Skeletal unloading induces osteoblast apoptosis and targets α5β1-PI3K-Bcl-2 signaling in rat bone

Dufour, Cécilie; Holy, Xavier; Marie, Pierre J.

doi:10.1016/j.yexcr.2006.10.021

Cited by 71 publications

(57 citation statements)

References 58 publications

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“…A possible mechanism for how PTH could explain the cortical bone remodeling observed in the current study is shown in Figure 6. Intact PTH (PTH 1-84), acting through the PTH1 receptor on osteocytes and osteoblasts, could prevent the increased apoptosis and decreased bone formation rates normally associated with disuse [3,52,53]. Prevention of osteocyte apoptosis would prevent increases in targeted remodeling.…”

Section: Discussionmentioning

confidence: 99%

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis)

McGee

Maki

Johnson

et al. 2008

Bone

102

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Disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. However, black bear bone properties are not adversely affected by aging despite annual periods of disuse (i.e., hibernation), which suggests that bears either prevent bone loss during disuse or lose bone and subsequently recover it at a faster rate than other animals. Here we show decreased cortical bone turnover during hibernation with balanced formation and resorption in grizzly bear femurs. Hibernating grizzly bear femurs were less porous and more mineralized, and did not demonstrate any changes in cortical bone geometry or whole bone mechanical properties compared to active grizzly bear femurs. The activation frequency of intracortical remodeling was 75% lower during hibernation than during periods of physical activity, but the normalized mineral apposition rate was unchanged. These data indicate bone turnover decreases during hibernation, but osteons continue to refill at normal rates. There were no changes in regional variation of porosity, geometry, or remodeling indices in femurs from hibernating bears, indicating that hibernation did not preferentially affect one region of the cortex. Thus, grizzly bears prevent bone loss during disuse by decreasing bone turnover and maintaining balanced formation and resorption, which preserves bone structure and strength. These results support the idea that bears possess a biological mechanism to prevent disuse osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis)

McGee

Maki

Johnson

et al. 2008

Bone

102

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“…[54][55][56] The constitutive activation of PI3K signaling is observed in various cancers, offering protection to the rampant dividing cells. 57,58 The anti-apoptotic role of PI3K has been observed in many different cell lines including melanocytes, 59 lung cancer cells, 60 intestinal epithelial cells, 61 colon cancer cells, 62 osteocytes, 63 prostate cancer cells, 64 glioma cells 65 and fibroblasts. 66 In the heart, PI3K has similarly been shown to provide anti-apoptotic signal transduction, and Negibil et al have demonstrated that inhibition of PI3K in myocytes using LY-294002 results in a significant (three-fold) increase in the number of apoptotic nuclei.…”

Section: The Role Of Pi3kmentioning

confidence: 99%

Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmice

Trivedi¹,

Yang²,

Barouch³

2008

Cell Cycle

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Disruption of leptin signaling has been associated with both obesity and heart failure. We recently demonstrated that leptin deficiency in ob/ob mice and leptin insensitivity in db/db mice leads to increased myocyte apoptosis and left ventricular (LV) hypertrophy. We showed that LV mass, while similar among young ob/ob, and wild type (WT) mice, is significantly higher in old ob/ob and db/db versus WT. Ob/ob and db/db mice developed markedly increased rates of myocyte apoptosis by TUNEL and activated caspase-3 levels. An intriguing candidate for the study of obesity-associated cardiac hypertrophy and apoptosis is PI3K, which functions to not only regulate cell size but also maintain cell integrity through protection from apoptosis. Here we further show that ob/ob mice have decreased catalytic activity of phosphoinositide 3-kinase (PI3K) (p110α) which is reversed with leptin treatment. Leptin repletion in ob/ob mice also reduced both myocyte apoptosis and LV hypertrophy to WT levels. We have therefore concluded that normal leptin signaling is necessary to prevent age-related myocyte apoptosis and LV hypertrophy and that PI3K is a critical component of the leptin signaling axis. The decrease in p110α catalytic activity could explain the development of increased myocyte apoptosis and cardiac hypertrophy in these obese mouse models.

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“…Although osteoblasts express several integrins in vitro, few of them have been shown to play an essential role in bone formation in vivo (20). The ␣5␤1 integrin, a cell-surface receptor for fibronectin (FN), controls osteoblast adhesion (21) and survival (15,22,23) and plays a critical role in MSC osteogenic differentiation and bone formation and repair (24 -26). However, the molecular mechanisms whereby ␣5␤1 integrin promotes osteogenic differentiation are not fully understood.…”

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confidence: 99%

Wnt/β-Catenin Signaling Mediates Osteoblast Differentiation Triggered by Peptide-induced α5β1 Integrin Priming in Mesenchymal Skeletal Cells

Saidak

Hénaff

Azzi

et al. 2015

Journal of Biological Chemistry

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Background:The mechanisms whereby ␣5␤1 integrin triggers osteogenesis are poorly understood. Results: CRRETAWAC-mediated ␣5␤1 integrin priming promotes osteoblast differentiation via PI3K/Wnt/␤-catenin signaling independently of the RGD-like REET sequence. Systemic delivery of the ␣5␤1 integrin-priming peptide improved long bone microarchitecture in senescent osteopenic mice. Conclusion: Wnt signaling mediates osteoblast differentiation induced by peptide-mediated ␣5␤1 integrin priming. Significance: A novel mechanism underlying ␣5␤1 integrin-mediated osteoblast differentiation is provided.

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Skeletal unloading induces osteoblast apoptosis and targets α5β1-PI3K-Bcl-2 signaling in rat bone

Cited by 71 publications

References 58 publications

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis)

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis)

Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmice

Wnt/β-Catenin Signaling Mediates Osteoblast Differentiation Triggered by Peptide-induced α5β1 Integrin Priming in Mesenchymal Skeletal Cells

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Skeletal unloading induces osteoblast apoptosis and targets α5β1-PI3K-Bcl-2 signaling in rat bone

Cited by 71 publications

References 58 publications

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis)

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis)

Decreased p110&alpha; catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmice

Wnt/β-Catenin Signaling Mediates Osteoblast Differentiation Triggered by Peptide-induced α5β1 Integrin Priming in Mesenchymal Skeletal Cells

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Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficientob/obmice