Climbing exercise enhances osteoblast differentiation and inhibits adipogenic differentiation with high expression of PTH/PTHrP receptor in bone marrow cells

Menuki, Kunitaka; Mori, Toshiharu; Sakai, Akinori; Sakuma, Miyuki; Okimoto, Nobukazu; Shimizu, Yuki; Kunugita, Naoki; Nakamura, Toshio

doi:10.1016/j.bone.2008.04.022

Cited by 82 publications

(73 citation statements)

References 36 publications

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“…1 Both authors contributed equally to this work. 2 To whom correspondence should be addressed: Dept. of Medicine, University of North Carolina, 5030 Burnett-Womack, CB 7170, Chapel Hill, NC 27599.…”

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confidence: 99%

Mechanical Regulation of Glycogen Synthase Kinase 3β (GSK3β) in Mesenchymal Stem Cells Is Dependent on Akt Protein Serine 473 Phosphorylation via mTORC2 Protein

Case¹,

Thomas²,

Sen

et al. 2011

Journal of Biological Chemistry

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Mechanical signals can inactivate glycogen synthase kinase 3␤ (GSK3␤), resulting in stabilization of ␤-catenin. This signaling cascade is necessary for the inhibition of adipogenesis in mesenchymal stem cells (MSC) that is produced by a daily strain regimen. We investigated whether Akt is the mechanically activated kinase responsible for phosphorylation and inactivation of GSK3␤ in MSC. Mechanical strain (2% magnitude, 0.17 Hz) induced phosphorylation of Akt at Ser-473 and Thr-308 in parallel with phosphorylation of GSK3␤ at Ser-9. Inhibiting Akt (Akt1/2 kinase inhibitor treatment or Akt knockdown) prevented strain-induced phosphorylation of GSK3␤ at Ser-9. Inhibition of PI3K prevented Thr-308 phosphorylation, but straininduced Ser-473 phosphorylation was measurable and induced phosphorylation of GSK3␤, suggesting that Ser-473 phosphorylation is sufficient for the downstream mechanoresponse. As Rictor/mTORC2 (mammalian target of rapamycin complex 2) is known to transduce phosphorylation of Akt at Ser-473 by insulin, we investigated whether it contributes to strain-induced Ser-473 phosphorylation. Phosphorylation of Ser-473 by both mechanical and insulin treatment in MSC was prevented by the mTOR inhibitor KU0063794. When mTORC2 was blocked, mechanical GSK3␤ inactivation was prevented, whereas insulin inhibition of GSK3␤ was still measured in the absence of Ser-473 phosphorylation, presumably through phosphorylation of Akt at Thr-308. In sum, mechanical input initiates a signaling cascade that is uniquely dependent on mTORC2 activation and phosphorylation of Akt at Ser-473, an effect sufficient to cause inactivation of GSK3␤. Thus, mechanical regulation of GSK3␤ downstream of Akt is dependent on phosphorylation of Akt at Ser-473 in a manner distinct from that of growth factors. As such, Akt reveals itself to be a pleiotropic signaling molecule whose downstream targets are differentially regulated depending upon the nature of the activating input.The mesenchymal stem cell (MSC) 3 pool resident in bone marrow serves as a critical repository for lineages that support bone remodeling throughout life. A multitude of environmental factors, including hormones, growth factors, and biophysical stimuli, influence MSC lineage allocation, leading to an inversely proportional commitment of MSC between adipogenic and osteoblastic lineages (1). In rodents, exercise regimens have been shown to reduce marrow adiposity and increase the number of committed osteoprogenitors (2, 3). In vitro, mechanical stimulation directly restrains adipogenic differentiation of mesenchymal progenitors (4, 5). Understanding the mechanical signaling pathways critical to this unique antiadipogenic response should help define new strategies for preserving MSC potential.Inhibition of MSC adipogenesis is mediated by activation of ␤-catenin. In contradistinction to Wnt signaling, where ␤-catenin is protected from degradation through LRP5/6 (LDL receptor-related protein 5/6)-mediated sequestration of glycogen synthase kinase 3␤ (GSK3␤) (6), mechanical pres...

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confidence: 99%

Mechanical Regulation of Glycogen Synthase Kinase 3β (GSK3β) in Mesenchymal Stem Cells Is Dependent on Akt Protein Serine 473 Phosphorylation via mTORC2 Protein

Case¹,

Thomas²,

Sen

et al. 2011

Journal of Biological Chemistry

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“…In contrast, the positive effect of physical exercise on bone metabolism shown by previous studies can be also explained by a mechanical impact of exercise on bone metabolism, because in these studies bone metabolism has been assessed in long bones, which are exposed to mechanical loading. [15][16][17][18][19][20] By using a cranial bone healing model, we can exclude that the local mechanical environment is responsible for the influence of physical exercise on vascularization during bone repair. Vice versa, we can Pearson's product-moment coefficient was used to determine the strength of association between the pairs of IVM parameters and running distances.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it has been demonstrated that physical exercise is capable of stimulating osteoblast proliferation, increasing bone mineral density and bone strength, and inhibiting bone resorption in osteoporotic and nonosteoporotic bone. [15][16][17][18][19][20] When using animal models, the transfer of results to the clinical situation should always be considered. Regarding the cranial window model, differences in the anatomy, morphology, blood supply, and healing process of membranous bones like the calvarium and long bones have to be addressed.…”

Section: Exercise and Angiogenesis During Bone Repairmentioning

confidence: 99%

“…The positive effects of exercise on bone metabolism include a stimulation of cell proliferation and differentiation, an increase of bone mineral density and strength, an inhibition of bone resorption, and an increase of VEGF-mediated angiogenesis during bone remodeling. [15][16][17][18][19][20] Further, cell proliferation and VEGFmediated angiogenesis have been shown to be improved by exercise during regeneration processes in a variety of other tissues. 12,13,21 Of interest, cell proliferation, bone mineralization, and VEGF-mediated angiogenesis play an important role in bone repair, too.…”

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Exercise enhances angiogenesis during bone defect healing in mice

Holstein

Becker

Fiedler

et al. 2011

Journal Orthopaedic Research

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The aim of the present study was to investigate the effect of exercise on angiogenesis during bone defect healing in mice. We evaluated angiogenesis during cranial bone defect healing by intravital fluorescence microscopy (IVM) at days 0-21. To characterize the type of bone repair, we performed additional histomorphometric analyses at days 3-15. IVM was conducted in mice, which were housed in cages supplied with running wheels (exercise group; n ¼ 7) and compared to IVM results of mice, which were housed in cages without running wheels (controls; n ¼ 7). In the exercise group, we additionally performed correlation analyses between results of the IVM and the running distance. IVM showed an accelerated decrease of bone defect area in the exercise group compared to the control group. This was associated with a significantly higher blood vessel diameter in animals undergoing exercise at days 9 and 12 and a significant correlation between running distance and blood vessel density at day 9 (r ¼ 0.74). Histomorphometry showed osseous bridging of the defect at day 9. The newly woven bone was covered by a neo-periosteum containing those blood vessels, which were visible by IVM. We conclude that exercise accelerates bone defect healing and stimulates angiogenesis during bore repair. ß

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“…Factors promoting osteoblast differentiation are generally considered as inhibitory for adipocyte maturation and vice versa [3][4][5][6][7][8][9]. In age-related osteoporosis or osteopenia, the decreased bone volume is at least partly due to the fact that bone marrow stromal cells (BMSCs) have a reduced capacity to differentiate into osteoblasts but an increased capacity for adipocyte differentiation.…”

Section: Introductionmentioning

confidence: 99%

Role of the P2Y13 Receptor in the Differentiation of Bone Marrow Stromal Cells into Osteoblasts and Adipocytes

et al. 2013

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Accumulating evidence indicates that extracellular nucleotides, signaling through purinergic receptors, play a significant role in bone remodeling. Mesenchymal stem cells (MSCs) express functional P2Y receptors whose expression level is regulated during osteoblast or adipocyte differentiation. P2Y 13 -deficient mice were previously shown to exhibit a decreased bone turnover associated with a reduction in the number of both osteoblasts and osteoclasts on the bone surfaces. We therefore examined whether P2Y 13 R activation was involved in the osteogenic differentiation of MSC. Our study demonstrated that ADP stimulation of P2Y 13 R 1/1 (but not P2Y 13 R -/-) adherent bone marrow stromal cells (BMSCs) increased significantly the formation of alkaline phosphatase-colony-forming units (CFU-ALP) as well as the expression of osteoblastic markers (osterix, alkaline phosphatase, and collagen I) involved in the maturation of preosteoblasts into osteoblasts. The number of CFU-ALP obtained from P2Y 13 R -/-BMSC and the level of osteoblastic gene expression after osteogenic stimulation were strongly reduced compared to those obtained in wild-type cell cultures. In contrast, when P2Y 13 R -/-BMSCs were incubated in an adipogenic medium, the number of adipocytes generated and the level of adipogenic gene expression (PPARc2 and Adipsin) were higher than those obtained in P2Y 13 R 1/1 MSC. Interestingly, we observed a significant increase of the number of bone marrow adipocytes in tibia of P2Y 13 R -/-mice. In conclusion, our findings indicate that the P2Y 13 R plays an important role in the balance of osteoblast and adipocyte terminal differentiation of bone marrow progenitors. Therefore, the P2Y 13 receptor can be considered as a new pharmacological target for the treatment of bone diseases like osteoporosis. STEM CELLS

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Climbing exercise enhances osteoblast differentiation and inhibits adipogenic differentiation with high expression of PTH/PTHrP receptor in bone marrow cells

Cited by 82 publications

References 36 publications

Mechanical Regulation of Glycogen Synthase Kinase 3β (GSK3β) in Mesenchymal Stem Cells Is Dependent on Akt Protein Serine 473 Phosphorylation via mTORC2 Protein

Mechanical Regulation of Glycogen Synthase Kinase 3β (GSK3β) in Mesenchymal Stem Cells Is Dependent on Akt Protein Serine 473 Phosphorylation via mTORC2 Protein

Exercise enhances angiogenesis during bone defect healing in mice

Role of the P2Y13 Receptor in the Differentiation of Bone Marrow Stromal Cells into Osteoblasts and Adipocytes

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