Collagenase-3 (MMP-13) and Integral Membrane Protein 2a (<i>Itm2a</i>) are Marker Genes of Chondrogenic/Osteoblastic Cells in Bone Formation: Sequential Temporal, and Spatial Expression of <i>Itm2a</i>, Alkaline Phosphatase, MMP-13, and Osteocalcin in the Mouse

Tuckermann, Jan; Pittois, Karen; Partridge, Nicola C.; Merregaert, J.; Angel, Peter

doi:10.1359/jbmr.2000.15.7.1257

Cited by 122 publications

(106 citation statements)

References 37 publications

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“…In these cells, the major collagenase expressed at the primary and secondary sites of ossification is MMP13. Detectable as early as 14.5 days of embryonic development in mice, MMP13 is highly expressed in the lower zone of hypertrophic cartilage, where its expression colocalizes with that of type X collagen [24]. At the chondroosseous junction, MMP13 is expressed by the newly recruited osteoblasts adjacent to tartrateresistant acid phosphatase (TRAP)-positive cells [25].…”

Section: Endochondral Ossification and Mmp Expressionmentioning

confidence: 99%

Matrix remodeling during endochondral ossification

Ortéga

Behonick

Werb

2004

Trends in Cell Biology

379

312

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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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Section: Endochondral Ossification and Mmp Expressionmentioning

confidence: 99%

Matrix remodeling during endochondral ossification

Ortéga

Behonick

Werb

2004

Trends in Cell Biology

379

312

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“…Chondrocytes then withdraw from the cell cycle and begin to increase their cell volume until reaching the fully differentiated state of hypertrophic chondrocytes. Transition from a proliferating to a hypertrophic phenotype involves numerous changes in gene expression, for example the induction of the collagen X (4, 5), matrix metalloproteinase 13 (6,7), and bone sialoprotein (BSP) 1 (8 -10) genes. The latter two genes are also expressed by osteoblasts, suggesting similar biological properties of hypertrophic chondrocytes and osteoblasts.…”

mentioning

confidence: 99%

RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation

Wang

Woods

Sabari

et al. 2004

Journal of Biological Chemistry

118

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Coordinated proliferation and differentiation of growth plate chondrocytes is required for normal growth and development of the endochondral skeleton, but little is known about the intracellular signal transduction pathways regulating these processes. We have investigated the roles of the GTPase RhoA and its effector kinases ROCK1/2 in hypertrophic chondrocyte differentiation. RhoA, ROCK1, and ROCK2 are expressed throughout chondrogenic differentiation. RhoA overexpression in chondrogenic ATDC5 cells results in increased proliferation and a marked delay of hypertrophic differentiation, as shown by decreased induction of alkaline phosphatase activity, mineralization, and expression of the hypertrophic markers collagen X, bone sialoprotein, and matrix metalloproteinase 13. These effects are accompanied by activation of cyclin D1 transcription and repression of the collagen X promoter by RhoA. In contrast, inhibition of Rho/ROCK signaling by the pharmacological inhibitor Y27632 inhibits chondrocyte proliferation and accelerates hypertrophic differentiation. Dominant-negative RhoA also inhibits induction of the cyclin D1 promoter by parathyroid hormone-related peptide. Finally, Y27632 treatment partially rescues the effects of RhoA overexpression. In summary, we identify the RhoA/ROCK signaling pathway as a novel and important regulator of chondrocyte proliferation and differentiation.The development and growth of endochondral bones (such as ribs, vertebrae, and the long bones of vertebrate limbs) are regulated through the highly controlled rates of proliferation and hypertrophic differentiation of growth plate chondrocytes (1-3). In the growth plate, chondrocytes first undergo a series of cell divisions along the longitudinal axis of the growing bone, thereby forming characteristic columns of clonal cells. Chondrocytes then withdraw from the cell cycle and begin to increase their cell volume until reaching the fully differentiated state of hypertrophic chondrocytes. Transition from a proliferating to a hypertrophic phenotype involves numerous changes in gene expression, for example the induction of the collagen X (4, 5), matrix metalloproteinase 13 (6, 7), and bone sialoprotein (BSP) 1 (8 -10) genes. The latter two genes are also expressed by osteoblasts, suggesting similar biological properties of hypertrophic chondrocytes and osteoblasts. The fate of hypertrophic chondrocytes is still debated, but it appears that the majority of these cells undergo apoptosis and are replaced by bone tissue (11). Longitudinal growth of endochondral bones therefore requires both proliferation and differentiation-associated hypertrophy of growth plate chondrocytes.Disruption of chondrocyte proliferation and/or differentiation by gene mutations commonly results in chondrodysplasias that are characterized by skeletal deformities and reduced growth (12)(13)(14). Mutations in genes encoding extracellular matrix molecules, growth factors, receptors, and transcription factors have been identified as causes of several chondrodysplasias. Fo...

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“…Earlier reports (Tuckermann et al, 2000) indicated that expression of Itm2a is upregulated across a zone of long bone growth plates that contains resting and proliferative chondrocytes. The expression of the gene did not overlap with other markers of endochondral ossification (MMP-13, alkaline phosphatase and osteocalcin).…”

Section: Discussionmentioning

confidence: 97%

“…Based on our previous studies that identified Itm2a as a novel marker for chondrogenic differentiation (Tuckermann et al, 2000), the present study investigated the expression of Itm2a in different cell lineages committed to chondrogenesis and a possible role of Itm2a in endochondral ossification.…”

Section: Discussionmentioning

confidence: 99%

“…In situ hybridisation on embryos and on bones of newborn mice showed that the expression of Itm2a preceded that of established marker genes for endochondral bone formation, such as alkaline phosphatase, collagenase-3 (MMP-13) and osteocalcin. Itm2a was therefore proposed as a new marker for resting and proliferating chondrocytes (Tuckermann et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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In vitro studies on Itm2a reveal its involvement in early stages of the chondrogenic differentiation pathway

plas

Merregaert

2004

Biology of the Cell

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The Integral membrane protein 2A (Itm2A) is a transmembrane protein belonging to a family composed of at least two other members, Itm2B and Itm2C, all of them having a different expression pattern. The Itm2a gene serves as a marker for early stages in endochondral ossification. In order to understand the role of Itm2A in this process, expression of the gene was investigated in different cell systems. In C3H10T1/2 cells, the gene was upregulated early on when the cells were induced to the chondrogenic lineage but less to the osteogenic lineage. In MCT cells, expression was upregulated at permissive temperatures but not at non-permissive temperatures. When induced with insulin, ATDC5 cells expressed Itm2a in early stages but not at late stages. Furthermore, PTH treatment seems to upregulate Itm2a transcription.In order to understand the role of Itm2a in the chondrogenic differentiation process in more detail, we constitutively overexpressed exogenous Itm2A in mouse ATDC5 cells. Two clones expressing high levels of Itm2a were isolated and characterized. Gene expression analysis of the overexpresser clones demonstrated that expression of collagen type X was delayed. These results demonstrate that overexpression of Itm2a in mouse ATDC5 cells impede the transition to hypertrophic cells. Taken together, our observation supports the involvement of Itm2a in the early stages of chondrogenesis in vitro.

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Collagenase-3 (MMP-13) and Integral Membrane Protein 2a (Itm2a) are Marker Genes of Chondrogenic/Osteoblastic Cells in Bone Formation: Sequential Temporal, and Spatial Expression of Itm2a, Alkaline Phosphatase, MMP-13, and Osteocalcin in the Mouse

Cited by 122 publications

References 37 publications

Matrix remodeling during endochondral ossification

Matrix remodeling during endochondral ossification

RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation

In vitro studies on Itm2a reveal its involvement in early stages of the chondrogenic differentiation pathway

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