Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

Pérez-Campo, Flor M.; Santurtún, Ana; García-Ibarbia, Carmen; Pascual, M. Asunción; Valero, Carmen; Garcés, Carlos; Sañudo, Carolina; Zarrabeitia, Marı́a T.; Riancho, José A.

doi:10.1007/s00223-016-0144-4

Cited by 73 publications

(46 citation statements)

References 35 publications

(38 reference statements)

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“…Since BET up regulates RUNX2 and OSX gene expression and promotes the synthesis of specific non collagenous bone proteins, like BSP and OPN, it is likely that this nutrient is involved in triggering major events in osteogenesis and bone remodeling, potentially restoring the negatively affected balance of bone remodeling during aging. RUNX2 and OSX are indeed key transcription factors of osteoblastic differentiation which activate the downstream processes of osteoblast maturation [15–19]; they also interact and coordinately regulate the expression of bone-specific genes [45]. Moreover, BSP and OPN are two non-collagenous proteins which serve as a matrix-associated signals presenting overlapping and multifunctional activities in bone with effects on bone formation, mineralization and remodeling [44].…”

Section: Discussionmentioning

confidence: 99%

Betaine promotes cell differentiation of human osteoblasts in primary culture

Villa¹,

Senesi

Montesano

et al. 2017

J Transl Med

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BackgroundBetaine (BET), a component of many foods, is an essential osmolyte and a source of methyl groups; it also shows an antioxidant activity. Moreover, BET stimulates muscle differentiation via insulin like growth factor I (IGF-I). The processes of myogenesis and osteogenesis involve common mechanisms with skeletal muscle cells and osteoblasts sharing the same precursor. Therefore, we have hypothesized that BET might be effective on osteoblast cell differentiation.MethodsThe effect of BET was tested in human osteoblasts (hObs) derived from trabecular bone samples obtained from waste material of orthopedic surgery. Cells were treated with 10 mM BET at 5, 15, 60 min and 3, 6 and 24 h. The possible effects of BET on hObs differentiation were evaluated by real time PCR, western blot and immunofluorescence analysis. Calcium imaging was used to monitor intracellular calcium changes.ResultsReal time PCR results showed that BET stimulated significantly the expression of RUNX2, osterix, bone sialoprotein and osteopontin. Western blot and immunofluorescence confirmed BET stimulation of osteopontin protein synthesis. BET stimulated ERK signaling, key pathway involved in osteoblastogenesis and calcium signaling. BET induced a rise of intracellular calcium by means of the calcium ions influx from the extracellular milieu through the L-type calcium channels and CaMKII signaling activation. A significant rise in IGF-I mRNA at 3 and 6 h and a significant increase of IGF-I protein at 6 and 24 h after BET stimulus was detected. Furthermore, BET was able to increase significantly both SOD2 gene expression and protein content.ConclusionsOur study showed that three signaling pathways, i.e. cytosolic calcium influx, ERK activation and IGF-I production, are enhanced by BET in human osteoblasts. These pathways could have synergistic effects on osteogenic gene expression and protein synthesis, thus potentially leading to enhanced bone formation. Taken together, these results suggest that BET could be a promising nutraceutical therapeutic agent in the strategy to counteract the concomitant and interacting impact of sarcopenia and osteoporosis, i.e. the major determinants of senile frailty and related mortality.

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Section: Discussionmentioning

confidence: 99%

Betaine promotes cell differentiation of human osteoblasts in primary culture

Villa¹,

Senesi

Montesano

et al. 2017

J Transl Med

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“…Its restricted expression in osteocytes is achieved through an epigenetic mechanism; the SOST promoter is DNA methylated in osteoblasts but becomes demethylated during the osteoblast to osteocyte transition, allowing initiation of gene expression [30]. Transcription factors known to bind elements in the demethylated SOST promoter include the bone-specific transcription factors Runx2 and Osterix [31], [32]. Bone non-specific transcription factors such as MyoD and C/EBP also bind the SOST promoter in human Saos-2 cells [31].…”

Section: Mechanisms Underlying Sclerostin Down-regulation By Loadingmentioning

confidence: 99%

Sclerostin's role in bone's adaptive response to mechanical loading

Galea

Lanyon

Price

2017

Bone

118

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Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis.

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“…These results suggest that HDAC4 is required to maintain Runx2 expression after continuous PTH treatment. RUNX2 and OSX have been shown to regulate the SOST promoter in human cells …”

Section: Resultsmentioning

confidence: 99%

“…Surprisingly, deletion of HDAC4 in osteoblast lineage cells resulted in a significant inhibition of Sost expression by PTH. Sclerostin, a protein encoded by the Sost gene and expressed by osteocytes, inhibits osteoblastic bone formation . To confirm protein levels of sclerostin, we performed immunohistochemistry (IHC) and found that staining for sclerostin was stronger and the percentage of sclerostin‐positive osteocytes in Hdac4 ob‐/‐ mice was increased compared with Hdac4 fl/fl mice, and in these mice, PTH treatment caused a decrease in sclerostin staining (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that Sost transcription is controlled mainly via its proximal promoter and distal enhancer (evolutionarily conserved region 5, ECR5) . RUNX2 and osterix (OSX) bind to the SOST promoter and have been shown to positively regulate SOST expression in human cells . The distal enhancer, ECR5, is a 255‐bp fragment within the 52‐kb VB region of the Sost gene.…”

Section: Discussionmentioning

confidence: 99%

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The Deletion of Hdac4 in Mouse Osteoblasts Influences Both Catabolic and Anabolic Effects in Bone

Nakatani

Chen

Johnson

et al. 2018

Journal of Bone and Mineral Research

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Histone deacetylase 4 (Hdac4) is known to control chondrocyte hypertrophy and bone formation. We have previously shown that parathyroid hormone (PTH) regulates many aspects of Hdac4 function in osteoblastic cells in vitro; however, in vivo confirmation was previously precluded by preweaning lethality of the Hdac4-deficient mice. To analyze the function of Hdac4 in bone in mature animals, we generated mice with osteoblast lineage-specific knockout of Hdac4 (Hdac4 ) by crossing transgenic mice expressing Cre recombinase under the control of a 2.3-kb fragment of the Col1a1 promoter with mice bearing loxP-Hdac4. The Hdac4 mice survive to adulthood and developed a mild skeletal phenotype. At age 12 weeks, they had short, irregularly shaped and stiff tails due to smaller tail vertebrae, with almost no growth plates. The tibial growth plate zone was also thinned, and Mmp13 and Sost mRNAs were increased in the distal femurs of Hdac4 mice. Immunohistochemistry showed that sclerostin was elevated in Hdac4 mice, suggesting that Hdac4 inhibits its gene and protein expression. To determine the effect of PTH in these mice, hPTH (1-34) or saline were delivered for 14 days with subcutaneously implanted devices in 8-week-old female Hdac4 and wild-type (Hdac4 ) mice. Serum CTX, a marker of bone resorption, was increased in Hdac4 mice with or without PTH treatment. Tibial cortical bone volume/total volume (BV/TV), cortical thickness (Ct.Th), and relative cortical area (RCA) were decreased in Hdac4 mice, but PTH caused no further decrease in Hdac4 mice. Tibial trabecular BV/TV and thickness were not changed significantly in Hdac4 mice but decreased with PTH treatment. These results indicate that Hdac4 inhibits bone resorption and has anabolic effects via inhibiting Mmp13 and Sost/sclerostin expression. Hdac4 influences cortical bone mass and thickness and knockout of Hdac4 prevents the catabolic effect of PTH in cortical bone. © 2018 American Society for Bone and Mineral Research.

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Osterix and RUNX2 are Transcriptional Regulators of Sclerostin in Human Bone

Cited by 73 publications

References 35 publications

Betaine promotes cell differentiation of human osteoblasts in primary culture

Betaine promotes cell differentiation of human osteoblasts in primary culture

Sclerostin's role in bone's adaptive response to mechanical loading

The Deletion of Hdac4 in Mouse Osteoblasts Influences Both Catabolic and Anabolic Effects in Bone

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