BMP Receptors in Limb and Tooth Formation

Cheifetz, Sela

doi:10.1177/10454411990100020501

Cited by 30 publications

(25 citation statements)

References 119 publications

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“…To examine the status of BMP receptors in MSC, we analyzed the expression of the BMP receptors ALK-3 and ALK-6 both by conventional RT-PCR and RNase protection assays. ALK-3 is found in a wide variety of developing tissues, while ALK-6 expression tends to be more restricted to skeletal tissues [Cheifetz, 1999]. As shown in figure 1, we detected ALK-6 mRNA in both rat MSC and in human U20S cells.…”

Section: Resultsmentioning

confidence: 58%

Different Effects of BMP-2 on Marrow Stromal Cells from Human and Rat Bone

Osyczka

Diefenderfer

Bhargave

et al. 2004

Cells Tissues Organs

150

109

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Bone morphogenetic proteins (BMPs) promote the differentiation of osteoprogenitor cells, and also induce osteogenesis in bone marrow stromal cells (MSC) from rats and mice. However, compared to results with animal models, BMPs are relatively inefficient in inducing human MSC to undergo osteogenesis, and are much less effective in promoting bone formation in human clinical trials. Previous studies indicated that, while human MSC respond to dexamethasone with elevated levels of the osteoblast marker alkaline phosphatase, most isolates of human MSC fail to show alkaline phosphatase induction in response to BMP-2, BMP-4, or BMP-7. Several other genes known to be induced by BMPs are appropriately regulated; thus, human MSC are capable of some BMP-activated signaling. Analysis of the BMP receptors ALK-3 and ALK-6 indicated that, although ALK-6 mRNA was not expressed in human MSC, overexpressing a constitutively active ALK-6 receptor did not induce elevated alkaline phosphatase. Real-time RT-PCR was used to investigate expression of several osteoblast-related transcription factors in MSC after 6 days’ exposure to BMP2 or dexamethasone. Msx-2, a transcription factor that has been reported to inhibit differentiation of osteoprogenitor cells, showed 10-fold elevation in BMP-2-treated human MSC, but not in BMP-2-treated rat MSC. Overexpression of Msx-2 in human and rat MSC, however, did not alter alkaline phosphatase levels, which suggests that absence of BMP-stimulated alkaline phosphatase was not caused by the BMP-2-induced increase in Msx-2. Although Runx2 isoforms have been implicated in control of osteoblast differentiation, levels of this transcription factor were unaffected by BMP treatment. Expression of the FKHR transcription factor, which has been reported to regulate alkaline phosphatase transcription in mouse cells, showed a modest increase in response to BMP-2, but a much greater increase in dexamethasone-treated cells. We propose that BMP regulation of the bone/liver/kidney alkaline phosphatase gene is indirect, requiring expression of new transcription factor(s) that behave differently in rodent and human MSC.

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Section: Resultsmentioning

confidence: 58%

Different Effects of BMP-2 on Marrow Stromal Cells from Human and Rat Bone

Osyczka

Diefenderfer

Bhargave

et al. 2004

Cells Tissues Organs

150

109

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“…However, the phenotype was milder in the Bmp4-cKO od . In Bmp2-cKO od , we see no change in Bmp4 expression, suggesting that they are not linked and may signal through different receptor combinations (Cheifetz, 1999;Little and Mullins, 2009). The extent of interaction of Bmp4 and Bmp2 with extracellular heparin-sulfate proteoglycan and noggin-like inhibitor molecules may also play a role in the difference between how Bmp2 and Bmp4 function (Dutko and Mullins, 2011).…”

Section: Discussionmentioning

confidence: 91%

Bmp2 Is Required for Odontoblast Differentiation and Pulp Vasculogenesis

et al. 2011

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A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. AbstrActUsing the Bmp2 floxed/3.6Col1a1-Cre (Bmp2-cKO od ) mouse model, we have observed severe defects in odontogenesis and dentin formation with the removal of the Bmp2 gene in early-polarizing odontoblasts. The odontoblasts in the Bmp2-cKO od do not mature properly and fail to form proper dentin with normal dentinal tubules and activate terminal differentiation, as reflected by decreased Osterix, Col1a1, and Dspp expression. There is less dentin, and the dentin is hypomineralized and patchy. We also describe an indirect effect of the Bmp2 gene in odontoblasts on formation of the vascular bed and associated pericytes in the pulp. This vascular niche and numbers of CD146+ pericytes are likely controlled by odontogenic and Bmp2-dependent VegfA production in odontoblasts. The complex roles of Bmp2, postulated to be both direct and indirect, lead to permanent defects in the teeth throughout life, and result in teeth with low quantities of dentin and dentin of poor quality.

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“…Interestingly, BMP-4 has been shown to regulate proximal-distal patterning during tooth development, suggesting that this regulatory role for BMP-4 may be generalized to tissues other than lung (Tucker et al, 1998;Cheifetz, 1999). Further exploration into the specificity between gremlin and different BMPs should help to clarify this regulatory system in the lung.…”

Section: Discussionmentioning

confidence: 99%

The bone morphogenic protein antagonist gremlin regulates proximal‐distal patterning of the lung

Lü

Yang

Zhang

et al. 2001

Developmental Dynamics

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The proximal-distal patterning of lung epithelium involves a complex series of signaling and transcriptional events resulting in the programmed differentiation of highly specialized cells for gas exchange and surfactant protein expression essential for postnatal lung function. The BMP signaling pathway has been shown to regulate cellular differentiation in the lung as well as other tissues. In this report, we show that the can family of related BMP antagonists, including gremlin, cer-1, PRDC, and Dan are expressed in the lung during embryonic development with gremlin expression observed in the proximal airway epithelium. The role of gremlin in lung development was explored by overexpressing it in the distal lung epithelium of transgenic mice using the human SP-C promoter. SP-C/gremlin transgenic mice exhibited a disruption of the proximal-distal patterning found in the airways of the mammalian lung. Expanded expression of the proximal epithelial cell markers CC10 and HFH-4 (Foxj1) was observed in the distal regions of transgenic lungs. Furthermore, smooth muscle ␣-actin expression was observed surrounding the distal airways of SP-C/gremlin mice, indicating a proximalization of distal lung tubules. These data suggest that gremlin plays an important role in lung morphogenesis by regulating the proximal-distal patterning of the lung during development.

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BMP Receptors in Limb and Tooth Formation

Cited by 30 publications

References 119 publications

Different Effects of BMP-2 on Marrow Stromal Cells from Human and Rat Bone

Different Effects of BMP-2 on Marrow Stromal Cells from Human and Rat Bone

Bmp2 Is Required for Odontoblast Differentiation and Pulp Vasculogenesis

The bone morphogenic protein antagonist gremlin regulates proximal‐distal patterning of the lung

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