Role of Collagen Type II and Perlecan in Skeletal Development

Gustafsson, Erika; Aszódi, Attila; Ortéga, Nathalie; Hunziker, Ernst B.; Denker, Hans‐Werner; Werb, Zena; Fässler, Reinhard

doi:10.1111/j.1749-6632.2003.tb03217.x

Cited by 55 publications

(51 citation statements)

References 17 publications

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“…Bar 100 m alterations of the growth plates were more severe in the perlecan-deWcient mice than in the agrin-deWcient mice. Based on the similarities in the skeletal defects of perlecan-and Col2a1-deWcient mice (Aszodi et al 1998), a role for perlecan in the protection of the ECM of cartilage had been proposed, though an increased activity of gelatinases (MMP-2 and MMP-9) could not be demonstrated (Gustafsson et al 2003). Importantly, our Tg/agrn ¡/¡ mice also exhibit a slightly reduced collagen type II density that is secondary to agrin loss.…”

Section: Discussionmentioning

confidence: 85%

Agrin is highly expressed by chondrocytes and is required for normal growth

Hausser

Rüegg

Brenner

et al. 2006

Histochem Cell Biol

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Agrin is a heparan sulfate proteoglycan that is best known for its crucial involvement in the organization and maintenance of postsynaptic structures at the neuromuscular junction. Consistent with this role, mice deficient of agrin die at birth due to respiratory failure. Here we examined the early postnatal development of agrin-deficient mice in which perinatal death was prevented by transgenic expression of neural agrin in motor neurons. Such transgenic, agrin-deficient mice were born at Mendelian ratio but exhibited severe postnatal growth retardation. Growth plate morpholgy was markedly altered in these mice, with changes being most prominent in the hypertrophic zone. Compression of this zone was not caused by reduced viability of hypertrophic chondrocytes, as no differences in the apoptosis rates could be observed. Furthermore, deposition of the major cartilage matrix components collagen type II and aggrecan was slightly reduced in these mice. Consistent with a role for agrin in skeletal development, we show for the first time that agrin is highly expressed by chondrocytes and localizes to the growth plate in wild-type mice. Our data show that agrin is expressed in cartilage and that it plays a critical role in normal skeletal growth.

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Section: Discussionmentioning

confidence: 85%

Agrin is highly expressed by chondrocytes and is required for normal growth

Hausser

Rüegg

Brenner

et al. 2006

Histochem Cell Biol

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“…Active MMP9 is concentrated at sites of cartilage resorption, proximal to the chondro-osseous junction, where vascular invasion occurs [7,33,34]. Analysis of MMP9 −/− mice has pointed to a requirement for this protease during endochondral ossification, when it appears to coordinate ECM degradation, hypertrophic chondrocyte apoptosis, angiogenesis and osteoblastic differentiation [6].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Matrix remodeling during endochondral ossification

Ortéga

Behonick

Werb

2004

Trends in Cell Biology

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Endochondral ossification, the process by which most of the skeleton is formed, is a powerful system for studying various aspects of the biological response to degraded extracellular matrix (ECM). In addition, the dependence of endochondral ossification upon neovascularization and continuous ECM remodeling provides a good model for studying the role of the matrix metalloproteases (MMPs) not only as simple effectors of ECM degradation but also as regulators of active signal-inducers for the initiation of endochondral ossification. The daunting task of elucidating their specific role during endochondral ossification has been facilitated by the development of mice deficient for various members of this family. Here, we discuss the ECM and its remodeling as one level of molecular regulation for the process of endochondral ossification, with special attention to the MMPs.In the past decade, multiple discoveries have facilitated our understanding of skeletal development. Transcription factors and/or growth factors that are involved in the genetic and molecular control of OSTEOGENESIS (see glossary box), CHONDROGENESIS and joint formation have been identified and their pathways partially elucidated [1]. The attention now turns to a different level of molecular regulation -that provided by the extracellular matrix (ECM) of the developing bone and the proteases that remodel it. Recent studies attest to the importance of unique composition of distinct ECMs within the developing skeleton, as well as their influence on cell differentiation and function [2][3][4].Bone develops in two different ways. Mesenchymal cells can directly differentiate into bone by the process of INTRAMEMBRANOUS OSSIFICATION, which is responsible for the formation of most of the craniofacial skeleton. Alternatively, these cells can differentiate into cartilage, which then provides a template for bone morphogenesis by the process of ENDOCHONDRAL OSSIFICATION; this process is responsible for the formation of most of the vertebrate appendicular and axial skeleton ( Figure 1a). Endochondral ossification occurs at two distinct sites in the vertebrate long bone -the primary (diaphyseal) and the secondary (epiphyseal) sites of ossification. Bone development initiates at the primary site. The secondary (epiphyseal) site is under independent control and is ossified later (Figure 1b). During this process, a new structure, the GROWTH PLATE, is formed between the DIAPHYSIS and the EPIPHYSIS by the segregation of CHONDROCYTES at different stages of differentiation. Under the control of signaling through Indian hedgehog (Ihh), bone morphogenetic proteins (BMPs) and fibroblast growth factor 18, a region of resting chondrocytes feeds into a zone of proliferating chondrocytes that then undergo hypertrophy and subsequently apoptosis. The ECM produced by and surrounding the terminally differentiated hypertrophic chondrocytes is calcified, partially degraded by the hypertrophic chondrocytes themselves [5], as well as by CHONDROCLASTS and/or preosteoclasts, and be...

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“…Among them, hypoxia induced factor 1-a (HIF1-a) and one of its targets, vascular endothelial growth factor (VEGF), are crucial in controlling chondrocyte survival, proliferation, angiogenesis and bone formation (Gerber et al, 1999;Schipani et al, 2001;Zelzer et al, 2004). Some ECM molecules are also essential: Col2a1 null mice lack endochondral ossification (Li et al, 1995) and perlecan null mice display chondrodysplasia (Arikawa-Hirasawa et al, 1999;Gustafsson et al, 2003). Several …”

Section: Introductionmentioning

confidence: 99%

Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation

Ortéga

Wang

Ferrara

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARY Long bone development depends on endochondral bone formation, a complex process requiring exquisite balance between hypertrophic cartilage (HC) formation and its ossification. Dysregulation of this process may result in skeletal dysplasias and heterotopic ossification. Endochondral ossification requires the precise orchestration of HC vascularization, extracellular matrix remodeling, and the recruitment of osteoclasts and osteoblasts. Matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and osteoclasts have all been shown to regulate endochondral ossification, but how their function interrelates is not known. We have investigated the functional relationship among these regulators of endochondral ossification, demonstrating that they have complementary but non-overlapping functions. MMP-9, VEGF and osteoclast deficiency all cause impaired growth plate ossification resulting in the accumulation of HC. VEGF mRNA and protein expression are increased at the MMP-9−/− growth plate, and VEGF activity contributes to endochondral ossification since sequestration of VEGF by soluble receptors results in further inhibition of growth plate vascularization and ossification. However, VEGF bioavailability is still limited in MMP-9 deficiency, as exogenous VEGF is able to rescue the MMP-9−/− phenotype, demonstrating that MMP-9 may partially, but not fully, regulate VEGF bioavailability. The organization of the HC extracellular matrix at the MMP-9−/− growth plate is altered, supporting a role for MMP-9 in HC remodeling. Inhibition of VEGF impairs osteoclast recruitment, whereas MMP-9 deficiency leads to an accumulation of osteoclasts at the chondro-osseous junction. Growth plate ossification in osteoclast-deficient mice is impaired in the presence of normal MMP-9 expression, indicating that other osteoclastic functions are also necessary. Our data delineate the complementary interplay between MMP-9, VEGF and osteoclast function that is necessary for normal endochondral bone formation and provide a molecular framework for investigating the molecular defects contributing to disorders of endochondral bone formation.

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Role of Collagen Type II and Perlecan in Skeletal Development

Cited by 55 publications

References 17 publications

Agrin is highly expressed by chondrocytes and is required for normal growth

Agrin is highly expressed by chondrocytes and is required for normal growth

Matrix remodeling during endochondral ossification

Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation

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