Zfp521 Is a Target Gene and Key Effector of Parathyroid Hormone-Related Peptide Signaling in Growth Plate Chondrocytes

Correa, Diego; Hesse, Eric; Seriwatanachai, Dutmanee; Kiviranta, Riku; Saito, Hiroaki; Yamana, Kei; Neff, Lynn; Atfi, Azeddine; Coillard, Lucie; Sitara, Despina; Maeda, Yukiko; Warming, Søren; Jenkins, Nancy A.; Copeland, Neal G.; Horne, William C.; Lanske, Beate; Baron, Roland

doi:10.1016/j.devcel.2010.09.008

Cited by 91 publications

(108 citation statements)

References 49 publications

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“…Hdac4 is expressed in prehypertrophic chondrocytes, consistent with the finding that Hdac4 loss of function causes premature chondrocyte hypertrophy (Vega et al, 2004). Hdac4 can either directly interact with Runx2 and inhibit its activity (Vega et al, 2004) or indirectly repress Runx2 transcriptional activity by binding to the zinc-finger transcriptional co-regulator Zfp521, which in turn binds to Runx2 and blocks its transcriptional activity (Correa et al, 2010). The activity of class II HDACs is, in turn, regulated by signaling pathways (Fig.…”

Section: Foxa Family Transcription Factorssupporting

confidence: 63%

“…One of the best characterized of these is histone deacetylase 4 (Hdac4), a member of the class II HDACs that was found to repress both Runx2 and Mef2 activity (Vega et al, 2004;Kozhemyakina et al, 2009;Correa et al, 2010) (Fig. 5A).…”

Section: Foxa Family Transcription Factorsmentioning

confidence: 99%

“…Receptors: Fgfr1 (Jacob et al, 2006), Fgfr2 (Yu et al, 2003), Fgfr3 (de Frutos et al, 2007, Pth1r de Frutos et al, 2007), Npr2 (Yamashita et al, 2000), Npr3 (Yamashita et al, 2000) and Egfr (Zhang et al, 2013). Transcription factors: Sox5/6/9 , Runx2 (Inada et al, 1999;Kim et al, 1999), Mef2c and Mef2d (Mef2c/d) (Arnold et al, 2007), Foxa2 (Ionescu et al, 2012), and Zfp521 (Correa et al, 2010). Structural proteins: aggrecan (Acan) (Inada et al, 1999), Col2a1 (de Frutos et al, 2007), Col10a1 (de Frutos et al, 2007), Mmp9 and Mmp13 (Mmp9/13) (Inada et al, 1999), and Spp1 (Inada et al, 1999).…”

Section: Tgfβ Signaling In Chondrogenesismentioning

confidence: 99%

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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: Foxa Family Transcription Factorssupporting

confidence: 63%

Section: Foxa Family Transcription Factorsmentioning

confidence: 99%

Section: Tgfβ Signaling In Chondrogenesismentioning

confidence: 99%

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

2015

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“…PTHrP stimulates cyclin D1 expression in chondrocytes, and is unable to down-regulate RUNX2 expression in chondrocytes from cyclin D1-null mice, apparently because cyclin D1 contributes to proteasomal degradation of RUNX2 (Beier et al 2001, Zhang et al 2009). The transcriptional co-regulator Zfp521, which is induced by PTHrP, has also recently been identified as an effector of PTHrP's actions in the growth plate; the growth cartilage of mice with chondrocyte-specific deletion of Zfp521 resembles that of PTHrP-null mice, and PTHrP is unable to stimulate cyclin D1 expression or inhibit RUNX2 expression in the absence of Zfp521 (Correa et al 2010).…”

Section: Hypertrophymentioning

confidence: 99%

“…A number of publications have described these cells as dying by apoptosis, but the evidence for this conclusion is based on the detection of molecular features known to be associated with apoptosis, such as DNA strand breaks and caspase activation, rather than on the more definitive morphological changes observed on ultrastructural examination (Gibson 1998, Adams & Shapiro 2002, Correa et al 2010. Cells undergoing apoptosis show intense condensation of chromatin into geometric shapes, and fragmentation of the nucleus and cytoplasm into membrane-bound apoptotic bodies (Kerr et al 1972).…”

Section: Chondrocyte Deathmentioning

confidence: 99%

The skeleton: a multi-functional complex organ. The growth plate chondrocyte and endochondral ossification

Mackie¹,

Tatarczuch²,

Mirams³

2011

Journal of Endocrinology

366

319

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Endochondral ossification is the process that results in both the replacement of the embryonic cartilaginous skeleton during organogenesis and the growth of long bones until adult height is achieved. Chondrocytes play a central role in this process, contributing to longitudinal growth through a combination of proliferation, extracellular matrix (ECM) secretion and hypertrophy. Terminally differentiated hypertrophic chondrocytes then die, allowing the invasion of a mixture of cells that collectively replace the cartilage tissue with bone tissue. The behaviour of growth plate chondrocytes is tightly regulated at all stages of endochondral ossification by a complex network of interactions between circulating hormones (including GH and thyroid hormone), locally produced growth factors (including Indian hedgehog, WNTs, bone morphogenetic proteins and fibroblast growth factors) and the components of the ECM secreted by the chondrocytes (including collagens, proteoglycans, thrombospondins and matrilins). In turn, chondrocytes secrete factors that regulate the behaviour of the invading bone cells, including vascular endothelial growth factor and receptor activator of NFkB ligand. This review discusses how the growth plate chondrocyte contributes to endochondral ossification, with some emphasis on recent advances.

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Skeletogenesis: Genetics

Wuelling

Vortkamp

2013

Encyclopedia of Life Sciences

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The vertebrate skeleton is formed by two mechanisms – endochondral and intramembranous ossification. During intramembranous ossification, mesenchymal cells directly differentiate into osteoblasts. Endochondral ossification is a two‐step process during which bones are preformed as cartilage templates, which are subsequently replaced by bone. During this process, the inner cells of the cartilage condensation differentiate into chondrocytes, which proliferate and differentiate into hypertrophic chondrocytes producing a mineralised matrix. The outer cells differentiate into the perichondrium surrounding the cartilage template and later into osteoblasts, which produce a bone collar surrounding the hypertrophic region. Blood vessels from the bone collar invade the hypertrophic region in close association with bone‐resorbing osteoclasts and bone‐forming osteoblasts. The orchestrated formation, differentiation and degradation of cartilage and bone are regulated by a multitude of growth factors and transcriptional regulators, which will be discussed in this article. Key Concepts: During intramembranous ossification, mesenchymal progenitor cells differentiate directly into bone‐forming osteoblasts. Endochondral ossification includes the formation of cartilage templates, which are subsequently replaced by bone and bone marrow. Cells in the cartilage condensation represent bipotential osteochondroprogenitor cells that differentiate depending on their level of Sox9 into chondrocytes. Ihh serves as a key regulator of endochondral ossification regulating chondrocyte proliferation, hypertrophic differentiation and ossification. Ihh and Pthrp interact in a negative feedback mechanism to control the domain of columnar, high‐proliferating chondrocytes. Pthrp negatively regulates cell cycle exit. Runx2 and Mef2c activate chondrocyte differentiation. Runx2 and Osterix are required to induce osteoblast differentiation. The balance between Rankl and osteoprotegerin determines the differentiation of osteoclasts. Chondrocyte differentiation is regulated by secreted growth factors, which activate distinct steps of the differentiation programme.

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Zfp521 Is a Target Gene and Key Effector of Parathyroid Hormone-Related Peptide Signaling in Growth Plate Chondrocytes

Cited by 91 publications

References 49 publications

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

The skeleton: a multi-functional complex organ. The growth plate chondrocyte and endochondral ossification

Skeletogenesis: Genetics

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