TGF-β mediated Dlx5 signaling plays a crucial role in osteo-chondroprogenitor cell lineage determination during mandible development

Oka, Kyoko; Oka, Shinichi; Hosokawa, Ryoichi; Bringas, Pablo; Brockhoff, Hans C.; Nonaka, Kenichi; Chai, Yang

doi:10.1016/j.ydbio.2008.03.046

Cited by 59 publications

(42 citation statements)

References 43 publications

(46 reference statements)

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“…This dual effect of TGF␤s on chondrogenesis has been related with the stage of differentiation of the cultured cells at the time of treatment (17,21,46), but the molecular and cellular basis of such opposite effects remains unknown. TGF␤s are also known to exert stage-specific opposite effects in other physiological processes (47), and genetic analysis in mice revealed the existence of cartilages in the face dependent (condilar, coronoid, and angular cartilages) and independent (nasal septum and Merckel's cartilage) of TGF␤ signaling (33). Here we show that treatment of the micromass cultures with TGF␤s at the initial stages of cartilage differentiation transforms the cultures into a fibrous-like tissue lamina.…”

Section: Discussionmentioning

confidence: 55%

“…Furthermore TGF␤s have been implicated in the maturation of the fibrous tissue of the tendons (31) and in the establishment of the regions of tendon attachment into the skeleton (32,33). Our hypothesis is that the negative influence of TGF␤s on chondrogenesis observed in a variety of experimental models might reflect the positive influence on fibrogenesis of these cytokines.…”

mentioning

confidence: 92%

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Transforming Growth Factors β Coordinate Cartilage and Tendon Differentiation in the Developing Limb Mesenchyme

Lorda‐Diez

Montero

Martı́nez-Cué

et al. 2009

Journal of Biological Chemistry

154

176

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Transforming growth factor ␤ (TGF␤) signaling has an increasing interest in regenerative medicine as a potential tool to repair cartilages, however the chondrogenic effect of this pathway in developing systems is controversial. Here we have analyzed the function of TGF␤ signaling in the differentiation of the developing limb mesoderm in vivo and in high density micromass cultures. In these systems highest signaling activity corresponded with cells at stages preceding overt chondrocyte differentiation. Interestingly treatments with TGF␤s shifted the differentiation outcome of the cultures from chondrogenesis to fibrogenesis. This phenotypic reprogramming involved downregulation of Sox9 and Aggrecan and up-regulation of Scleraxis, and Tenomodulin through the Smad pathway. We further show that TGF␤ signaling up-regulates Sox9 in the in vivo experimental model system in which TGF␤ treatments induce ectopic chondrogenesis. Looking for clues explaining the dual role of TGF␤ signaling, we found that TGF␤s appear to be direct inducers of the chondrogenic gene Sox9, but the existence of transcriptional repressors of TGF␤ signaling modulates this role. We identified TGF-interacting factor Tgif1 and SKI-like oncogene SnoN as potential candidates for this inhibitory function. Tgif1 gene regulation by TGF␤ signaling correlated with the differential chondrogenic and fibrogenic effects of this pathway, and its expression pattern in the limb marks the developing tendons. In functional experiments we found that Tgif1 reproduces the profibrogenic effect of TGF␤ treatments. TGF␤s4 form a small family of multipotent regulatory polypeptides that gives the name to a large cytokine superfamily, which also includes Activins and bone morphogenetic proteins, characterized by structural and signaling similarities. In mammalians and birds the family is composed of three highly homologous isoforms, although the avian homologue of the mammalian TGF␤1 was initially named TGF␤4 (1). Signaling by these factors is mediated by ligand binding with type II and type I receptors to form heteromeric complexes, which phosphorylate Smad2 and -3 proteins. The activated p-Smads associate with Smad4 prior to translocation into the nucleus, where they regulate the expression of a variety of genes (see Ref. 2). TGF␤s may also signal through the mitogen-activated protein kinase (MAPK) transduction pathway (3).TGF␤s are considered major regulators of the differentiation and growth of the skeletal connective tissues, with a promising future in regenerative medicine as tools to modulate the differentiation of stem cells for reconstruction of cartilage, tendon, or bone. In the long appendicular bones TGF␤s are expressed in the chondrocytes of the growth plate and regulate the rate of differentiation of prehypertrophic chondrocytes to hypertrophic chondrocytes (4 -7). In embryonic systems, TGF␤s are expressed in the developing limb forming well defined domains in the digit chondrogenic aggregates, in the developing joints and in the differentiating tendon blastema...

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 92%

Transforming Growth Factors β Coordinate Cartilage and Tendon Differentiation in the Developing Limb Mesenchyme

Lorda‐Diez

Montero

Martı́nez-Cué

et al. 2009

Journal of Biological Chemistry

154

176

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“…Both Scx and Mkx interact with Smad3, an essential transcriptional mediator of TGFβ signaling, to regulate tendon ECM production (Berthet et al, 2013;Hosokawa et al, 2010;Katzel et al, 2011;Oka et al, 2008;Pryce et al, 2009).…”

Section: /Egr2mentioning

confidence: 99%

Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix

2015

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Tendons and ligaments are extracellular matrix (ECM)-rich structures that interconnect muscles and bones. Recent work has shown how tendon fibroblasts (tenocytes) interact with muscles via the ECM to establish connectivity and strengthen attachments under tension. Similarly, ECM-dependent interactions between tenocytes and cartilage/bone ensure that tendon-bone attachments form with the appropriate strength for the force required. Recent studies have also established a close lineal relationship between tenocytes and skeletal progenitors, highlighting the fact that defects in signals modulated by the ECM can alter the balance between these fates, as occurs in calcifying tendinopathies associated with aging. The dynamic finetuning of tendon ECM composition and assembly thus gives rise to the remarkable characteristics of this unique tissue type. Here, we provide an overview of the functions of the ECM in tendon formation and maturation that attempts to integrate findings from developmental genetics with those of matrix biology.

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“…Activation of TGF signaling leads to a robust induction of Scx and additional tendon markers, including tenomodulin, a type II transmembrane protein and an inhibitor of angiogenesis (LordaDiez et al, 2009;Oka et al, 2008;Pryce et al, 2009). Furthermore, disruption of TGF signaling (in Tgfb2/Tgfb3 double-mutant mouse embryos) results in the complete loss of all tendon tissue.…”

Section: Axial Tendon Induction Depends On a Myotomal Signalmentioning

confidence: 99%

Connecting muscles to tendons: tendons and musculoskeletal development in flies and vertebrates

2010

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There was an error published in Development 137, 2807-2817.On p. 2808, StripeB was incorrectly referred to as an epidermal growth factor (Egf)-like, rather than an early growth response (Egr)-like, transcription factor. The corrected sentence appears below.One of the earliest genes that induce tendon progenitor cells within the ectoderm encodes the early growth response (Egr)-like transcription factor StripeB, one of the two isoforms produced by the stripe gene.We apologise to the authors and readers for this mistake. SummaryThe formation of the musculoskeletal system represents an intricate process of tissue assembly involving heterotypic inductive interactions between tendons, muscles and cartilage. An essential component of all musculoskeletal systems is the anchoring of the force-generating muscles to the solid support of the organism: the skeleton in vertebrates and the exoskeleton in invertebrates. Here, we discuss recent findings that illuminate musculoskeletal assembly in the vertebrate embryo, findings that emphasize the reciprocal interactions between the forming tendons, muscle and cartilage tissues. We also compare these events with those of the corresponding system in the Drosophila embryo, highlighting distinct and common pathways that promote efficient locomotion while preserving the form of the organism.

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TGF-β mediated Dlx5 signaling plays a crucial role in osteo-chondroprogenitor cell lineage determination during mandible development

Cited by 59 publications

References 43 publications

Transforming Growth Factors β Coordinate Cartilage and Tendon Differentiation in the Developing Limb Mesenchyme

Transforming Growth Factors β Coordinate Cartilage and Tendon Differentiation in the Developing Limb Mesenchyme

Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix

Connecting muscles to tendons: tendons and musculoskeletal development in flies and vertebrates

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