Positive Regulation of Adult Bone Formation by Osteoblast-Specific Transcription Factor Osterix

Baek, Woon Yi; Lee, Mina; Jung, Ji Won; Kim, Shin‐Yoon; Akiyama, Haruhiko; Crombrugghe, Benoít de; Kim, Jung-Eun

doi:10.1359/jbmr.081248

Cited by 170 publications

(168 citation statements)

References 33 publications

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“…Inactivation of Osx by a ubiquitously expressed recombinase allowed us to explore the potential function of Osx in cells of the osteoblast lineage before expression of osteoblast-specific marker genes A recent study showed that mice, in which the conditional allele of Osx was inactivated by using a Cre transgene driven by a osteoblast-specific Col1a1 promoter (15), developed a much milder phenotype compared with the Osx postnatal mutant mice described here. Unlike our Osx postnatal mutant mice, in which osteoblast differentiation and bone formation was completely arrested, these mice exhibited only a moderately decreased osteoblast activity.…”

Section: Discussionmentioning

confidence: 84%

Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice

Zhou¹,

Zhang²,

Feng

et al. 2010

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

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274

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The transcription factor Osterix (Osx) is required for osteoblast differentiation and bone formation during embryonic development, but it is not known whether Osx has an essential function in postnatal bone growth and in bone homeostasis. Conditional deletion of Osx at several time points postnatally revealed that Osx was essential for osteoblast differentiation and new bone formation in growing and adult bones. Additionally, inactivation of Osx in bones severely disrupted the maturation, morphology, and function of osteocytes. These findings identify Osx as having an essential role in the cell-specific genetic program of osteocytes. Interestingly, Osx inactivation also led to the massive accumulation of unresorbed calcified cartilage in a large area below the growth plate of endochondral bones. This specific area was also marked by an unanticipated almost complete lack of bone marrow cells and a marked decrease in the density and size of osteoclasts. This diminished density of osteoclasts could contribute to the lack of resorption of mineralized cartilage. In addition, we speculate that the abnormally accumulated, mainly naked cartilage represents an unfavorable substrate for osteoclasts. Our study identifies Osx as an essential multifunctional player in postnatal bone growth and homeostasis.osteoblast differentiation | skeletal homeostasis | transcription factor | osteocyte | cartilage resorption T he identification of master transcription factors essential for osteoblast differentiation and bone formation during embryonic development has greatly advanced our knowledge of bone biology. However, the transcriptional control of postnatal bone formation and homeostasis remain poorly understood. Normal skeletal growth and homeostasis depends on the coordinated activities of three types of bone cells: osteoblasts, osteoclasts, and osteocytes. Factors secreted by the mesenchyme-derived osteoblasts also control the differentiation and activity of the boneresorbing osteoclasts derived from hematopoietic stem cells. Conversely, bone resorption by osteoclasts releases factors important for bone formation. Osteocytes, which make up over 90-95% of all bone cells in adult animals, are derived from mature osteoblasts and are embedded inside the bone matrix. It has been suggested that osteocytes are mediators of mechanical and hormonal stimulations to control the activity of both osteoblasts and osteoclasts (1). Osteocytes are regulators of mineralization and mineral homeostasis (2, 3), and by controlling Sost expression also act as modulators of Wnt signaling (4).Three transcription factors [β-catenin, Runx2, and Osterix (Osx)] are required for osteoblast differentiation and bone formation during embryonic development (5-9). Osx, which acts downstream of Runx2, is a zinc-finger-containing transcription factor essential for embryonic osteoblast differentiation and bone formation (8). During development, Osx is specifically expressed in osteoblast lineage cells and, at lower levels, in prehypertrophic chondrocytes, but not in ...

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Section: Discussionmentioning

confidence: 84%

Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice

Zhou¹,

Zhang²,

Feng

et al. 2010

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

Self Cite

274

255

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“…Many pivotal genes in mineralization of the bone matrix such as collagen 1 (a1), bone sialoprotein, osteopontin, and osteocalcin were regulated by Sp7. (26,27) Furthermore, Baek and colleagues (28) have concluded that Sp7 continues to be required for bone formation in growing and adult bones. Due to this critical regulation of the osteoblast phenotype by Sp7, identifying upstream regulators of this gene is the key to our understanding of osteoblast mineralization.…”

Section: Discussionmentioning

confidence: 99%

miR-93/Sp7 function loop mediates osteoblast mineralization

Yang

Peng

Chen

et al. 2012

Journal of Bone and Mineral Research

101

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microRNAs (miRNAs) play pivotal roles in osteoblast differentiation. However, the mechanisms of miRNAs regulating osteoblast mineralization still need further investigation. Here, we performed miRNA profiling and identified that miR-93 was the most significantly downregulated miRNA during osteoblast mineralization. Overexpression of miR-93 in cultured primary mouse osteoblasts attenuated osteoblast mineralization. Expression of the Sp7 transcription factor 7 (Sp7, Osterix), a zinc finger transcription factor and critical regulator of osteoblast mineralization, was found to be inversely correlated with miR-93. Then Sp7 was confirmed to be a target of miR-93. Overexpression of miR-93 in cultured osteoblasts reduced Sp7 protein expression without affecting its mRNA level. Luciferase reporter assay showed that miR-93 directly targeted Sp7 by specifically binding to the target coding sequence region (CDS) of Sp7. Experiments such as electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and promoter luciferase reporter assay confirmed that Sp7 bound to the promoter of miR-93. Furthermore, overexpression of Sp7 reduced miR-93 transcription, whereas blocking the expression of Sp7 promoted miR-93 transcription. Our study showed that miR-93 was an important regulator in osteoblast mineralization and miR-93 carried out its function through a novel miR-93/Sp7 regulatory feedback loop. Our findings provide new insights into the roles of miRNAs in osteoblast mineralization. ß

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“…Due to the increasing need for anabolic therapies to prevent age-related bone loss, research has been focused over the last decade on molecular mechanisms regulating osteoblast function in postnatal remodeling [20][21][22]. For instance, Runx2 and Osx have been found to regulate osteoblast function in adult bone in addition to their primarily established role in osteoblastogenesis [23,24]. Another transcription factor, Atf4 regulates bone matrix deposition by mature osteoblasts [25].…”

Section: Discussionmentioning

confidence: 99%

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Thouverey

Caverzasio

2012

Cell. Mol. Life Sci.

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Bone continuously remodels throughout life by coordinated actions of osteoclasts and osteoblasts. Abnormalities in either osteoclast or osteoblast functions lead to bone disorders. The p38 MAPK pathway has been shown to be essential in controlling osteoblast differentiation and skeletogenesis. Although p38a is the most abundant p38 member in osteoblasts, its specific individual contribution in regulating postnatal osteoblast activity and bone metabolism is unknown. To elucidate the specific role of p38a in regulating osteoblast function and bone homeostasis, we generated mice lacking p38a in differentiated osteoblasts. Osteoblast-specific p38a knockout mice were of normal weight and size. Despite non-significant bone alterations until 5 weeks of age, mutant mice demonstrated significant and progressive decrease in bone mineral density from that age. Adult mice deficient in p38a in osteoblasts displayed a striking reduction in cancellous bone volume at both axial and appendicular skeletal sites. At 6 months of age, trabecular bone volume was reduced by 62 % in those mice. Mutant mice also exhibited progressive decrease in cortical thickness of long bones. These abnormalities correlated with decreased endocortical and trabecular bone formation rate and reduced expressions of type 1 collagen, alkaline phosphatase, osteopontin and osteocalcin whereas bone resorption and osteoclasts remained unaffected. Finally, osteoblasts lacking p38a showed impaired marker gene expressions and defective mineralization in vitro. These findings indicate that p38a is an essential positive regulator of osteoblast function and postnatal bone formation in vivo.

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Positive Regulation of Adult Bone Formation by Osteoblast-Specific Transcription Factor Osterix

Cited by 170 publications

References 33 publications

Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice

Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice

miR-93/Sp7 function loop mediates osteoblast mineralization

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

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