COL9A3: A Third Locus for Multiple Epiphyseal Dysplasia

Paassilta, Petteri; Lohiniva, Jaana; Annunen, Susanna; Bonaventure, Jacky; Merrer, Martine Le; Pai, Lori; Ala‐Kokko, Leena

doi:10.1086/302328

Cited by 131 publications

(93 citation statements)

References 38 publications

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“…This conclusion is further supported by the similar phenotype of transgenic mice expressing truncated α1(IX) chains (Nakata et al, 1993). In addition, human patients with mutations either in COL9A2 or COL9A3 genes develop early-onset osteoarthritis which predominantly affects the knee joints (Muragaki et al, 1996;Holden et al, 1999;Paassilta et al, 1999). More recently, a mutation in the COL9A1 gene, that converts a codon for glutamine to tryptophan, has been found in patients with intervertebral disc disease characterized by sciatica and herniation .…”

Section: Mild or Lack Of Phenotype After Ablation Of Cartilage Mmentioning

confidence: 91%

Mammalian Skeletogenesis and Extracellular Matrix. What can We Learn from Knockout Mice?

Aszódi

Bateman

Gustafsson

et al. 2000

Cell Struct. Funct.

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ABSTRACT. Formation of the vertebrate skeleton and the proper functions of bony and cartilaginous elements are determined by extracellular, cell surface and intracellular molecules. Genetic and biochemical analyses of human heritable skeletal disorders as well as the generation of knockout mice provide useful tools to identify the key players of mammalian skeletogenesis. This review summarises our recent work with transgenic animals carrying ablated genes for cartilage extracellular matrix proteins. Some of these mice exhibit a lethal phenotype associated with severe skeletal defects (type II collagen-null, perlecan-null), whereas others show mild (type IX collagen-null) or no skeletal abnormalities (matrilin-1-null, fibromodulin-null, tenascin-C-null). The appropriate human genetic disorders are discussed and contrasted with the knockout mice phenotypes.Key words: skeletogenesis/extracellular matrix/skeletal disorders/knockout mice Development of the mammalian skeleton is a temporally and spatially coordinated process, which is initiated by the condensation and differentiation of mesenchymal progenitor cells. Progenitors from the neural crest generate the craniofacial skeleton, sklerotomal cells form most elements of the axial skeleton, and the lateral plate mesoderm gives rise to the appendicular skeleton. Bone can develop via two basic mechanisms: mesenchymal precursor cells either differentiate directly into bone matrix-producing osteoblasts (intramembranous ossification) or first form a cartilaginous intermediate which is subsequently replaced by bone (endochondral ossification). The first mechanism is responsible for the formation of the flat bones of the skull, much of the facial skeleton, a part of the clavicle, and the cortical bone shaft of the long bones. The second mechanism occurs during the development of other bones such as long bones of the legs, vertebrae and ribs.Skeletal morphogenesis is characterized by the expression of a special set of extracellular matrix proteins and is tightly regulated via transcription factors, signaling molecules, hormones and local growth factors (Erlebacher et al., 1995). Our knowledge of how these molecules and factors act on skeletogenesis continuously increases, which not only helps to understand the normal development of skeletal elements but also contributes to a better understanding of skeletal diseases. During the last two decades human genetics has successfully identified gene mutations for many hereditary skeletal disorders resulting in osteochondrodysplasias or altered bone homeostasis (reviewed by Olsen, 1997a, 1997b). Furthermore, the conventional and conditional gene targeting experiments in mice have opened a new window which allow us to clarify the role of a particular gene product in skeletal development. The establishment of transgenic mouse strains with defined genetic alterations can also provide animal models for human skeletal disorders and might help to develop therapeutic tools for the treatment of various diseases affecting the skeleton.In ...

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Section: Mild or Lack Of Phenotype After Ablation Of Cartilage Mmentioning

confidence: 91%

Mammalian Skeletogenesis and Extracellular Matrix. What can We Learn from Knockout Mice?

Aszódi

Bateman

Gustafsson

et al. 2000

Cell Struct. Funct.

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“…Abnormalities in the structure of human type II (17), type IX (18), or type XI (19) collagens (which together constitute the collagen fibril) can each lead to the early development of a familial osteoarthritis. Thus loss of structural integrity of collagen fibrils due to a molecular abnormality can lead to the development of OA.…”

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confidence: 99%

Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice

Neuhold

Killar²,

Zhao³

et al. 2001

J. Clin. Invest.

503

347

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IntroductionDegenerative joint diseases including osteoarthritis (OA) are common, particularly in the elderly. Early signs of OA include progressive loss from articular cartilage of the proteoglycan aggrecan, reflected by a loss of safranin O staining, excessive damage to type II collagen, and general degeneration and fibrillation of the cartilage surface, resulting ultimately in a loss of articular cartilage (1).One of the primary targets of this disease is type II collagen, the major structural collagen found in articular cartilage in healthy individuals. There is ordinarily a strict balance between the production of type II collagen and degradation of this protein by catabolic enzymes during normal remodeling of cartilage (1). Pathological conditions such as OA are characterized by a loss of this balance with increased proteolysis (1-5) and upregulation of the synthesis of type II procollagen (5) and aggrecan (6).Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent enzymes that degrade extracellular matrix components. MMPs are synthesized in articulating joints by synovial cells and chondrocytes. In mature articular cartilage, chondrocytes maintain the cartilage-specific matrix phenotype. Elevated expression of MMPs is associated with cartilage degradation (1). MMP-13, also known as human collagenase-3, is thought to play an important role in type II collagen degradation in articular cartilage and especially in OA (4, 7-9). Type II collagen is the preferred substrate for MMP-13 (4, 7, 10). Expression and contents of MMP-1 (collagenase-1) and 11,12), expression of MMP-8 (collagenase-2), and collagenase activity (4,8) are upregulated in human OA cartilage.Spontaneous development of focal sites degeneration has been described in aging guinea pigs (13). Sublines of the inbred STR/ORT strain of mice also develop spontaneous OA with aging (14). Mice exhibit upregulated expression of MMP-13 and collagenase activity is upregulated in focal lesions (15). In guinea pigs, MMP-1 and MMP-13 are also upregulated in OA lesions associated with increased collagenase activity (16). It has been suggested that increased collagenase-3 (MMP-13) activity plays a pivotal role in the pathogenesis of osteoarthritis (OA). We have used tetracycline-regulated transcription in conjunction with a cartilage-specific promoter to target a constitutively active human MMP-13 to the hyaline cartilages and joints of transgenic mice. Postnatal expression of this transgene resulted in pathological changes in articular cartilage of the mouse joints similar to those observed in human OA. These included characteristic erosion of the articular cartilage associated with loss of proteoglycan and excessive cleavage of type II collagen by collagenase, as well as synovial hyperplasia. These results demonstrate that excessive MMP-13 activity can result in articular cartilage degradation and joint pathology of the kind observed in OA, suggesting that excessive activity of this proteinase can lead to this disease.

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“…Collagen IX is essential for the normal structure and function of cartilage. Its mutations in man cause multiple epiphyseal dysplasia (7)(8)(9)(10)(11)(12)(13) and in mouse cause degenerative changes in articular cartilage (14,15).…”

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confidence: 99%

The Fibril-associated Collagen IX Provides a Novel Mechanism for Cell Adhesion to Cartilaginous Matrix

Käpylä

Jäälinoja

Tulla

et al. 2004

Journal of Biological Chemistry

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Collagen IX is the prototype fibril-associated collagen with interruptions in triple helix. In human cartilage it covers collagen fibrils, but its putative cellular receptors have been unknown. The reverse transcription-PCR analysis of human fetal tissues suggested that based on their distribution all four collagen receptor integrins, namely ␣ 1 ␤ 1 , ␣ 2 ␤ 1 , ␣ 10 ␤ 1 , and ␣ 11 ␤ 1 , are possible receptors for collagen IX. Furthermore primary chondrocytes and chondrosarcoma cells express the four integrins simultaneously. Chondrosarcoma cells, as well as Chinese hamster ovary cells transfected to express ␣ 1 ␤ 1 , ␣ 2 ␤ 1 , or ␣ 10 ␤ 1 integrin as their only collagen receptor, showed fast attachment and spreading on human recombinant collagen IX indicating that it is an effective cell adhesion protein. To further study the recognition of collagen IX we produced recombinant ␣I domains in Escherichia coli. For each of the four ␣I domains, collagen IX was among the best collagenous ligands, making collagen IX exceptional compared with all other collagen subtypes tested so far. Rotary shadowing electron microscopy images of both ␣ 1 I-and ␣ 2 Icollagen IX complexes unveiled only one binding site located in the COL3 domain close to the kink between it and the COL2 domain. The recognition of collagen IX by ␣ 2 I was considered to represent a novel mechanism for two reasons. First, collagen IX has no GFOGER motif, and the identified binding region lacks any similar sequences. Second, the ␣ 2 I domain mutations D219R and H258V, which both decreased binding to collagen I and GFOGER, had very different effects on its binding to collagen IX. D219R had no effect, and H258V prevented type IX binding. Thus, our results indicate that collagen IX has unique cell adhesion properties when compared with other collagens, and it provides a novel mechanism for cell adhesion to cartilaginous matrix.Collagen IX was the first member to be discovered of a subgroup of collagens, now known as the fibril-associated collagens with interrupted triple helix (FACITs) 1 (1). At the present, FACITs also include collagens XII, XIV, XVI, XIX, XX, XXI, and XXII. Collagen IX is composed of three different ␣ chains, termed ␣1(IX), ␣2(IX), and ␣3(IX). Structurally the collagen IX molecule can be divided into three triple helical domains (COL1, COL2, and COL3) separated and flanked by non-triple helical (NC) domains. Collagen IX is expressed in cartilage and in a limited number of other locations, including developing eye. Collagen IX can be covalently cross-linked to collagen II, and typically it covers the large fibrils formed by collagens II and XI (2-5). There is a kink between COL2 and COL3 domains making the COL3 domain project into the perifibrillar space, whereas the COL1 and COL2 domains are arranged on the surface of the fibril. Many but not all collagen IX molecules are proteoglycans because a glycosaminoglycan (GAG) chain may be attached to NC3 domain via a serine residue in the ␣2(IX) chain (6). Collagen IX is essential for the normal st...

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COL9A3: A Third Locus for Multiple Epiphyseal Dysplasia

Cited by 131 publications

References 38 publications

Mammalian Skeletogenesis and Extracellular Matrix. What can We Learn from Knockout Mice?

Mammalian Skeletogenesis and Extracellular Matrix. What can We Learn from Knockout Mice?

Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice

The Fibril-associated Collagen IX Provides a Novel Mechanism for Cell Adhesion to Cartilaginous Matrix

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