Bone Morphogenetic Proteins Induce Gremlin, a Protein That Limits Their Activity in Osteoblasts

Pereira, Rafael

doi:10.1210/en.141.12.4558

Cited by 60 publications

(69 citation statements)

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“…Nevertheless, various explanations have been suggested for the failure of BMP induction in ASCs and bone marrow stromal cells (BMSCs), including up-regulation of BMP antagonists such as noggin and gremlin (Pereira et al, 2000;Diefenderfer et al, 2003;Sutherland et al, 2004;Zuk et al, 2011). On the other hand, the problem may originate from an insufficient activation of downstream signalling related to phosphorylation and nuclear translocation of certain Smads, the intracellular target proteins of e.g.…”

Section: Discussionmentioning

confidence: 99%

Osteogenic medium is superior to growth factors in differentiation of human adipose stem cells towards bone-forming cells in 3D culture

Tirkkonen¹,

Haimi²,

Huttunen³

et al. 2013

eCM

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Human adipose stem cells (hASCs) have been recently used to treat bone defects in clinical practice. Yet there is a need for more optimal scaffolds and cost-effective approaches to induce osteogenic differentiation of hASCs. Therefore, we compared the efficiency of bone morphogenetic proteins (BMP-2 and BMP-7), vascular endothelial growth factor (VEGF), and osteogenic medium (OM) for the osteoinduction of hASCs in 3D culture. In addition, growth factors were tested in combination with OM. Commercially available bioactive glass scaffolds (BioRestore) and biphasic calcium phosphate granules (BoneCeramic) were evaluated as prospective carriers for hASCs. Both biomaterials supported hASC-viability, but BioRestore resulted in higher cell number than BoneCeramic, whereas BoneCeramic supported more significant collagen production. The most efficient osteo-induction was achieved with plain OM, promoting higher alkaline phosphatase activity and collagen production than growth factors. In fact, treatment with BMP-2 or VEGF did not increase osteogenic differentiation or cell number significantly more than maintenance medium with either biomaterial. Moreover, BMP-7 treatment consistently inhibited proliferation and osteogenic differentiation of hASCs. Interestingly, there was no benefit from growth factors added to OM. This is the first study to demonstrate that OM enhances hASCdifferentiation towards bone-forming cells significantly more than growth factors in 3D culture.

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Section: Discussionmentioning

confidence: 99%

Osteogenic medium is superior to growth factors in differentiation of human adipose stem cells towards bone-forming cells in 3D culture

Tirkkonen¹,

Haimi²,

Huttunen³

et al. 2013

eCM

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“…This activity is normally antagonized by gremlin (Khokha et al, 2003). Gremlin was also upregulated upon activation of ␤-catenin; however, we think that this is a secondary effect, because concurrent expansion of the Bmp target genes Msx1 and Msx2 suggests that active Bmp signaling was occurring in ␤-cat ⌬ex3Prx1/+ limbs, and because Bmps can induce gremlin expression (Pereira et al, 2000).…”

Section: Research Articlementioning

confidence: 92%

Multiple roles of mesenchymal β-catenin during murine limb patterning

et al. 2006

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Recently canonical Wnt signaling in the ectoderm has been shown to be required for maintenance of the apical ectodermal ridge (AER) and for dorsoventral signaling. Using conditional gain-and loss-of-function ␤-catenin alleles, we have studied the role of mesenchymal ␤-catenin activity during limb development. Here, we show that loss of ␤-catenin results in limb truncations due to a defect in AER maintenance. Stabilization of ␤-catenin also results in truncated limbs, caused by a premature regression of the AER. Concomitantly, in these limbs, the expression of Bmp2, Bmp4 and Bmp7, and of the Bmp target genes Msx1, Msx2 and gremlin, is expanded in the mesenchyme. Furthermore, we found that the expression of Lmx1b, a gene exclusively expressed in the dorsal limb mesenchyme and involved in dorsoventral patterning, is reduced upon loss of ␤-catenin activity and is expanded ventrally in gainof-function limbs. However, the known ectodermal regulators Wnt7a and engrailed 1 are expressed normally. This suggests that Lmx1b is also regulated, in part, by a ␤-catenin-mediated Wnt signal, independent of the non-canoncial Wnt7a signaling pathway. In addition, loss of ␤-catenin results in a severe agenesis of the scapula. Concurrently, the expression of two genes, Pax1 and Emx2, which have been implicated in scapula development, is lost in ␤-catenin loss-of-function limbs; however, only Emx2 is upregulated in gain-of-function limbs. Mesenchymal ␤-catenin activity is therefore required for AER maintenance, and for normal expression of Lmx1b and Emx2.

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“…It was recently shown that expression of drm is under the control of BMP signaling in osteoblasts (Pereira et al, 2000) as well as into chick limb buds. In this case, BMP-soaked beads decreased drm expression in a region close to the BMP source, whereas upregulation occurred at a distance (Capdevila et al, 1999;Merino et al, 1999).…”

Section: Bmps Regulate Drm/gremlin Expressionmentioning

confidence: 99%

Drm/Gremlin, a BMP antagonist, defines the interbud region during feather development.

Bardot

Lecoin²,

Fliniaux³

et al. 2004

Int. J. Dev. Biol.

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The pattern of feather buds in a tract is thought to result from the relative ratios between activator and inhibitor signals through a lateral inhibition process. We analyse the role of Drm/Gremlin, a BMPs antagonist expressed during feather pattern formation, in the dermal precursor, the dense dermis, the interbud dermis and in the posterior dermal condensation. We have altered the activity of Drm in embryonic chick skin using retroviral vectors expressing drm/ gremlin and bmps. We show that expression of endogenous drm is under the control of a feedback loop induced by the BMP pathway, and that overexpression of drm results in fusion between adjacent feather buds. We propose that endogenous BMP proteins induce drm expression in the interbud dermis. In turn, the Drm/Gremlin protein limits the inhibitory effect of BMPs, allowing the adjacent row of feathers to form. Thus, the balance between BMPs and its antagonist Drm would regulate the size and spacing of the buds.

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Bone Morphogenetic Proteins Induce Gremlin, a Protein That Limits Their Activity in Osteoblasts

Cited by 60 publications

References 0 publications

Osteogenic medium is superior to growth factors in differentiation of human adipose stem cells towards bone-forming cells in 3D culture

Osteogenic medium is superior to growth factors in differentiation of human adipose stem cells towards bone-forming cells in 3D culture

Multiple roles of mesenchymal β-catenin during murine limb patterning

Drm/Gremlin, a BMP antagonist, defines the interbud region during feather development.

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