Negative Regulation of BMP/Smad Signaling by Tob in Osteoblasts

Yoshida, Yutaka; Tanaka, Sakae; Umemori, Hisashi; Minowa, Osamu; Usui, Michihiko; Ikematsu, Naoko; Hosoda, Eri; Imamura, Takeshi; Kuno, Junko; Yamashita, Toshio; Miyazono, Kohei; Noda, Masaki; Noda, Tetsuo; Yamamoto, Tadashi

doi:10.1016/s0092-8674(00)00211-7

Cited by 299 publications

(312 citation statements)

References 40 publications

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“…Another transcription factor, Atf4 regulates bone matrix deposition by mature osteoblasts [25]. Furthermore, several signaling pathways have been shown to regulate postnatal osteoblast function including Ihh [26], Wnt/Lrp5 [27], TGFb-BMP/Smads [28][29][30], BMP/MEKK2/MEK5-7/Jnk [31], b-adrenergic [32], IGF-1 [16], insulin [33] and PTH signaling [34]. The p38 MAPK pathway has been recently shown to be an essential regulator of osteoblastogenesis during skeletogenesis [12,13].…”

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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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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“…Tob inhibits BMP-induced, Smaddependent transcription in osteoblasts through its association with Smads 1 and 5 proteins (Yoshida et al, 2000). In Tob knockout mice, BMP-2 signaling is enhanced and the effects of BMP-2 on osteoblast proliferation and differentiation are increased.…”

Section: Negative Regulation Of Bmp Signalingmentioning

confidence: 99%

“…In Tob knockout mice, BMP-2 signaling is enhanced and the effects of BMP-2 on osteoblast proliferation and differentiation are increased. In long bones, bone volume and bone formation rates are increased (Yoshida et al, 2000). BMP-2-induced local bone formation is also enhanced in Tob knockout mice (Usui et al, 2002).…”

Section: Negative Regulation Of Bmp Signalingmentioning

confidence: 99%

The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

274

197

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Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor β(TGFβ) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smads 1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and their signaling molecules have shown that BMP signaling plays critical roles in bone and cartilage development and postnatal bone formation. BMP activities are regulated at different molecular levels. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.

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“…7,9,10). The proteins of this family are implicated in regulation of transcription [11][12][13][14] .…”

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confidence: 99%

Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta

et al. 2004

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Spermatogenesis is a complex process that involves cooperation of germ cells and testicular somatic cells. Various genetic disorders lead to impaired spermatogenesis, defective sperm function and male infertility 1 . Here we show that Cnot7 -/-males are sterile owing to oligo-astheno-teratozoospermia, suggesting that Cnot7, a CCR4-associated transcriptional cofactor 2 , is essential for spermatogenesis. Maturation of spermatids is unsynchronized and impaired in seminiferous tubules of Cnot7 -/-mice. Transplantation of spermatogonial stem cells from male Cnot7 -/-mice to seminiferous tubules of Kit mutant mice (Kit W/W-v ) restores spermatogenesis, suggesting that the function of testicular somatic cells is damaged in the Cnot7 -/-condition. The testicular phenotypes of Cnot7 -/-mice are similar to those of mice deficient in retinoid X receptor beta (Rxrb) 3 . We further show that Cnot7 binds the AF-1 domain of Rxrb and that Rxrb malfunctions in the absence of Cnot7. Therefore, Cnot7 seems to function as a coregulator of Rxrb in testicular somatic cells and is thus involved in spermatogenesis.

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Negative Regulation of BMP/Smad Signaling by Tob in Osteoblasts

Cited by 299 publications

References 40 publications

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

The BMP signaling and in vivo bone formation

Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta

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