Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways

Yu, Hsin Su; Wu, Tzu‐Chin; Chen, Mei‐Ru; Liu, Shan-Wen; Chen, Jen-Hao; Lin, Keh Ming

doi:10.1002/jbmr.9

Cited by 23 publications

(21 citation statements)

References 70 publications

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“…The extracellular-related kinase (ERK) and p38 kinase pathways are strong candidates for this activity since previous work has shown that mechanical stimulation induces a rapid and transient change in both kinase activities in C2C12 and osteoblast-like cells [41][42][43]. Also, the Wnt signalling pathway is involved in the response of bone-like cells to mechanical loading [44] and is also active during osteogenic differentiation of C2C12 cells [45][46][47]. Consistent with these findings, our Western blot data suggest that low-frequency mechanical stimulation following BMP-2 priming may act primarily through ERK and -catenin (Wnt) signalling.…”

Section: Discussionmentioning

confidence: 99%

Low-Frequency Mechanical Stimulation Modulates Osteogenic Differentiation of C2C12 Cells

et al. 2013

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Mechanical stimulation influences stem cell differentiation and may therefore provide improved lineage specification control for clinical applications. Low-frequency oscillatory mechanical stimulation (0.01 Hz) has recently been shown to suppress adipogenic differentiation of mesenchymal stem cells, indicating that the range of effective stimulation frequencies is not limited to those associated with locomotion, circulation, and respiration. We hypothesized that low-frequency mechanical stimulation (0.01 Hz) can also promote osteogenic cell differentiation of myoblastic C2C12 cells in combination with BMP-2. Results indicate that lowfrequency mechanical stimulation can significantly enhance osteogenic gene expression, provided that differentiation is initiated by a priming period involving BMP-2 alone. Subsequent application of low-frequency mechanical stimulation appears to act synergistically with continued BMP-2 exposure to promote osteogenic differentiation of C2C12 cells and can even partially compensate for the removal of BMP-2. These effects may be mediated by the ERK and Wnt signalling pathways. Osteogenic induction of C2C12 cells by low-frequency mechanical stimulation is therefore critically dependent upon previous exposure to growth factors, and the timing of superimposed BMP-2 and mechanical stimuli can sensitively influence osteogenesis. These insights may provide a technically simple means for control of stem cell differentiation in cell-based therapies, particularly for the enhancement of differentiation toward desired lineages.

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Section: Discussionmentioning

confidence: 99%

Low-Frequency Mechanical Stimulation Modulates Osteogenic Differentiation of C2C12 Cells

et al. 2013

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“…Furthermore, the prototypical agonist for noncanonical Wnt-signaling Wnt5a was dramatically enhanced by both differentiation and TSH. Wnt5a is known to increase bone mass and to drive OPG production, mainly from mature osteoblasts (24).…”

Section: Discussionmentioning

confidence: 99%

Thyroid-stimulating hormone induces a Wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures

Baliram

Latif

Berkowitz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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We have shown that the anterior pituitary hormone, thyroidstimulating hormone (TSH), can bypass the thyroid to exert a direct protective effect on the skeleton. Thus, we have suggested that a low TSH level may contribute to the bone loss of hyperthyroidism that has been attributed traditionally to high thyroid hormone levels. Earlier mouse genetic, cell-based, and clinical studies together have established that TSH inhibits osteoclastic bone resorption. However, the direct influence of TSH on the osteoblast has remained unclear. Here, we have used a model system developed from murine ES cells, induced to form mature mineralizing osteoblasts, and show that TSH stimulates osteoblast differentiation primarily through the activation of protein kinase Cδ and the up-regulation of the noncanonical Wnt components frizzled and Wnt5a. We predict that a TSH-induced, fast-forward short loop in bone marrow permits Wnt5a production, which, in addition to enhancing osteoblast differentiation, also stimulates osteoprotegerin secretion to attenuate bone resorption by neighboring osteoclasts. We surmise that this loop should uncouple bone formation from bone resorption with a net increase in bone mass, which is what has been observed upon injecting TSH.

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“…Pluripotent mesenchymal precursor cell line C2C12 was utilized, which has been widely used as an in vitro model system to assess osteoblast differentiation [33], [34]. Furthermore, we explored the underlying mechanisms of cyclin G2 to suppress estrogen-mediated osteogenesis.…”

Section: Introductionmentioning

confidence: 99%

Cyclin G2 Suppresses Estrogen-Mediated Osteogenesis through Inhibition of Wnt/β-Catenin Signaling

Gao

Liu

et al. 2014

PLoS ONE

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Estrogen plays an important role in the maintenance of bone formation, and deficiency in the production of estrogen is directly linked to postmenopausal osteoporosis. To date, the underlying mechanisms of estrogen-mediated osteogenic differentiation are not well understood. In this study, a pluripotent mesenchymal precursor cell line C2C12 was used to induce osteogenic differentiation and subjected to detection of gene expressions or to manipulation of cyclin G2 expressions. C57BL/6 mice were used to generate bilateral ovariectomized and sham-operated mice for analysis of bone mineral density and protein expression. We identified cyclin G2, an unconventional member of cyclin, is involved in osteoblast differentiation regulated by estrogen in vivo and in vitro. In addition, the data showed that ectopic expression of cyclin G2 suppressed expression of osteoblast transcription factor Runx2 and osteogenic differentiation marker genes, as well as ALP activity and in vitro extracellular matrix mineralization. Mechanistically, Wnt/β-catenin signaling pathway is essential for cyclin G2 to inhibit osteogenic differentiation. To the best of our knowledge, the current study presents the first evidence that cyclin G2 serves as a negative regulator of both osteogenesis and Wnt/β-catenin signaling. Most importantly, the basal and 17β-estradiol-induced osteogenic differentiation was restored by overexpression of cyclin G2. These results taken together suggest that cyclin G2 may function as an endogenous suppressor of estrogen-induced osteogenic differentiation through inhibition of Wnt/β-catenin signaling.

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Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways

Cited by 23 publications

References 70 publications

Low-Frequency Mechanical Stimulation Modulates Osteogenic Differentiation of C2C12 Cells

Low-Frequency Mechanical Stimulation Modulates Osteogenic Differentiation of C2C12 Cells

Thyroid-stimulating hormone induces a Wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures

Cyclin G2 Suppresses Estrogen-Mediated Osteogenesis through Inhibition of Wnt/β-Catenin Signaling

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