Zic1 transcription factor in bone: neural developmental protein regulates mechanotransduction in osteocytes

Kalogeropoulos, Michail; Varanasi, Satya S.; Olstad, Ole Kristoffer; Sanderson, P. L.; Gautvik, Vigdis T.; Reppe, Sjur; Francis, Roger M.; Gautvik, Kaare M.; Birch, Mark; Datta, Harish K.

doi:10.1096/fj.09-148908

Cited by 43 publications

(35 citation statements)

References 49 publications

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“…In this study, by silencing IFT80 in osteoblastic precursor cell stage, we have investigated the effect of IFT80 silencing on osteoblast differentiation and mineralization. However, we cannot rule out the possibility that IFT80 might also play an important role in mature osteoblast mechanotransduction, because cilia are not only involved in cell differentiation and function, but also acts as a mechanical sensor [19, 20]. …”

Section: Discussionmentioning

confidence: 99%

“…In recent years, the importance of IFT proteins for the development and function of the skeleton has been demonstrated due to the findings of skeletal abnormalities in human cilia-associated disorders [2–6] and in IFT-related mouse knockout studies [7–13]. Increasing studies have shown that primary cilia/IFT regulate embryonic bone development [8, 14–18] and mechanically regulate bone formation in adults[19, 20]. However, the function and mechanism of IFT/cilia proteins in osteoblast differentiation and function are still largely undefined.…”

Section: Introductionmentioning

confidence: 99%

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The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis

Yang

Wang

2012

Bone

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Intraflagellar transport (IFT) proteins are essential for the assembly and maintenance of cilia, which play important roles in development and homeostasis. IFT80 is a newly defined IFT protein. Partial mutation of IFT80 in humans causes diseases such as Jeune asphyxiating thoracic dystrophy (JATD) and short rib polydactyly (SRP) type III with abnormal skeletal development. However, the role and mechanism of IFT80 in osteogenesis is unknown. Here, we first detected IFT80 expression pattern and found that IFT80 was highly expressed in mouse long bone, skull, and during osteoblast differentiation. By using lentivirus-mediated RNA interference (RNAi) technology to silence IFT80 in murine mesenchymal progenitor cell line-C3H10T1/2 and bone marrow derived stromal cells, we found that silencing IFT80 led to either shortening or loss of cilia and the decrease of Arl13b expression - a small GTPase that is localized in cilia. Additionally, silencing IFT80 blocked the expression of osteoblast markers and significantly inhibited ALP activity and cell mineralization. We further found that IFT80 silencing inhibited the expression of Gli2, a critical transcriptional factor in the hedgehog signaling pathway. Overexpression of Gli2 rescued the deficiency of osteoblast differentiation from IFT80-silenced cells, and dramatically promoted osteoblast differentiation. Moreover, introduction of Smo agonist (SAG) promotes osteoblast differentiation, which was partially inhibited by IFT80 silencing. Thus, these results suggested that IFT80 plays an important role in osteogenesis through regulating Hedgehog/Gli signal pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis

Yang

Wang

2012

Bone

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“…A recent report [118] highlights a potentially novel mechanosome protein that may link activation of the primary cilia to mechanotransduction in bone; this is the zinc finger protein of the cerebellum (Zic1). A comparison of gene expression in human bone samples from sites that experience high and low levels of mechanical stress, lumbar spine and iliac crest, respectively, revealed that Zic1 was significantly upregulated in the lumbar spine compared to the iliac crest.…”

Section: The Mechanosome Revisited: Expansion Revision and Supportmentioning

confidence: 99%

The Load-Bearing Mechanosome Revisited

Bidwell

Pavalko

2010

Clinic Rev Bone Miner Metab

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We introduced the mechanosome hypothesis in 2003 as a heuristic model for investigating mechanotransduction in bone (Pavalko et al., J Cell Biochem, 2003, 88(1):104–112). This model suggested specific approaches for investigating how mechanical information is conveyed from the membrane of the sensor bone cell to the target genes and how this transmitted information from the membrane is converted into changes in transcription. The key concepts underlying the mechanosome hypothesis are that load-induced deformation of bone deforms the sensor cell membrane; embedded in the membrane are the focal adhesion and cadherin–catenin complexes, which in turn are physically connected to the chromatin via a solid-state scaffold. The physical stimulation of the membrane launches multiprotein complexes (mechanosomes) from the adhesion platforms while concomitantly tugging target genes into position for contact with the incoming mechanosomes, the carriers of the mechanical information to the nucleus. The mechanosome is comprised of an adhesion-associated protein and a nucleocytoplasmic shuttling transcription factor. Upon arrival at the target gene, mechanosomes alter DNA conformation and thus influence the interactions between trans-acting proteins along the gene, changing gene activity. Here, we update significant progress related to the mechanosome concept since publication of our original hypothesis. The launching of adhesion- and cytoskeletal-associated proteins into the nucleus toward target genes appears to be a common mechanism for regulating cell response to changes in its mechanical microenvironment.

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“…Connective tissue and muscle were removed before freezing in liquid nitrogen. For the replica study, 13 bone biopsies from vertebral lamina were obtained from British Caucasian males as described [10].…”

Section: Bone Donors and Biopsiesmentioning

confidence: 99%

Identification of transcriptional macromolecular associations in human bone using browser based in silico analysis in a giant correlation matrix

Reppe

Sachse

Olstad

et al. 2013

Bone

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Intracellular signaling is critically dependent on gene regulatory networks comprising physical molecular interactions. Presently, there is a lack of comprehensive databases for most human tissue types to verify such macromolecular interactions. We present a user friendly browser which helps to identify functional macromolecular interactions in human bone as significant correlations at the transcriptional level. The molecular skeletal phenotype has been characterized by transcriptome analysis of iliac crest bone biopsies from 84 postmenopausal women through quantifications of ~23,000 mRNA species. When the signal levels were inter-correlated, an array containing >260 million correlations was generated, thus recognizing the human bone interactome at the RNA level. The matrix correlation and p values were made easily accessible by a freely available online browser. We show that significant correlations within the giant matrix are reproduced in a replica set of 13 male vertebral biopsies. The identified correlations differ somewhat from transcriptional interactions identified in cell culture experiments and transgenic mice, thus demonstrating that care should be taken in extrapolating such results to the in vivo situation in human bone. The current giant matrix and web browser are a valuable tool for easy access to the human bone transcriptome and molecular interactions represented as significant correlations at the RNA-level. The browser and matrix should be a valuable hypothesis generating tool for identification of regulatory mechanisms and serve as a library of transcript relationships in human bone, a relatively inaccessible tissue.

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Zic1 transcription factor in bone: neural developmental protein regulates mechanotransduction in osteocytes

Cited by 43 publications

References 49 publications

The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis

The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis

The Load-Bearing Mechanosome Revisited

Identification of transcriptional macromolecular associations in human bone using browser based in silico analysis in a giant correlation matrix

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