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Murphy, Gillian; Knäuper, Vera; Atkinson, Susan J.; Butler, G; English, William R.; Hutton, Mike; Stracke, Jan Olaf; Clark, Ian M.

doi:10.1186/ar572

Cited by 267 publications

(104 citation statements)

References 61 publications

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“…2 E and 3). Discussion MMP13 (collagenase-3), a highly expressed collagenolytic MMP in developing bone and cartilage, has been assigned a role in the joint tissue destruction that is a major feature of various forms of human arthritis (3,35,36). We demonstrate here that a targeted null mutation in mouse Mmp13 resulted in a profound embryonic and adult skeletal phenotype characterized by abnormal growth plates and delayed ossification.…”

Section: Persistent Abnormal Skeletal Phenotype In Adult Mmp13mentioning

confidence: 81%

“…The MMPs are members of a large family of proteinases that have several structural features in common including the presence of a conserved zinc-binding catalytic domain (1)(2)(3)(4). Only the products of specific MMP genes, MMP1, -2, -8, -13, and -14, however, have the capacity to cleave native, undenatured, interstitial collagens at a specific helical locus (9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

“…collagen ͉ extracellular matrix ͉ vascularization C ollagenases, a group of matrix metalloproteinases (MMPs) that act at neutral pH (1)(2)(3)(4), have been postulated to have a role in skeletal development and bone remodeling (5)(6)(7)(8). The MMPs are members of a large family of proteinases that have several structural features in common including the presence of a conserved zinc-binding catalytic domain (1)(2)(3)(4).…”

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confidence: 99%

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Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification

Inada

Wang

Byrne

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

510

437

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Collagenase-3 (MMP13), a member of the matrix metalloproteinase (MMP) family of neutral endopeptidases, is expressed in the skeleton during embryonic development and is highly overexpressed in human carcinomas and in chondrocytes and synovial cells in rheumatoid arthritis and osteoarthritis. To determine the functional roles of Mmp13, we generated Mmp13-null mice that showed profound defects in growth plate cartilage with markedly increased hypertrophic domains as well as delay in endochondral ossification and formation and vascularization of primary ossification centers. Absence of Mmp13 resulted in significant interstitial collagen accumulation due, in part, to the lack of appropriate collagenase-mediated cleavage that normally occurs in growth plates and primary ossification centers. Cartilaginous growth plate abnormalities persisted in adult mice and phenocopied defects observed in human hereditary chondrodysplasias. Our findings demonstrate a unique role of Mmp13 in skeletal development.collagen ͉ extracellular matrix ͉ vascularization C ollagenases, a group of matrix metalloproteinases (MMPs) that act at neutral pH (1-4), have been postulated to have a role in skeletal development and bone remodeling (5-8). The MMPs are members of a large family of proteinases that have several structural features in common including the presence of a conserved zinc-binding catalytic domain (1-4). Only the products of specific MMP genes, MMP1, -2, -8, -13, and -14, however, have the capacity to cleave native, undenatured, interstitial collagens at a specific helical locus (9-13). Of the collagenases, MMP13 (collagenase-3) has been considered to have an important role in skeletal biology in view of its exclusive presence in the skeleton during embryonic development in cartilaginous growth plates and primary centers of ossification (5-8). MMP13 is also a downstream target of parathyroid hormone (PTH)-related protein (PTHrP) (14) and the transcription factor Osf2͞Cbfa1͞Runx2 in growth plate chondrocytes (15,16). In contrast to humans, where MMP1 may be strongly expressed, e.g., in inflammation, the orthologue of MMP1, McolA (12), is expressed in mice only at low levels.To examine possible functional roles of collagenases during skeletal development in vivo, we targeted a null mutation to the Mmp13 gene in mice. Our targeting strategy resulted in splicing out exon 5 that encodes the zinc-binding residues in the catalytic domain. As described here, deletion of functional Mmp13 had profound effects on skeletal development. In Mmp13 Ϫ/Ϫ embryos compared with WT embryos, the growth plates were strikingly lengthened, a defect ascribable predominantly to a delay in terminal events in the growth plates, with failure to resorb collagens, as well as a delay in ossification at the primary centers. Materials and MethodsGeneration of Mmp13 ؊/؊ Mice. We isolated two Mmp13 genomic clones from a 129͞J1 library to construct the knockout vector.The first was a BamHI͞SalI fragment that spanned from Ϸ3.4 kb of promoter sequence through the first...

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Section: Persistent Abnormal Skeletal Phenotype In Adult Mmp13mentioning

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification

Inada

Wang

Byrne

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

510

437

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“…[10][11][12][13] MMPs are released as inactive proenzyme forms and are then activated by limited proteolysis of the propeptide domain by plasmin, kallikrein, or trypsin.…”

Section: )mentioning

confidence: 99%

“…9) MMPs can be classified into four subgroups: collagenases (MMP-1, -8, -13), stromyelins (MMP-3, -10, -11), gelatinases (MMP-2, -9), and membrane-type MMPs. 10) MMPs are synthesized in response to cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-a, which is thought to be involved in the pathogenesis of arthritis. [10][11][12][13] MMPs are released as inactive proenzyme forms and are then activated by limited proteolysis of the propeptide domain by plasmin, kallikrein, or trypsin.…”

mentioning

confidence: 99%

Effect of Betula platyphylla var. japonica on Proteoglycan Release, Type II Collagen Degradation, and Matrix Metalloproteinase Expression in Rabbit Articular Cartilage Explants

Cho¹,

Huh

Kim³

et al. 2006

Biological & Pharmaceutical Bulletin

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Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive loss of articular cartilage, subchondral bond remodeling, spur formation, synovial inflammation, and in particular, the degradation of proteoglycan and collagen. The integrity of these macromolecules is vital to cartilage and joint function. 1)Proteoglycan is a component of the articular cartilage extracellular matrix, providing it with many of its characteristic physicochemical properties.2) The carbohydrate component of aggrecan, which constitutes at least 90% of its molecular mass, consists of many long keratin sulfate, chondroitin sulfate, and glycosaminoglycan (GAG) chains covalently linked to a core protein.3) The contribution of these GAG polymers to cartilage function can be divided into two categories: firstly, maintenance of hydration, a property dependent on their polyanionicity, which engenders in cartilage the ability to withstand compression, and secondly, interactions with other macromolecules that depend on the specific distribution of the negative charges of GAG and its carbohydrate backbone conformation. 4,5) Thus, the importance of these proteoglycans is clear. However, neither their specific role nor the mechanisms regulating their synthesis are fully understood.Collagen is another component of articular cartilage, and it is present primarily as type II collagen.6) It plays a role in maintaining the integrity of the cartilage matrix and allows proteoglycan to be held in the matrix. 7) Healthy cartilage maintains a dynamic equilibrium between processes that produce and processes that degrade matrix components. It is thought that this equilibrium is disturbed in OA, and that matrix-component degradative processes dominate, leading to an increased loss of the matrix. According to in vitro studies, collagen is much less readily released than proteoglycan, but collagen degradation results in the irreversible loss of structural integrity.8) There is circumstantial in vitro and in vivo evidence indicating a significant role for matrix metalloproteinases (MMPs) in cartilage destruction in arthritis. 9)MMPs can be classified into four subgroups: collagenases (MMP-1, -8, -13), stromyelins (MMP-3, -10, -11), gelatinases (MMP-2, -9), and membrane-type MMPs.10) MMPs are synthesized in response to cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-a, which is thought to be involved in the pathogenesis of arthritis. [10][11][12][13] MMPs are released as inactive proenzyme forms and are then activated by limited proteolysis of the propeptide domain by plasmin, kallikrein, or trypsin.10,14) MMP-3 is capable of cleaving aggrecan core protein, as well as type II collagen (in the aminoterminal telopeptide) in vitro, but it is not clear if it is involved in the degradation of these proteins in cartilage. 15,16) MMP-13 is expressed by normal and osteoarthritic chondrocytes, and has been localized to both rheumatoid and osteoarthritic cartilage.17) MMP-13 is the most efficient collagenase against type II collagen, sug...

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Osteoarthritis

Gosset¹,

Sellam²,

Jacques³

et al. 2009

Wiley Encyclopedia of Chemical Biology

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Osteoarthritis (OA) is considered the most common skeletal disorder and is characterized by cartilage degradation and osteophyte formation in joints. Although it is the most common joint disease, OA is often difficult to define because it is heterogeneous in its presentation style, rate of progression, and manifestations. Recently, new insights into the molecular biological basis of chondrocyte differentiation and cartilage homeostasis have been reported. The pathology of osteoarthritis is now interpreted as the disruption of balance between anabolic and catabolic signals. This article focuses on the risk factors, cellular and molecular mechanisms involved in OA, tools to study OA such as animal models and biomarkers, as well as treatment. Findings with regard to the physiologic and pathologic mechanisms involved in OA have made it possible to target therapeutic approaches more accurately, which allows the development of new drugs to reduce or block the progression of the disease.

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Cited by 267 publications

References 61 publications

Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification

Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification

Effect of Betula platyphylla var. japonica on Proteoglycan Release, Type II Collagen Degradation, and Matrix Metalloproteinase Expression in Rabbit Articular Cartilage Explants

Osteoarthritis

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