Regulation of BMP-dependent chondrogenesis in early limb mesenchyme by TGFβ signals

Karamboulas, Konstantina; Dranse, Helen J.; Underhill, T. Michael

doi:10.1242/dev.054809

Cited by 25 publications

(38 citation statements)

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“…Gain-of-function studies in cell culture models suggest that TGFβ triggers chondrogenesis (Carrington et al, 1991;Leonard et al, 1991;Chimal-Monroy and Diaz de Leon, 1997;Merino et al, 1998;Karamboulas et al, 2010). However, blocking TGFβ signaling in the limb mesenchyme by targeting the expression of TGFβ receptor 2 (Tgfbr2) has some effect on chondrocyte differentiation and on joint formation in the digits (Seo and Serra, 2007;Spagnoli et al, 2007) but appears not to affect the initial stages of chondrogenesis.…”

Section: Tgfβ Signaling In Chondrogenesismentioning

confidence: 99%

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

2015

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Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from mesenchymal progenitor cells to their terminal maturation into hypertrophic chondrocytes. Here, we review how multiple signaling molecules, mechanical signals and morphological cell features are integrated to activate a set of key transcription factors that determine and regulate the genetic program that induces chondrogenesis and chondrocyte differentiation. Moreover, we describe recent findings regarding the roles of several signaling pathways in modulating the proliferation and maturation of chondrocytes in the growth plate, which is the 'engine' of bone elongation.

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Section: Tgfβ Signaling In Chondrogenesismentioning

confidence: 99%

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

2015

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“…This termination results in a renewed increase in BMP activity during development of the digit ray primordia (giving rise to metacarpals and phalanges) (Bénazet et al, 2009), which probably serves two purposes: first, to control digit identity by signaling from the interdigit mesenchyme to the distal phalanx-forming region (PFR) (Dahn and Fallon, 2000;Suzuki et al, 2008;Witte et al, 2010), and second, to induce apoptosis of the interdigit mesenchyme (Bandyopadhyay et al, 2006;Pajni-Underwood et al, 2007;Maatouk et al, 2009;Wong et al, 2012). In agreement with these dynamic changes in BMP activity, BMPs inhibit chondrogenic differentiation of early limb bud mesenchymal progenitors while promoting chondrogenesis at late stages (Karamboulas et al, 2010). Noggin-mediated BMP antagonism under experimental conditions showed that BMPs are required to initiate compaction and chondrogenic differentiation of Sox9-positive mesenchymal progenitors (Brunet et al, 1998;Pizette and Niswander, 2000;Barna and Niswander, 2007).…”

Section: Introductionmentioning

confidence: 95%

“…TGF ligands are expressed from early limb bud stages onward, and inhibition of TGF signal transduction in cultured mesenchymal cells provided evidence that TGF signaling functions in early limb buds to alleviate the inhibitory effects of BMPs on initiation of chondrogenic differentiation (Karamboulas et al, 2010). Therefore, brief exposure of mesenchymal progenitors to TGFsignaling seems necessary to allow subsequent induction of chondrogenesis by BMPs (Roark and Greer, 1994;Karamboulas et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, brief exposure of mesenchymal progenitors to TGFsignaling seems necessary to allow subsequent induction of chondrogenesis by BMPs (Roark and Greer, 1994;Karamboulas et al, 2010). Furthermore, implantation of TGF1-loaded beads into the interdigit mesenchyme of chicken limb buds is able to induce formation of ectopic digit phalanges, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds

et al. 2012

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SUMMARYSMAD4 is an essential mediator of canonical TGF/BMP signal transduction and we inactivated Smad4 in mouse limb buds from early stages onward to study its functions in the mesenchyme. While this Smad4 inactivation did not alter the early Sox9 distribution, prefiguring the chondrogenic primordia of the stylopod and zeugopod, it disrupted formation of all Sox9-positive digit ray primordia. Specific inactivation of Smad4 during handplate development pointed to its differential requirement for posterior and anterior digit ray primordia. At the cellular level, Smad4 deficiency blocked the aggregation of Sox9-positive progenitors, thereby preventing chondrogenic differentiation as revealed by absence of collagen type II. The progressive loss of SOX9 due to disrupting digit ray primordia and chondrogenesis was paralleled by alterations in genes marking other lineages. This pointed to a general loss of tissue organization and diversion of mutant cells toward non-specific connective tissue. Conditional inactivation of Bmp2 and Bmp4 indicated that the loss of digit ray primordia and increase in connective tissue were predominantly a consequence of disrupting SMAD4-mediated BMP signal transduction. In summary, our analysis reveals that SMAD4 is required to initiate: (1) formation of the Sox9-positive digit ray primordia; and (2) aggregation and chondrogenic differentiation of all limb skeletal elements.

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“…A trimerised RARE upstream of the firefly luciferase gene (pGL3-RARE-luciferase) was used to assess RA activity (Hoffman et al, 2006). Primary limb mesenchymal cultures were transiently transfected with Effectene (Qiagen) using a modified protocol as described (Karamboulas et al, 2010). Analysis of reporter gene activity was performed using the Dual Luciferase Reporter Assay System (Promega), according to the manufacturer's instructions.…”

Section: Reporter-based Assaysmentioning

confidence: 99%

Genetic deletion ofCyp26b1negatively impacts limb skeletogenesis by inhibiting chondrogenesis

Dranse

Sampaio

Petkovich

et al. 2011

Journal of Cell Science

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SummaryCyp26b1, a retinoic acid (RA)-metabolising enzyme, is expressed in the developing limb bud, and Cyp26b1 -/-mice present with severe limb defects. These malformations might be attributable to an RA-induced patterning defect; however, recent reports suggest that RA is dispensable for limb patterning. In this study, we examined the role of endogenous retinoid signalling in skeletogenesis using Cyp26b1 -/-mice and transgenic mice in which Cyp26b1 is conditionally deleted under control of the Prrx1 promoter beginning at E9.5 (Prrx1Cre + /Cyp26b1 fl/fl ). We found that the limb phenotype in Prrx1Cre + /Cyp26b1 fl/fl mice was less severe than that observed in Cyp26b1 -/-animals and that a change in retinoid signalling contributed to the difference in phenotypes. We systematically examined the role of endogenous RA signalling in chondrogenesis and found that Cyp26b1 -/-cells and limb mesenchymal cells treated with a CYP inhibitor, are maintained in a pre-chondrogenic state, exhibit reduced chondroblast differentiation and have modestly accelerated chondrocyte hypertrophy. Furthermore, Cyp26b1 -/-mesenchyme exhibited an increase in expression of genes in a closely related tendogenic lineage, indicating that retinoid signals in the limb interfere with differentiation and maintain progenitor status. Together, these findings support an important function for RA in regulating the behaviour of mesenchymal progenitors, and their subsequent differentiation and maturation.

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Regulation of BMP-dependent chondrogenesis in early limb mesenchyme by TGFβ signals

Cited by 25 publications

References 1 publication

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds

Genetic deletion ofCyp26b1negatively impacts limb skeletogenesis by inhibiting chondrogenesis

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