Musculoskeletal System - Cartilage Development - Revision history

Z8600021 at 22:57, 19 November 2019

2019-11-19T22:57:38Z

← Older revision		Revision as of 09:57, 20 November 2019
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	* '''L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during {{limb}} development{'''{#pmid:31591237\|PMID31591237}} "All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation."		* '''L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during {{limb}} development'''{{#pmid:31591237\|PMID31591237}} "All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation."

	* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."		* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."

Z8600021 at 22:56, 19 November 2019

2019-11-19T22:56:54Z

← Older revision		Revision as of 09:56, 20 November 2019
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			* '''L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during {{limb}} development{'''{#pmid:31591237\|PMID31591237}} "All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation."

	* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."		* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."

	* '''Lin28a overexpression reveals the role of Erk signaling in articular cartilage development'''{{#pmid:30042178\|PMID30042178}} "Adult articular cartilage shows limited tissue turnover, and therefore development of the proper structure of articular cartilage is crucial for life-long joint function. However, the mechanism by which the articular cartilage structure is developmentally regulated is poorly understood. In this study, we show evidence that activation of extracellular signal-regulated kinases (Erk1/2) in articular chondrocyte progenitors during developmental stages control articular cartilage thickness. We found that overexpression of Lin28a, an RNA-binding protein that regulates organismal growth and metabolism, in articular chondrocyte progenitor cells upregulated Erk signaling and increased articular cartilage thickness. Overexpression of a constitutively active Kras mimicked Lin28a overexpression, and inhibition of Erk signaling during embryonic stages normalized the cartilage phenotype of both Kras- and Lin28a-overexpressing mice. These results suggest that articular cartilage thickness is mainly determined during the process of embryonic synovial joint development, which is positively regulated by Erk signaling."		* '''Lin28a overexpression reveals the role of Erk signaling in articular cartilage development'''{{#pmid:30042178\|PMID30042178}} "Adult articular cartilage shows limited tissue turnover, and therefore development of the proper structure of articular cartilage is crucial for life-long joint function. However, the mechanism by which the articular cartilage structure is developmentally regulated is poorly understood. In this study, we show evidence that activation of extracellular signal-regulated kinases (Erk1/2) in articular chondrocyte progenitors during developmental stages control articular cartilage thickness. We found that overexpression of Lin28a, an RNA-binding protein that regulates organismal growth and metabolism, in articular chondrocyte progenitor cells upregulated Erk signaling and increased articular cartilage thickness. Overexpression of a constitutively active Kras mimicked Lin28a overexpression, and inhibition of Erk signaling during embryonic stages normalized the cartilage phenotype of both Kras- and Lin28a-overexpressing mice. These results suggest that articular cartilage thickness is mainly determined during the process of embryonic synovial joint development, which is positively regulated by Erk signaling."

	* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''{{#pmid:25818812\|PMID25818812}} "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]

	* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''{{#pmid:25558817\|PMID25558817}} Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."

	* '''Review - Current understanding on the molecular basis of chondrogenesis'''{{#pmid:24532955\|PMID24532955}} "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."
	\|}		\|}
	{\| class="wikitable mw-collapsible mw-collapsed"		{\| class="wikitable mw-collapsible mw-collapsed"
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	\| [[File:Mark_Hill.jpg\|90px\|left]] {{Most_Recent_Refs}}		\| [[File:Mark_Hill.jpg\|90px\|left]] {{Most_Recent_Refs}}

	Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Cartilage+Embryology ''Cartilage Embryology'']		Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Cartilage+Development ''Cartilage Development''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Cartilage+Embryology ''Cartilage Embryology''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Chondrogenesis ''Chondrogenesis'']

	~~<pubmed limit=5>Cartilage Embryology</pubmed>~~
	\|}		\|}
	{\| class="wikitable mw-collapsible mw-collapsed"		{\| class="wikitable mw-collapsible mw-collapsed"
	! Older papers		! Older papers
	\|-		\|-
	\|		\| {{Older papers}}
			* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''{{#pmid:25818812\|PMID25818812}} "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]

			* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''{{#pmid:25558817\|PMID25558817}} Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."

			* '''Review - Current understanding on the molecular basis of chondrogenesis'''{{#pmid:24532955\|PMID24532955}} "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."

	* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation'''{{#pmid:20593410\|PMID20593410}} "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."		* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation'''{{#pmid:20593410\|PMID20593410}} "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."

Z8600021 at 22:57, 6 November 2019

2019-11-06T22:57:01Z

← Older revision		Revision as of 09:57, 7 November 2019
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			* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."

	* '''Lin28a overexpression reveals the role of Erk signaling in articular cartilage development'''{{#pmid:30042178\|PMID30042178}} "Adult articular cartilage shows limited tissue turnover, and therefore development of the proper structure of articular cartilage is crucial for life-long joint function. However, the mechanism by which the articular cartilage structure is developmentally regulated is poorly understood. In this study, we show evidence that activation of extracellular signal-regulated kinases (Erk1/2) in articular chondrocyte progenitors during developmental stages control articular cartilage thickness. We found that overexpression of Lin28a, an RNA-binding protein that regulates organismal growth and metabolism, in articular chondrocyte progenitor cells upregulated Erk signaling and increased articular cartilage thickness. Overexpression of a constitutively active Kras mimicked Lin28a overexpression, and inhibition of Erk signaling during embryonic stages normalized the cartilage phenotype of both Kras- and Lin28a-overexpressing mice. These results suggest that articular cartilage thickness is mainly determined during the process of embryonic synovial joint development, which is positively regulated by Erk signaling."		* '''Lin28a overexpression reveals the role of Erk signaling in articular cartilage development'''{{#pmid:30042178\|PMID30042178}} "Adult articular cartilage shows limited tissue turnover, and therefore development of the proper structure of articular cartilage is crucial for life-long joint function. However, the mechanism by which the articular cartilage structure is developmentally regulated is poorly understood. In this study, we show evidence that activation of extracellular signal-regulated kinases (Erk1/2) in articular chondrocyte progenitors during developmental stages control articular cartilage thickness. We found that overexpression of Lin28a, an RNA-binding protein that regulates organismal growth and metabolism, in articular chondrocyte progenitor cells upregulated Erk signaling and increased articular cartilage thickness. Overexpression of a constitutively active Kras mimicked Lin28a overexpression, and inhibition of Erk signaling during embryonic stages normalized the cartilage phenotype of both Kras- and Lin28a-overexpressing mice. These results suggest that articular cartilage thickness is mainly determined during the process of embryonic synovial joint development, which is positively regulated by Erk signaling."

Z8600021 at 09:18, 11 Mayıs 2019

2019-05-11T09:18:40Z

← Older revision		Revision as of 20:18, 11 Mayıs 2019
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			==Chondroblast==

			==Chondrocyte==


	== References ==		== References ==

Z8600021 at 11:30, 1 September 2018

2018-09-01T11:30:21Z

← Older revision		Revision as of 22:30, 1 September 2018
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			* '''Lin28a overexpression reveals the role of Erk signaling in articular cartilage development'''{{#pmid:30042178\|PMID30042178}} "Adult articular cartilage shows limited tissue turnover, and therefore development of the proper structure of articular cartilage is crucial for life-long joint function. However, the mechanism by which the articular cartilage structure is developmentally regulated is poorly understood. In this study, we show evidence that activation of extracellular signal-regulated kinases (Erk1/2) in articular chondrocyte progenitors during developmental stages control articular cartilage thickness. We found that overexpression of Lin28a, an RNA-binding protein that regulates organismal growth and metabolism, in articular chondrocyte progenitor cells upregulated Erk signaling and increased articular cartilage thickness. Overexpression of a constitutively active Kras mimicked Lin28a overexpression, and inhibition of Erk signaling during embryonic stages normalized the cartilage phenotype of both Kras- and Lin28a-overexpressing mice. These results suggest that articular cartilage thickness is mainly determined during the process of embryonic synovial joint development, which is positively regulated by Erk signaling."

	* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''{{#pmid:25818812\|PMID25818812}} "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]		* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''{{#pmid:25818812\|PMID25818812}} "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]

Z8600021 at 09:50, 20 February 2018

2018-02-20T09:50:12Z

← Older revision		Revision as of 20:50, 20 February 2018
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	* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation'''{{#pmid:20593410\|PMID20593410}} "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."		* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation'''{{#pmid:20593410\|PMID20593410}} "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."
	* '''SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification'''~~<ref name=~~PMID20179096~~><pubmed>20179096</pubmed></ref>~~ "...SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification."
			* '''SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification'''{{#pmid:20179096\|PMID20179096}} "...SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification."
	\|}		\|}
	== Textbooks ==		== Textbooks ==
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	===Reviews===		===Reviews===
			{{#pmid:23794334}}

			{{#pmid:17049221}}

			{{#pmid:16215986}}

	~~<pubmed>23794334</pubmed>\| [http~~:~~//www.ncbi.nlm.nih.gov/pmc/articles/PMC3709051 MC3709051] \| [http://link.springer.com/article/10.1007%2Fs12079-013-0204-8 J Cell Commun Signal.]~~		{{#pmid:11879545}}
	~~<pubmed>17049221</pubmed>~~
	~~<pubmed>16215986</pubmed>~~
	~~<pubmed>~~11879545~~</pubmed>~~

	===Articles===		===Articles===

Z8600021 at 09:45, 20 February 2018

2018-02-20T09:45:59Z

← Older revision		Revision as of 20:45, 20 February 2018
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	[[File:Fetal_head_lateral.jpg\|thumb\|300px\|Fetal head (week 12)]]		[[File:Fetal_head_lateral.jpg\|thumb\|300px\|Fetal head (week 12)]]
	The mesoderm forms nearly all the connective tissues of the musculoskeletal system. Each tissue (cartilage, bone, and muscle) goes through many different mechanisms of differentiation. Recent studies~~<ref name=~~PMID25818812~~><pubmed>25818812</pubmed></ref>~~ show that Sox9 acts as a key regulator of early chondrocyte differentiation.		The mesoderm forms nearly all the connective tissues of the musculoskeletal system. Each tissue (cartilage, bone, and muscle) goes through many different mechanisms of differentiation. Recent studies{{#pmid:25818812\|PMID25818812}} show that Sox9 acts as a key regulator of early chondrocyte differentiation.


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	\|-bgcolor="F5FAFF"		\|-bgcolor="F5FAFF"
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	* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''~~<ref name=~~PMID25818812~~><pubmed>25818812</pubmed></ref>~~ "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]		* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''{{#pmid:25818812\|PMID25818812}} "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]
	* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''~~<ref name=~~PMID25558817~~><pubmed>25558817</pubmed></ref>~~Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."
	* '''Review - Current understanding on the molecular basis of chondrogenesis'''~~<ref name=PMID24532955><pubmed>~~24532955~~</pubmed>~~\| ~~[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924171 Clin Pediatr Endocrinol.]</ref>~~ "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."		* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''{{#pmid:25558817\|PMID25558817}} Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."

			* '''Review - Current understanding on the molecular basis of chondrogenesis'''{{#pmid:24532955\|PMID24532955}} "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."
	\|}		\|}
	{\| class="wikitable mw-collapsible mw-collapsed"		{\| class="wikitable mw-collapsible mw-collapsed"
Line 38:		Line 40:
	\|-		\|-
	\|		\|
	* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation''' ~~<ref name=~~PMID20593410~~><pubmed>20593410</pubmed></ref>~~ "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."		* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation'''{{#pmid:20593410\|PMID20593410}} "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."
	* '''SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification'''<ref name=PMID20179096><pubmed>20179096</pubmed></ref> "...SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification."		* '''SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification'''<ref name=PMID20179096><pubmed>20179096</pubmed></ref> "...SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification."
	\|}		\|}

Z8600021 at 00:00, 12 September 2016

2016-09-12T00:00:23Z

← Older revision		Revision as of 11:00, 12 September 2016
Line 24:		Line 24:
	* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''<ref name=PMID25558817><pubmed>25558817</pubmed></ref>Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."		* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''<ref name=PMID25558817><pubmed>25558817</pubmed></ref>Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."
	* '''Review - Current understanding on the molecular basis of chondrogenesis'''<ref name=PMID24532955><pubmed>24532955</pubmed>\| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924171 Clin Pediatr Endocrinol.]</ref> "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."		* '''Review - Current understanding on the molecular basis of chondrogenesis'''<ref name=PMID24532955><pubmed>24532955</pubmed>\| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924171 Clin Pediatr Endocrinol.]</ref> "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."
	* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation''' <ref name=PMID20593410><pubmed>20593410</pubmed></ref> "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."
	* '''SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification'''<ref name=PMID20179096><pubmed>20179096</pubmed></ref> "...SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification."
	\|}		\|}
	{\| class="wikitable mw-collapsible mw-collapsed"		{\| class="wikitable mw-collapsible mw-collapsed"
	! More recent papers		! More recent papers
	\|-		\|-
	\| [[File:Mark_Hill.jpg\|90px\|left]] {{Most_Recent_Refs}}		\| [[File:Mark_Hill.jpg\|90px\|left]] {{Most_Recent_Refs}}
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	<pubmed limit=5>Cartilage Embryology</pubmed>		<pubmed limit=5>Cartilage Embryology</pubmed>
			\|}
			{\| class="wikitable mw-collapsible mw-collapsed"
			! Older papers
			\|-
			\|
			* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation''' <ref name=PMID20593410><pubmed>20593410</pubmed></ref> "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."
			* '''SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification'''<ref name=PMID20179096><pubmed>20179096</pubmed></ref> "...SOX9 is able to directly suppress Vegfa expression by binding to SRY sites in the Vegfa gene. Postnatally, bone marrow formation and cartilage resorption in transgenic offspring are resumed by massive invasion of capillaries through the cortical bone shaft, similar to secondary ossification. These findings imply that downregulation of Sox9 in the hypertrophic zone of the normal growth plate is essential for allowing vascular invasion, bone marrow formation and endochondral ossification."
	\|}		\|}
	== Textbooks ==		== Textbooks ==

Z8600021 at 00:42, 4 July 2015

2015-07-04T00:42:43Z

← Older revision		Revision as of 11:42, 4 July 2015
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	\|-bgcolor="F5FAFF"		\|-bgcolor="F5FAFF"
	\|		\|
	* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''<ref name=PMID25818812><pubmed>25818812</pubmed></ref> "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice."		* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''<ref name=PMID25818812><pubmed>25818812</pubmed></ref> "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]
	* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''<ref name=PMID25558817><pubmed>25558817</pubmed></ref>Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."		* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''<ref name=PMID25558817><pubmed>25558817</pubmed></ref>Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."
	* '''Review - Current understanding on the molecular basis of chondrogenesis'''<ref name=PMID24532955><pubmed>24532955</pubmed>\| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924171 Clin Pediatr Endocrinol.]</ref> "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."		* '''Review - Current understanding on the molecular basis of chondrogenesis'''<ref name=PMID24532955><pubmed>24532955</pubmed>\| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924171 Clin Pediatr Endocrinol.]</ref> "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."

Z8600021 at 00:41, 4 July 2015

2015-07-04T00:41:29Z

← Older revision		Revision as of 11:41, 4 July 2015
Line 4:		Line 4:

	[[File:Fetal_head_lateral.jpg\|thumb\|300px\|Fetal head (week 12)]]		[[File:Fetal_head_lateral.jpg\|thumb\|300px\|Fetal head (week 12)]]
	The mesoderm forms nearly all the connective tissues of the musculoskeletal system. Each tissue (cartilage, bone, and muscle) goes through many different mechanisms of differentiation. Recent studies ~~suggest~~ that Sox9 is a key regulator of early chondrocyte differentiation.		The mesoderm forms nearly all the connective tissues of the musculoskeletal system. Each tissue (cartilage, bone, and muscle) goes through many different mechanisms of differentiation. Recent studies<ref name=PMID25818812><pubmed>25818812</pubmed></ref> show that Sox9 acts as a key regulator of early chondrocyte differentiation.


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	\|-bgcolor="F5FAFF"		\|-bgcolor="F5FAFF"
	\|		\|
			* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''<ref name=PMID25818812><pubmed>25818812</pubmed></ref> "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice."
	* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''<ref name=PMID25558817><pubmed>25558817</pubmed></ref>Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."		* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''<ref name=PMID25558817><pubmed>25558817</pubmed></ref>Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."
	* '''Review - Current understanding on the molecular basis of chondrogenesis'''<ref name=PMID24532955><pubmed>24532955</pubmed>\| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924171 Clin Pediatr Endocrinol.]</ref> "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."		* '''Review - Current understanding on the molecular basis of chondrogenesis'''<ref name=PMID24532955><pubmed>24532955</pubmed>\| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924171 Clin Pediatr Endocrinol.]</ref> "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."

← Older revision		Revision as of 09:56, 20 November 2019
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	\|		\|
			* '''L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during {{limb}} development{'''{#pmid:31591237\|PMID31591237}} "All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation."

	* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."		* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."

	* '''Lin28a overexpression reveals the role of Erk signaling in articular cartilage development'''{{#pmid:30042178\|PMID30042178}} "Adult articular cartilage shows limited tissue turnover, and therefore development of the proper structure of articular cartilage is crucial for life-long joint function. However, the mechanism by which the articular cartilage structure is developmentally regulated is poorly understood. In this study, we show evidence that activation of extracellular signal-regulated kinases (Erk1/2) in articular chondrocyte progenitors during developmental stages control articular cartilage thickness. We found that overexpression of Lin28a, an RNA-binding protein that regulates organismal growth and metabolism, in articular chondrocyte progenitor cells upregulated Erk signaling and increased articular cartilage thickness. Overexpression of a constitutively active Kras mimicked Lin28a overexpression, and inhibition of Erk signaling during embryonic stages normalized the cartilage phenotype of both Kras- and Lin28a-overexpressing mice. These results suggest that articular cartilage thickness is mainly determined during the process of embryonic synovial joint development, which is positively regulated by Erk signaling."		* '''Lin28a overexpression reveals the role of Erk signaling in articular cartilage development'''{{#pmid:30042178\|PMID30042178}} "Adult articular cartilage shows limited tissue turnover, and therefore development of the proper structure of articular cartilage is crucial for life-long joint function. However, the mechanism by which the articular cartilage structure is developmentally regulated is poorly understood. In this study, we show evidence that activation of extracellular signal-regulated kinases (Erk1/2) in articular chondrocyte progenitors during developmental stages control articular cartilage thickness. We found that overexpression of Lin28a, an RNA-binding protein that regulates organismal growth and metabolism, in articular chondrocyte progenitor cells upregulated Erk signaling and increased articular cartilage thickness. Overexpression of a constitutively active Kras mimicked Lin28a overexpression, and inhibition of Erk signaling during embryonic stages normalized the cartilage phenotype of both Kras- and Lin28a-overexpressing mice. These results suggest that articular cartilage thickness is mainly determined during the process of embryonic synovial joint development, which is positively regulated by Erk signaling."

	* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''{{#pmid:25818812\|PMID25818812}} "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]

	* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''{{#pmid:25558817\|PMID25558817}} Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."

	* '''Review - Current understanding on the molecular basis of chondrogenesis'''{{#pmid:24532955\|PMID24532955}} "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."
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	Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Cartilage+Embryology ''Cartilage Embryology'']		Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Cartilage+Development ''Cartilage Development''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Cartilage+Embryology ''Cartilage Embryology''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Chondrogenesis ''Chondrogenesis'']

	~~<pubmed limit=5>Cartilage Embryology</pubmed>~~
	\|}		\|}
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	! Older papers		! Older papers
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			* '''Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells'''{{#pmid:25818812\|PMID25818812}} "Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice." [[Developmental Signals - Sox]]

			* '''Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage'''{{#pmid:25558817\|PMID25558817}} Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/β-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/β-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/β-catenin in suppression of chondrocyte differentiation."

			* '''Review - Current understanding on the molecular basis of chondrogenesis'''{{#pmid:24532955\|PMID24532955}} "Endochondral bone formation involves multiple steps, consisting of the condensation of undifferentiated mesenchymal cells, proliferation and hypertrophic differentiation of chondrocytes, and then mineralization. To date, various factors including transcription factors, soluble mediators, extracellular matrices (ECMs), and cell-cell and cell-matrix interactions have been identified to regulate this sequential, complex process. Moreover, recent studies have revealed that epigenetic and microRNA-mediated mechanisms also play roles in chondrogenesis. Defects in the regulators for the development of growth plate cartilage often cause skeletal dysplasias and growth failure."

	* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation'''{{#pmid:20593410\|PMID20593410}} "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."		* '''SOX9 determines RUNX2 transactivity by directing intracellular degradation'''{{#pmid:20593410\|PMID20593410}} "In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dose-dependent degradation of RUNX2. ...Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed β-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown."