The Experts below are selected from a list of 7716 Experts worldwide ranked by ideXlab platform
Yingzi Yang - One of the best experts on this subject based on the ideXlab platform.
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wnt β catenin signaling interacts differentially with ihh signaling in controlling endochondral bone and Synovial Joint formation
Development, 2006Co-Authors: Miaohsueh Chen, Paotien Chuang, Yingzi YangAbstract:Both the Wnt/β-catenin and Ihh signaling pathways play essential roles in crucial aspects of endochondral ossification: osteoblast differentiation, chondrocyte proliferation and hypertrophy. To understand the genetic interaction between these two signaling pathways, we have inactivated theβ -catenin gene and upregulated Ihh signaling simultaneously in the same cells during endochondral skeletal development using β-catenin and patched 1 floxed alleles. We uncovered previously unexpected roles of Ihh signaling in Synovial Joint formation and the essential function of Wnt/β-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and Ihh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and Synovial Joint formation in the developing endochondral bone. β-catenin is required downstream of Ihh signaling and osterix expression for osteoblast differentiation. But in chondrocyte survival, β-catenin is required upstream of Ihh signaling to inhibit chondrocyte apoptosis. In addition, Ihh signaling can inhibit chondrocyte hypertrophy and Synovial Joint formation independently ofβ -catenin. However, there is a strong synergistic interaction between Wnt/β-catenin and Ihh signaling in regulating Synovial Joint formation.
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Wnt/β-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and Synovial Joint formation
Development, 2006Co-Authors: Miaohsueh Chen, Paotien Chuang, Yingzi YangAbstract:Both the Wnt/β-catenin and Ihh signaling pathways play essential roles in crucial aspects of endochondral ossification: osteoblast differentiation, chondrocyte proliferation and hypertrophy. To understand the genetic interaction between these two signaling pathways, we have inactivated theβ -catenin gene and upregulated Ihh signaling simultaneously in the same cells during endochondral skeletal development using β-catenin and patched 1 floxed alleles. We uncovered previously unexpected roles of Ihh signaling in Synovial Joint formation and the essential function of Wnt/β-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and Ihh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and Synovial Joint formation in the developing endochondral bone. β-catenin is required downstream of Ihh signaling and osterix expression for osteoblast differentiation. But in chondrocyte survival, β-catenin is required upstream of Ihh signaling to inhibit chondrocyte apoptosis. In addition, Ihh signaling can inhibit chondrocyte hypertrophy and Synovial Joint formation independently ofβ -catenin. However, there is a strong synergistic interaction between Wnt/β-catenin and Ihh signaling in regulating Synovial Joint formation.
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wnt β catenin signaling is sufficient and necessary for Synovial Joint formation
Genes & Development, 2004Co-Authors: Xueyuan Jiang, Lisa Garrettbeal, Lilia Topol, Yingzi YangAbstract:A critical step in skeletal morphogenesis is the formation of Synovial Joints, which define the relative size of discrete skeletal elements and are required for the mobility of vertebrates. We have found that several Wnt genes, including Wnt4, Wnt14, and Wnt16, were expressed in overlapping and complementary patterns in the developing Synovial Joints, where β-catenin protein levels and transcription activity were up-regulated. Removal of β-catenin early in mesenchymal progenitor cells promoted chondrocyte differentiation and blocked the activity of Wnt14 in Joint formation. Ectopic expression of an activated form of β-catenin or Wnt14 in early differentiating chondrocytes induced ectopic Joint formation both morphologically and molecularly. In contrast, genetic removal of β-catenin in chondrocytes led to Joint fusion. These results demonstrate that the Wnt/β-catenin signaling pathway is necessary and sufficient to induce early steps of Synovial Joint formation. Wnt4, Wnt14, and Wnt16 may play redundant roles in Synovial Joint induction by signaling through the β-catenin-mediated canonical Wnt pathway.
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Wnt/β-catenin signaling is sufficient and necessary for Synovial Joint formation
Genes & Development, 2004Co-Authors: Xueyuan Jiang, Lilia Topol, Lisa Garrett-beal, Yingzi YangAbstract:A critical step in skeletal morphogenesis is the formation of Synovial Joints, which define the relative size of discrete skeletal elements and are required for the mobility of vertebrates. We have found that several Wnt genes, including Wnt4, Wnt14, and Wnt16, were expressed in overlapping and complementary patterns in the developing Synovial Joints, where β-catenin protein levels and transcription activity were up-regulated. Removal of β-catenin early in mesenchymal progenitor cells promoted chondrocyte differentiation and blocked the activity of Wnt14 in Joint formation. Ectopic expression of an activated form of β-catenin or Wnt14 in early differentiating chondrocytes induced ectopic Joint formation both morphologically and molecularly. In contrast, genetic removal of β-catenin in chondrocytes led to Joint fusion. These results demonstrate that the Wnt/β-catenin signaling pathway is necessary and sufficient to induce early steps of Synovial Joint formation. Wnt4, Wnt14, and Wnt16 may play redundant roles in Synovial Joint induction by signaling through the β-catenin-mediated canonical Wnt pathway.
Masahiro Iwamoto - One of the best experts on this subject based on the ideXlab platform.
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Synovial Joint formation requires local ext1 expression and heparan sulfate production in developing mouse embryo limbs and spine
Developmental Biology, 2011Co-Authors: Christina Mundy, Tadashi Yasuda, Takashi Kinumatsu, Motomi Enomotoiwamoto, Masahiro Iwamoto, Eiki Koyama, Yu Yamaguchi, Maurizio PacificiAbstract:Heparan sulfate proteoglycans (HSPGs) regulate a number of major developmental processes, but their roles in Synovial Joint formation remain unknown. Here we created conditional mouse embryo mutants lacking Ext1 in developing Joints by mating Ext1f/f and Gdf5-Cre mice. Ext1 encodes a subunit of the Ext1/Ext2 Golgi-associated protein complex responsible for heparan sulfate (HS) synthesis. The proximal limb Joints did form in the Gdf5-Cre;Ext1f/f mutants, but contained an uneven articulating superficial zone that expressed very low lubricin levels. The underlying cartilaginous epiphysis was deranged as well and displayed random patterns of cell proliferation and matrillin-1 and collagen IIA expression, indicative of an aberrant phenotypic definition of the epiphysis itself. Digit Joints were even more affected, lacked a distinct mesenchymal interzone and were often fused likely as a result of local abnormal BMP and hedgehog activity and signaling. Interestingly, overall growth and lengthening of long bones were also delayed in the mutants. To test whether Ext1 function is needed for Joint formation at other sites, we examined the spine. Indeed, entire intervertebral discs, normally composed by nucleus pulposus surrounded by the annulus fibrosus, were often missing in Gdf5-Cre;Ext1f/f mice. When disc remnants were present, they displayed aberrant organization and defective Joint marker expression. Similar intervertebral Joint defects and fusions occurred in Col2-Cre;β-cateninf/f mutants. The study provides novel evidence that local Ext1 expression and HS production are needed to maintain the phenotype and function of Joint-forming cells and coordinate local signaling by BMP, hedgehog and Wnt/β-catenin pathways. The data indicate also that defects in Joint formation reverberate on, and delay, overall long bone growth.
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Mechanisms of Synovial Joint formation
Clinical calcium, 2006Co-Authors: Eiki Koyama, Masahiro IwamotoAbstract:: Synovial Joints are comprised of relatively simple biomechanical structures including articular cartilage, Synovial membrane, Synovial fluid, ligaments and a fibrous capsule; they are fundamentally important for function and quality of life. Recent studies described the spatio-temporal expression patterns of signaling molecules and transcription factors in the developing Synovial Joints. Though few in number, the gain and/or loss of function-experiments demonstrated direct involvement of these molecules in Joint formation. This review focuses on recent advances in understanding the mechanisms of Synovial Joint formation in the limbs.
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cellular and molecular mechanisms of Synovial Joint and articular cartilage formation
Annals of the New York Academy of Sciences, 2006Co-Authors: Maurizio Pacifici, Motomi Enomotoiwamoto, Eiki Koyama, Yoshihiro Shibukawa, Changshan Wu, Yoshihiro Tamamura, Masahiro IwamotoAbstract:Synovial Joints and articular cartilage play crucial roles in the skeletal function, but relatively little is actually known about their embryonic development. Here we first focused on the interzone, a thin mesenchymal cell layer forming at future Joint sites that is widely thought to be critical for Joint and articular cartilage development. To determine interzone cell origin and fate, we microinjected the vital fluorescent dye DiI at several peri-Joint sites in chick limbs and monitored the behavior and fate of labeled cells over time. Peri-Joint mesenchymal cells located immediately adjacent to incipient Joints migrated, became part of the interzone, and were eventually found in epiphyseal articular layer and Joint capsule. Interzone cells isolated and reared in vitro expressed typical phenotypic markers, including GDF-5, Wnt-14, and CD-44, and differ- entiated into chondrocytes over time. To determine the molecular mech- anisms of articular chondrocyte formation, we carried out additional studies on the ets transcription factor family member ERG and its alter- natively spliced variant C-1-1 that we previously found to be expressed in developing avian articular chondrocytes. We cloned the human coun- terpart of avian C-1-1 (ERGp55Δ81) and conditionally expressed it in transgenic mice under cartilage-specific Col2 gene promotor-enhancer control. The entire transgenic mouse limb chondrocyte population exhib- ited an immature articular-like phenotype and a virtual lack of growth plate formation and chondrocyte maturation compared to wild-type lit- termate. Together, our studies reveal that peri-Joint mesenchymal cells take part in interzone and articular layer formation, interzone cells can differentiate into chondrocytes, and acquisition of a permanent articular chondrocyte phenotype is aided and perhaps dictated by ets transcription factor ERG.
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mechanisms of Synovial Joint and articular cartilage formation recent advances but many lingering mysteries
Birth Defects Research Part C-embryo Today-reviews, 2005Co-Authors: Maurizio Pacifici, Eiki Koyama, Masahiro IwamotoAbstract:Synovial Joints are elegant, critically important, and deceptively simple biomechanical structures. They are comprised of articular cartilage that covers each end of the opposing skeletal elements, Synovial fluid that lubricates and nourishes the tissues, ligaments that hold the skeletal elements in check, and a fibrous capsule that insulates the Joints from surrounding tissues. Joints also exhibit an exquisite arrays of shapes and sizes, best exemplified by the nearly spherical convex femoral head articulating into a nearly spherical concave hip acetabulum, or a phalangeal Joint with two condyles on the distal side articulating in reciprocally-shaped sockets on the opposing proximal side. Though few in number, Joint tissues are highly specialized in structure and function. This is illustrated by articular cartilage with its unique extracellular matrix, unique biomechanical resilience, its largely avascular nature, and its ability to persist through life with minimal turnover of its cells and components. The fact that interest in Synovial Joints has remained unabated for decades is a reflection of their fundamental importance for organism function and quality of life, and for their susceptibility to a variety of acquired and congenital conditions, most importantly arthritis. This has led to many advances in this field that encompass molecular genetics to biomechanics to medicine. Regrettably, what continues to be poorly understood are the mechanisms by which Synovial Joints actually form in the developing embryo. If available, this information would be not only of indisputable biological interest, but would also have significant biomedical ramifications, particularly in terms of designing novel tissue regeneration or reconstruction therapies. This review focuses on recent advances in understanding the mechanisms of Synovial Joint formation in the limbs, and places and discusses the information within the context of classic studies and the many mysteries and questions that remain unanswered. Birth Defects Research (Part C) 75:237–248, 2005. © 2005 Wiley-Liss, Inc.
Maurizio Pacifici - One of the best experts on this subject based on the ideXlab platform.
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mouse limb skeletal growth and Synovial Joint development are coordinately enhanced by kartogenin
Developmental Biology, 2014Co-Authors: Rebekah S Decker, Motomi Enomotoiwamoto, Eiki Koyama, Peter Maye, David W Rowe, Peter G Schultz, Maurizio PacificiAbstract:Abstract Limb development requires the coordinated growth of several tissues and structures including long bones, Joints and tendons, but the underlying mechanisms are not wholly clear. Recently, we identified a small drug-like molecule – we named Kartogenin (KGN) – that greatly stimulates chondrogenesis in marrow-derived mesenchymal stem cells (MSCs) and enhances cartilage repair in mouse osteoarthritis (OA) models. To determine whether limb developmental processes are regulated by KGN, we tested its activity on committed preskeletal mesenchymal cells from mouse embryo limb buds and whole limb explants. KGN did stimulate cartilage nodule formation and more strikingly, boosted digit cartilaginous anlaga elongation, Synovial Joint formation and interzone compaction, tendon maturation as monitored by ScxGFP , and interdigit invagination. To identify mechanisms, we carried out gene expression analyses and found that several genes, including those encoding key signaling proteins, were up-regulated by KGN. Amongst highly up-regulated genes were those encoding hedgehog and TGFβ superfamily members, particularly TFGβ1. The former response was verified by increases in Gli1-LacZ activity and Gli1 mRNA expression. Exogenous TGFβ1 stimulated cartilage nodule formation to levels similar to KGN, and KGN and TGFβ1 both greatly enhanced expression of lubricin / Prg4 in articular superficial zone cells. KGN also strongly increased the cellular levels of phospho-Smads that mediate canonical TGFβ and BMP signaling. Thus, limb development is potently and harmoniously stimulated by KGN. The growth effects of KGN appear to result from its ability to boost several key signaling pathways and in particular TGFβ signaling, working in addition to and/or in concert with the filamin A/CBFβ/RUNX1 pathway we identified previously to orchestrate overall limb development. KGN may thus represent a very powerful tool not only for OA therapy, but also limb regeneration and tissue repair strategies.
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Synovial Joint formation requires local ext1 expression and heparan sulfate production in developing mouse embryo limbs and spine
Developmental Biology, 2011Co-Authors: Christina Mundy, Tadashi Yasuda, Takashi Kinumatsu, Motomi Enomotoiwamoto, Masahiro Iwamoto, Eiki Koyama, Yu Yamaguchi, Maurizio PacificiAbstract:Heparan sulfate proteoglycans (HSPGs) regulate a number of major developmental processes, but their roles in Synovial Joint formation remain unknown. Here we created conditional mouse embryo mutants lacking Ext1 in developing Joints by mating Ext1f/f and Gdf5-Cre mice. Ext1 encodes a subunit of the Ext1/Ext2 Golgi-associated protein complex responsible for heparan sulfate (HS) synthesis. The proximal limb Joints did form in the Gdf5-Cre;Ext1f/f mutants, but contained an uneven articulating superficial zone that expressed very low lubricin levels. The underlying cartilaginous epiphysis was deranged as well and displayed random patterns of cell proliferation and matrillin-1 and collagen IIA expression, indicative of an aberrant phenotypic definition of the epiphysis itself. Digit Joints were even more affected, lacked a distinct mesenchymal interzone and were often fused likely as a result of local abnormal BMP and hedgehog activity and signaling. Interestingly, overall growth and lengthening of long bones were also delayed in the mutants. To test whether Ext1 function is needed for Joint formation at other sites, we examined the spine. Indeed, entire intervertebral discs, normally composed by nucleus pulposus surrounded by the annulus fibrosus, were often missing in Gdf5-Cre;Ext1f/f mice. When disc remnants were present, they displayed aberrant organization and defective Joint marker expression. Similar intervertebral Joint defects and fusions occurred in Col2-Cre;β-cateninf/f mutants. The study provides novel evidence that local Ext1 expression and HS production are needed to maintain the phenotype and function of Joint-forming cells and coordinate local signaling by BMP, hedgehog and Wnt/β-catenin pathways. The data indicate also that defects in Joint formation reverberate on, and delay, overall long bone growth.
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Hox11 genes establish Synovial Joint organization and phylogenetic characteristics in developing mouse zeugopod skeletal elements
Development, 2010Co-Authors: Eiki Koyama, Tadashi Yasuda, Nancy Minugh-purvis, Takashi Kinumatsu, Alisha R. Yallowitz, Deneen M. Wellik, Maurizio PacificiAbstract:Hox11 genes are essential for zeugopod skeletal element development but their roles in Synovial Joint formation remain largely unknown. Here, we show that the elbow and knee Joints of mouse embryos lacking all Hox11 paralogous genes are specifically remodeled and reorganized. The proximal ends of developing mutant ulna and radius elements became morphologically similar and formed an anatomically distinct elbow Joint. The mutant ulna lacked the olecranon that normally attaches to the triceps brachii muscle tendon and connects the humerus to the ulna. In its place, an ulnar patella-like element developed that expressed lubricin on its ventral side facing the Joint and was connected to the triceps muscle tendon. In mutant knees, both tibia and fibula fully articulated with an enlarged femoral epiphyseal end that accommodated both elements, and the neo-tripartite knee Joint was enclosed in a single Synovial cavity and displayed an additional anterior ligament. The mutant Joints also exhibited a different organization of the superficial zone of articular cartilage that normally exerts an anti-friction function. In conclusion, Hox11 genes co-regulate and coordinate the development of zeugopod skeletal elements and adjacent elbow and knee Joints, and dictate Joint identity, morphogenesis and anatomical and functional organization. Notably, the ulnar patella and tripartite knee Joints in the mouse mutants actually characterize several lower vertebrates, including certain reptiles and amphibians. The re-emergence of such anatomical structures suggests that their genetic blueprint is still present in the mouse genome but is normally modified to the needs of the mammalian Joint-formation program by distinct Hox11 function.
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cellular and molecular mechanisms of Synovial Joint and articular cartilage formation
Annals of the New York Academy of Sciences, 2006Co-Authors: Maurizio Pacifici, Motomi Enomotoiwamoto, Eiki Koyama, Yoshihiro Shibukawa, Changshan Wu, Yoshihiro Tamamura, Masahiro IwamotoAbstract:Synovial Joints and articular cartilage play crucial roles in the skeletal function, but relatively little is actually known about their embryonic development. Here we first focused on the interzone, a thin mesenchymal cell layer forming at future Joint sites that is widely thought to be critical for Joint and articular cartilage development. To determine interzone cell origin and fate, we microinjected the vital fluorescent dye DiI at several peri-Joint sites in chick limbs and monitored the behavior and fate of labeled cells over time. Peri-Joint mesenchymal cells located immediately adjacent to incipient Joints migrated, became part of the interzone, and were eventually found in epiphyseal articular layer and Joint capsule. Interzone cells isolated and reared in vitro expressed typical phenotypic markers, including GDF-5, Wnt-14, and CD-44, and differ- entiated into chondrocytes over time. To determine the molecular mech- anisms of articular chondrocyte formation, we carried out additional studies on the ets transcription factor family member ERG and its alter- natively spliced variant C-1-1 that we previously found to be expressed in developing avian articular chondrocytes. We cloned the human coun- terpart of avian C-1-1 (ERGp55Δ81) and conditionally expressed it in transgenic mice under cartilage-specific Col2 gene promotor-enhancer control. The entire transgenic mouse limb chondrocyte population exhib- ited an immature articular-like phenotype and a virtual lack of growth plate formation and chondrocyte maturation compared to wild-type lit- termate. Together, our studies reveal that peri-Joint mesenchymal cells take part in interzone and articular layer formation, interzone cells can differentiate into chondrocytes, and acquisition of a permanent articular chondrocyte phenotype is aided and perhaps dictated by ets transcription factor ERG.
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mechanisms of Synovial Joint and articular cartilage formation recent advances but many lingering mysteries
Birth Defects Research Part C-embryo Today-reviews, 2005Co-Authors: Maurizio Pacifici, Eiki Koyama, Masahiro IwamotoAbstract:Synovial Joints are elegant, critically important, and deceptively simple biomechanical structures. They are comprised of articular cartilage that covers each end of the opposing skeletal elements, Synovial fluid that lubricates and nourishes the tissues, ligaments that hold the skeletal elements in check, and a fibrous capsule that insulates the Joints from surrounding tissues. Joints also exhibit an exquisite arrays of shapes and sizes, best exemplified by the nearly spherical convex femoral head articulating into a nearly spherical concave hip acetabulum, or a phalangeal Joint with two condyles on the distal side articulating in reciprocally-shaped sockets on the opposing proximal side. Though few in number, Joint tissues are highly specialized in structure and function. This is illustrated by articular cartilage with its unique extracellular matrix, unique biomechanical resilience, its largely avascular nature, and its ability to persist through life with minimal turnover of its cells and components. The fact that interest in Synovial Joints has remained unabated for decades is a reflection of their fundamental importance for organism function and quality of life, and for their susceptibility to a variety of acquired and congenital conditions, most importantly arthritis. This has led to many advances in this field that encompass molecular genetics to biomechanics to medicine. Regrettably, what continues to be poorly understood are the mechanisms by which Synovial Joints actually form in the developing embryo. If available, this information would be not only of indisputable biological interest, but would also have significant biomedical ramifications, particularly in terms of designing novel tissue regeneration or reconstruction therapies. This review focuses on recent advances in understanding the mechanisms of Synovial Joint formation in the limbs, and places and discusses the information within the context of classic studies and the many mysteries and questions that remain unanswered. Birth Defects Research (Part C) 75:237–248, 2005. © 2005 Wiley-Liss, Inc.
Eiki Koyama - One of the best experts on this subject based on the ideXlab platform.
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mouse limb skeletal growth and Synovial Joint development are coordinately enhanced by kartogenin
Developmental Biology, 2014Co-Authors: Rebekah S Decker, Motomi Enomotoiwamoto, Eiki Koyama, Peter Maye, David W Rowe, Peter G Schultz, Maurizio PacificiAbstract:Abstract Limb development requires the coordinated growth of several tissues and structures including long bones, Joints and tendons, but the underlying mechanisms are not wholly clear. Recently, we identified a small drug-like molecule – we named Kartogenin (KGN) – that greatly stimulates chondrogenesis in marrow-derived mesenchymal stem cells (MSCs) and enhances cartilage repair in mouse osteoarthritis (OA) models. To determine whether limb developmental processes are regulated by KGN, we tested its activity on committed preskeletal mesenchymal cells from mouse embryo limb buds and whole limb explants. KGN did stimulate cartilage nodule formation and more strikingly, boosted digit cartilaginous anlaga elongation, Synovial Joint formation and interzone compaction, tendon maturation as monitored by ScxGFP , and interdigit invagination. To identify mechanisms, we carried out gene expression analyses and found that several genes, including those encoding key signaling proteins, were up-regulated by KGN. Amongst highly up-regulated genes were those encoding hedgehog and TGFβ superfamily members, particularly TFGβ1. The former response was verified by increases in Gli1-LacZ activity and Gli1 mRNA expression. Exogenous TGFβ1 stimulated cartilage nodule formation to levels similar to KGN, and KGN and TGFβ1 both greatly enhanced expression of lubricin / Prg4 in articular superficial zone cells. KGN also strongly increased the cellular levels of phospho-Smads that mediate canonical TGFβ and BMP signaling. Thus, limb development is potently and harmoniously stimulated by KGN. The growth effects of KGN appear to result from its ability to boost several key signaling pathways and in particular TGFβ signaling, working in addition to and/or in concert with the filamin A/CBFβ/RUNX1 pathway we identified previously to orchestrate overall limb development. KGN may thus represent a very powerful tool not only for OA therapy, but also limb regeneration and tissue repair strategies.
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Synovial Joint formation requires local ext1 expression and heparan sulfate production in developing mouse embryo limbs and spine
Developmental Biology, 2011Co-Authors: Christina Mundy, Tadashi Yasuda, Takashi Kinumatsu, Motomi Enomotoiwamoto, Masahiro Iwamoto, Eiki Koyama, Yu Yamaguchi, Maurizio PacificiAbstract:Heparan sulfate proteoglycans (HSPGs) regulate a number of major developmental processes, but their roles in Synovial Joint formation remain unknown. Here we created conditional mouse embryo mutants lacking Ext1 in developing Joints by mating Ext1f/f and Gdf5-Cre mice. Ext1 encodes a subunit of the Ext1/Ext2 Golgi-associated protein complex responsible for heparan sulfate (HS) synthesis. The proximal limb Joints did form in the Gdf5-Cre;Ext1f/f mutants, but contained an uneven articulating superficial zone that expressed very low lubricin levels. The underlying cartilaginous epiphysis was deranged as well and displayed random patterns of cell proliferation and matrillin-1 and collagen IIA expression, indicative of an aberrant phenotypic definition of the epiphysis itself. Digit Joints were even more affected, lacked a distinct mesenchymal interzone and were often fused likely as a result of local abnormal BMP and hedgehog activity and signaling. Interestingly, overall growth and lengthening of long bones were also delayed in the mutants. To test whether Ext1 function is needed for Joint formation at other sites, we examined the spine. Indeed, entire intervertebral discs, normally composed by nucleus pulposus surrounded by the annulus fibrosus, were often missing in Gdf5-Cre;Ext1f/f mice. When disc remnants were present, they displayed aberrant organization and defective Joint marker expression. Similar intervertebral Joint defects and fusions occurred in Col2-Cre;β-cateninf/f mutants. The study provides novel evidence that local Ext1 expression and HS production are needed to maintain the phenotype and function of Joint-forming cells and coordinate local signaling by BMP, hedgehog and Wnt/β-catenin pathways. The data indicate also that defects in Joint formation reverberate on, and delay, overall long bone growth.
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Hox11 genes establish Synovial Joint organization and phylogenetic characteristics in developing mouse zeugopod skeletal elements
Development, 2010Co-Authors: Eiki Koyama, Tadashi Yasuda, Nancy Minugh-purvis, Takashi Kinumatsu, Alisha R. Yallowitz, Deneen M. Wellik, Maurizio PacificiAbstract:Hox11 genes are essential for zeugopod skeletal element development but their roles in Synovial Joint formation remain largely unknown. Here, we show that the elbow and knee Joints of mouse embryos lacking all Hox11 paralogous genes are specifically remodeled and reorganized. The proximal ends of developing mutant ulna and radius elements became morphologically similar and formed an anatomically distinct elbow Joint. The mutant ulna lacked the olecranon that normally attaches to the triceps brachii muscle tendon and connects the humerus to the ulna. In its place, an ulnar patella-like element developed that expressed lubricin on its ventral side facing the Joint and was connected to the triceps muscle tendon. In mutant knees, both tibia and fibula fully articulated with an enlarged femoral epiphyseal end that accommodated both elements, and the neo-tripartite knee Joint was enclosed in a single Synovial cavity and displayed an additional anterior ligament. The mutant Joints also exhibited a different organization of the superficial zone of articular cartilage that normally exerts an anti-friction function. In conclusion, Hox11 genes co-regulate and coordinate the development of zeugopod skeletal elements and adjacent elbow and knee Joints, and dictate Joint identity, morphogenesis and anatomical and functional organization. Notably, the ulnar patella and tripartite knee Joints in the mouse mutants actually characterize several lower vertebrates, including certain reptiles and amphibians. The re-emergence of such anatomical structures suggests that their genetic blueprint is still present in the mouse genome but is normally modified to the needs of the mammalian Joint-formation program by distinct Hox11 function.
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Mechanisms of Synovial Joint formation
Clinical calcium, 2006Co-Authors: Eiki Koyama, Masahiro IwamotoAbstract:: Synovial Joints are comprised of relatively simple biomechanical structures including articular cartilage, Synovial membrane, Synovial fluid, ligaments and a fibrous capsule; they are fundamentally important for function and quality of life. Recent studies described the spatio-temporal expression patterns of signaling molecules and transcription factors in the developing Synovial Joints. Though few in number, the gain and/or loss of function-experiments demonstrated direct involvement of these molecules in Joint formation. This review focuses on recent advances in understanding the mechanisms of Synovial Joint formation in the limbs.
-
cellular and molecular mechanisms of Synovial Joint and articular cartilage formation
Annals of the New York Academy of Sciences, 2006Co-Authors: Maurizio Pacifici, Motomi Enomotoiwamoto, Eiki Koyama, Yoshihiro Shibukawa, Changshan Wu, Yoshihiro Tamamura, Masahiro IwamotoAbstract:Synovial Joints and articular cartilage play crucial roles in the skeletal function, but relatively little is actually known about their embryonic development. Here we first focused on the interzone, a thin mesenchymal cell layer forming at future Joint sites that is widely thought to be critical for Joint and articular cartilage development. To determine interzone cell origin and fate, we microinjected the vital fluorescent dye DiI at several peri-Joint sites in chick limbs and monitored the behavior and fate of labeled cells over time. Peri-Joint mesenchymal cells located immediately adjacent to incipient Joints migrated, became part of the interzone, and were eventually found in epiphyseal articular layer and Joint capsule. Interzone cells isolated and reared in vitro expressed typical phenotypic markers, including GDF-5, Wnt-14, and CD-44, and differ- entiated into chondrocytes over time. To determine the molecular mech- anisms of articular chondrocyte formation, we carried out additional studies on the ets transcription factor family member ERG and its alter- natively spliced variant C-1-1 that we previously found to be expressed in developing avian articular chondrocytes. We cloned the human coun- terpart of avian C-1-1 (ERGp55Δ81) and conditionally expressed it in transgenic mice under cartilage-specific Col2 gene promotor-enhancer control. The entire transgenic mouse limb chondrocyte population exhib- ited an immature articular-like phenotype and a virtual lack of growth plate formation and chondrocyte maturation compared to wild-type lit- termate. Together, our studies reveal that peri-Joint mesenchymal cells take part in interzone and articular layer formation, interzone cells can differentiate into chondrocytes, and acquisition of a permanent articular chondrocyte phenotype is aided and perhaps dictated by ets transcription factor ERG.
M Hlavacek - One of the best experts on this subject based on the ideXlab platform.
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the influence of the acetabular labrum seal intact articular superficial zone and Synovial fluid thixotropy on squeeze film lubrication of a spherical Synovial Joint
Journal of Biomechanics, 2002Co-Authors: M HlavacekAbstract:Abstract A model of Synovial fluid (SF) filtration by articular cartilage (AC) in a step-loaded spherical Synovial Joint at rest is presented. The effects of Joint pathology (such as a depleted acetabular labrum, a depleted cartilage superficial zone consistent with early osteoarthritis and an inflammatory SF) on the squeezed Synovial film are also investigated. Biphasic mixture models for AC (ideal fluid and elastic porous transversely isotropic two-layer matrix) and for SF (ideal and thixotropic fluids) are applied and the following results are obtained. If the acetabular labrum is able to seal the pressurised SF between the articular surfaces (as in the normal hip Joint), the fluid in the Synovial film and in the cartilage within the labral ring is homogeneously pressurised. The articular surfaces remain separated by a fluid film for minutes. If the labrum is destroyed or absent and the SF can escape across the contact edge, the fluid pressure is non-homogeneous and with a small jump at the articular surface at the very moment of load application. The ensuing Synovial film filtration by porous cartilage is lower for the normal cartilage (with the intact superficial zone) than if this zone is already depleted or rubbed off as in the early stage of primary osteoarthritis. Compared with the inflammatory (Newtonian) SF, the normal (thixotropic) fluid applies favourably in the squeezed film near the contact centre only, yielding a thicker SF film there, but not affecting the minimum thickness in the fluid film profile at a fixed time. For all that, in the unsealed case for both the normal and pathological Joint, the macromolecular concentration of the hyaluronic acid–protein complex in the Synovial film quickly increases due to the filtration in the greater part of the contact. A stable Synovial gel film, thick on the order of 10 −7 m, protecting the articular surfaces from the intimate contact, is formed within a couple of seconds. Boundary lubrication by the Synovial gel is established if sliding motion follows until a fresh SF is entrained into the contact. This theoretical prediction is open for experimental verifications.
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lubrication of a cylindrical Synovial Joint considering rolling motion and elastic incompressible cartilage
Wear, 1993Co-Authors: M Hlavacek, D VokounAbstract:Abstract In the analysis of lubrication of rolling cylinders with low modulus coatings, attention is drawn to elastic incompressible layers. The constrained column model (a simplified model where layer compression is assumed proportional to fluid pressure) fails for the Poisson ratio v of the layers close to 0.5. An approximate lubrication model is proposed for v =0.5 and highly deformed coatings, i.e. for the low ratio of elastic layer thickness to fluid film length. This model does not result in a rigid differential equation for high loading as is the case with the constrained column model. The model is applied to the rolling motion of the human ankle Joint.
