory cytokine-induced and oncostatin M-induced MMP-9 and MMP-13 (46,48). In addition, activation of the PI 3-kinase/Akt pathway in osteoblasts has been demonstrated to play a crucial role in promoting the differentiation of these cells by preventing an apoptotic mechanism (47). The PI 3-kinase/Akt pathway was also shown to be essential in controlling IL-6 synthesis in osteoblasts.…”

Section: Discussionsupporting

confidence: 91%

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Tat¹,

Pelletier²,

Amiable³

et al. 2008

Arthritis & Rheumatism

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Objective. Abnormal subchondral bone metabolism is involved in osteoarthritis (OA). It has been suggested that ephrin B2 and its specific receptor EphB4 participate in bone homeostasis. We previously reported that human OA subchondral bone osteoblasts could be classified into 2 subpopulations: low (L), having proresorption properties, and high (H), having proformation properties. The purpose of this study was to investigate the importance of the ephrin system in OA subchondral bone osteoblasts.Methods. The presence of the EphB4 receptor was determined by immunohistochemistry, and its expression level, modulation upon treatment, and consequences of activation by ephrin B2 were determined by quantitative polymerase chain reaction. The effects of ephrin B2 activation of the EphB4 receptor on bone resorption activity were also determined. EphB4 receptor activation signaling pathways were investigated by specific enzyme-linked immunosorbent assay.Results. EphB4 receptors were present in subchondral bone osteoblasts and osteocytes. Compared with normal and H-OA osteoblasts, EphB4 receptor expression levels were significantly increased in L-OA osteoblasts, with no difference between normal and H-OA osteoblasts. EphB4 receptor levels in L-OA osteoblasts were significantly up-regulated by prostaglandin E 2 (PGE 2 ) and interleukin-17 (IL-17). Ephrin B2, PGE 2 , and IL-17 significantly inhibited bone resorption activity in these cells. EphB4 activation by ephrin B2 significantly inhibited the expression of IL-1␤, IL-6, matrix metalloproteinase 1 (MMP-1), MMP-9, MMP-13, and RANKL, but not MMP-2 and osteoprotegerin. EphB4 receptor activation significantly inhibited the phosphatidylinositol 3-kinase/Akt pathway.Conclusion. This study is the first to provide evidence that EphB4 receptor activation by ephrin B2 in OA subchondral bone could affect abnormal metabolism in this tissue by inhibiting resorption factors and their activities. Ephrin B2 could be targeted as a specific therapeutic approach in the development of a diseasemodifying OA drug.Subchondral bone is made up of a specialized connective tissue formed by a mineralized matrix containing the specific type I collagen, proteoglycans, and several growth factors and cytokines, as well as bonespecific cell types (osteoblasts, osteocytes, and osteoclasts) (1,2). Osteoblast and osteoclast activities, either alone or in combination, contribute to the bone remodeling process, and any disturbance in the activities of these 2 cells is responsible for the development of altered bone metabolism.The ephrin B molecules (ephrin B1, ephrin B2, and ephrin B3) bind in a specific manner to their EphB

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Section: Discussionsupporting

confidence: 91%

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Tat¹,

Pelletier²,

Amiable³

et al. 2008

Arthritis & Rheumatism

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“…Dual-phosphorylation of Akt may explain the prosurvival effect of strontium that was previously reported (21). Knock-out mouse studies have shown that of the three isoforms of Akt, Akt1 regulates the control of osteoblast survival (45), whereas Akt2 promotes induction of differentiation prior to Runx2 expression (46). Here we show that strontium induces the phosphorylation of Akt at Thr 308 in HOBs in a PI3K-dependent manner (Fig.…”

Section: Discussionsupporting

confidence: 76%

An Akt-dependent Increase in Canonical Wnt Signaling and a Decrease in Sclerostin Protein Levels Are Involved in Strontium Ranelate-induced Osteogenic Effects in Human Osteoblasts

Rybchyn

Slater

Conigrave

et al. 2011

Journal of Biological Chemistry

101

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Sclerostin is an important regulator of bone homeostasis and canonical Wnt signaling is a key regulator of osteogenesis. Strontium ranelate is a treatment for osteoporosis that has been shown to reduce fracture risk, in part, by increasing bone formation. Here we show that exposure of human osteoblasts in primary culture to strontium increased mineralization and decreased the expression of sclerostin, an osteocyte-specific secreted protein that acts as a negative regulator of bone formation by inhibiting canonical Wnt signaling. Strontium also activated, in an apparently separate process, an Akt-dependent signaling cascade via the calcium-sensing receptor that promoted the nuclear translocation of ␤-catenin. We propose that two discrete pathways linked to canonical Wnt signaling contribute to strontium-induced osteogenic effects in osteoblasts.Strontium ranelate is a treatment for osteoporosis that decreases the incidence of vertebral and femoral fracture risk in postmenopausal women (1-3). Strontium ranelate has been shown to modulate the physiological processes of bone formation and bone resorption (2), resulting in increased bone apposition rates (3) and bone mineral density (1, 2, 4 -6), while maintaining the quality of bone mineral (6).Sclerostin is exclusively expressed by osteocytes in adult life (7, 8) but is more widely expressed during development (7) and plays a physiological role as a negative regulator of bone formation by repressing bone morphogenic protein-induced osteogenesis (9 -11). The importance of sclerostin in bone-loss disorders has been described in several in vivo studies. Positional cloning studies identified loss of function mutations in the SOST gene that cause sclerostosis and van Buchem disease, bone dysplasias characterized by progressive skeletal overgrowth (12). In contrast, transgenic mice overexpressing sclerostin had significant reductions in bone mass and mineral apposition rate compared with wild type (7). A sclerostin knock-out mouse model was shown to have increased osteoblast activity and enhanced osteoblast/osteocyte viability and was resistant to mechanical unloading-induced bone loss. This phenotype was associated with an increase in canonical Wnt signaling when compared with wild-type mice (8).Sclerostin functions as an antagonist of canonical Wnt signaling, whereby GSK-3␤ 2 -stimulated, ubiquitin-mediated breakdown of ␤-catenin is alleviated, resulting in its nuclear translocation, and binding to transcription factors of the T-cell factor/lymphoid enhancer factor family, to induce the transcription of growth-associated genes (13). Non-canonical Wnt signaling does not involve ␤-catenin translocation to the nucleus (11). Sclerostin binds to the extracellular domains of the Wnt co-receptors LRP5, LRP6, and LRP4 and disrupts extracellular Wnt-induced Frizzled/LRP complex formation thus providing a molecular mechanism by which loss of sclerostin function may lead to conditions such as sclerostosis (12,14). In addition to Frizzled/LRP-mediated activation of canonical Wnt s...

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“…Several studies have demonstrated that the downstream signaling molecules of insulin receptors, including IR, IRS1 and Akt, are required for osteoblastic proliferation and differentiation (Ogata et al 2000, Kawamura et al 2007. Our previous study demonstrated that obese-insulin resistant rats induced by a 12-week high-fat diet (HF) resulted in impairment of osteoblastic insulin signaling, decreased osteoblastic proliferation, increased osteoblastic apoptosis, and can lead to osteoporosis in the jaw bone (Pramojanee et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Obesity does not aggravate osteoporosis or osteoblastic insulin resistance in orchiectomized rats

Potikanond¹,

Rattanachote²,

Pintana³

et al. 2016

Journal of Endocrinology

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The present study aimed to test the hypothesis that testosterone deprivation impairs osteoblastic insulin signaling, decreases osteoblast survival, reduces bone density, and that obesity aggravates those deleterious effects in testosterone-deprived rats. Twenty four male Wistar rats underwent either a bilateral orchiectomy (O, nZ12) or a sham operation (S, nZ12). Then the rats in each group were further divided into two subgroups fed with either a normal diet (ND) or a high-fat diet (HF) for 12 weeks. At the end of the protocol, blood samples were collected to determine metabolic parameters and osteocalcin ratios. The tibiae were collected to determine bone mass using microcomputed tomography and for osteoblast isolation. The results showed that rats fed with HF (sham-operated HF-fed rats (HFS) and ORX HF-fed rats (HFO)) developed peripheral insulin resistance and had decreased trabecular bone density. In ND-fed rats, only the ORX ND-fed rats (NDO) group had decreased trabecular bone density. In addition, osteoblastic insulin resistance, as indicated by a decrease in tyrosine phosphorylation of the insulin receptor and Akt, were observed in all groups except the sham-operated ND-fed rats (NDS) rats. Those groups, again with the exception of the NDS rats, also had decreased osteoblastic survival. No differences in the levels of osteoblastic insulin resistance and osteoblastic survival were found among the NDO, HFS, and HFO groups. These findings suggest that either testosterone deprivation or obesity alone can impair osteoblastic insulin signaling and decrease osteoblastic survival leading to the development of osteoporosis. However, obesity does not aggravate those deleterious effects in the bone of testosterone-deprived rats.

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Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling

Cited by 223 publications

References 39 publications

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

An Akt-dependent Increase in Canonical Wnt Signaling and a Decrease in Sclerostin Protein Levels Are Involved in Strontium Ranelate-induced Osteogenic Effects in Human Osteoblasts

Obesity does not aggravate osteoporosis or osteoblastic insulin resistance in orchiectomized rats

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