MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMDMO)

Kennedy, Ann M.; Inada, Masaki; Krane, Stephen M.; Christie, Paul T.; Harding, Brian; López-Otı́n, Carlos; Sánchez, Luis Maria Bonnecarrère; Pannett, A. A. J.; Dearlove, A M; Hartley, Claire; Byrne, Michael H.; Reed, Anita; Nesbit, M. Andrew; Whyte, Michael P.; Thakker, Rajesh V.

doi:10.1172/jci22900

Cited by 103 publications

(78 citation statements)

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“…Therefore, our strategy for development of DMOADs was to focus on identification of highly selective allosteric MMP-13 inhibitors free of hydroxamic acid or other zinc-chelating functional groups that contribute to inhibition of multiple MMPs. The rationale for targeting MMP-13 came from 1) overwhelming data on a potential role of MMP-13 in the pathogenesis of OA (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), and 2) data from studies of MMP-13 knockout mice and humans with an MMP-13 mutation, suggesting lack of MSS liability (29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

152

127

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Objective. Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Methods. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.Results. A number of non-hydroxamic acidcontaining compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompeti-

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Section: Discussionmentioning

confidence: 99%

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

152

127

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“…MMP-13 is expressed by hypertrophic chondrocytes, and appears to be critical for the normal removal of cartilage extracellular matrix during endochondral ossification in mice and humans. 7,23,24 The results of studies in MMP-13-null mice 7,24 had led us to predict that, if anything, MMP-13 would be down-regulated in lesions. The fact that the opposite is the case indicates that the retention of cartilage in subchondral bone in OC probably does not occur as a result of loss of the capacity to degrade cartilage matrix components.…”

Section: Discussionmentioning

confidence: 99%

Altered gene expression in early osteochondrosis lesions

Mirams

Tatarczuch

Ahmed

et al. 2009

Journal Orthopaedic Research

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Osteochondrosis is a condition involving defective endochondral ossification and retention of cartilage in subchondral bone. The pathophysiology of this condition is poorly characterized, but it has been proposed that the fundamental defect is failure of chondrocyte hypertrophy. The aim of the current study was to characterize phenotypic changes in chondrocytes associated with the initiation of osteochondrosis. Early lesions were induced in an equine model of osteochondrosis by feeding foals a high energy diet for 8 or 15 weeks. Lesions in articular-epiphyseal growth cartilage were examined histologically and by quantitative PCR analysis of expression of a number of genes representative of pathways that regulate chondrocyte behavior during endochondral ossification. There were more cells present in clusters in the lesions compared to normal articular cartilage. Expression of matrix metalloproteinase-13, type I collagen, type X collagen, and Runx2 mRNA was significantly greater in the lesions compared to normal cartilage from the same joint. Expression of vascular endothelial growth factor, type II collagen, connective tissue growth factor, aggrecan, Sox9, and fibroblast growth factor receptor 3 mRNA was not significantly different in lesions than in control cartilage. These observations suggest that osteochondrosis does not result from failure of chondrocytes to undergo hypertrophy. During the process of endochondral ossification, chondrocytes in growth cartilage undergo proliferation, followed by hypertrophy and physiological death. This orderly series of events is regulated by a number of secreted proteins, the actions of which are mediated by specific receptors, signaling cascades, and transcription factors. 1 Several factors are of particular interest. The high-mobility-group transcription factor Sox9 is the earliest known determinant of chondrocyte differentiation and cartilage formation, also regulating expression of the chondrocyte-specific extracellular matrix proteins type II collagen and aggrecan. 2 Fibroblast growth factor receptor 3 (FGFR3) has been shown to inhibit chondrocyte proliferation, with FGF18 possibly the important ligand in growth cartilage. 3,4 Endochondral ossification is blocked in Runx2-deficient mice, indicating an essential role for this transcription factor in chondrocyte differentiation. It has been shown that expression of Runx2 induces hypertrophy, alkaline phosphatase activity, and expression of type X collagen and matrix metalloproteinase-13 (MMP-13) 5 in chondrocytes, as well as mineralization of the cartilage matrix. In the later stages of endochondral ossification, Runx2 is involved in the vascular invasion of the cartilage, inducing the expression of the angiogenic factor, vascular endothelial growth factor (VEGF), which is necessary for vascular invasion, as well as the expression of VEGF receptors. 6 Evidence from a mouse model has shown that the collagen-degrading enzyme MMP-13 plays a role in invasion of the ossification front, with delayed endochondral ossif...

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“…These diseases are a rare osteolytic syndrome, which is caused by MMP2 mutations 47 , the Missouri variant of spondyloepimetaphyseal dysplasia (SEMD), which is caused by point mutations in MMP13 (REF. 48 ), and the tooth enamel defect amelogenesis imperfecta, which is caused by splice-acceptor mutations in MMP20 (REF. 49 ).…”

Section: Human Mmp Mutations Lead To Defects In Bone Developmentmentioning

confidence: 99%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,589

2,180

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMDMO)

Cited by 103 publications

References 50 publications

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Altered gene expression in early osteochondrosis lesions

Matrix metalloproteinases and the regulation of tissue remodelling

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