A matrilin-3 mutation associated with osteoarthritis does not affect collagen affinity but promotes the formation of wider cartilage collagen fibrils

Otten, Christiane; Hansen, Uwe; Talke, Anja; Wagener, Raimund; Paulsson, Mats; Zaucke, Frank

doi:10.1002/humu.21182

Cited by 22 publications

(23 citation statements)

References 54 publications

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“…Notably, effects of collagen binding/VWA domain containing proteins on collagen assembly were also shown for Matrilin 3 (ref. 38), albeit the observed effects were not as tremendous as shown for PTMP1, suggesting that collagen binding of proteins with tandem-arranged VWA domains could generally provide a so far undetected control mechanism for collagen/matrix assemblies. In the byssus, PTMP1 is predominantly present in the proximal thread section 11 , with its natural targets being most likely PreCol-P or PreCol-NG rather than PreCol-D.…”

Section: Resultsmentioning

confidence: 83%

“…Furthermore, the impact of matrix proteins like PTMP1 on collagen fibril formation and assembly is obvious when fibres are artificially drawn from purified PreCol proteins 40,41 , since these fibres were different from the natural byssal threads with respect to size and mechanical characteristics 10 . Concerning the establishment of collagenous materials with new properties, the in vitro function of PTMP1 might inspire material scientists to adjust morphologies and also mechanical features of reconstituted collagen fibres to be used in different applications, for example, in the generation of gradient materials inspired by the mussel byssus 38 . The possibility to recombinantly produce PTMP1 and other byssal proteins 39 opens the gate for a variety of novel bio-inspired materials based on collagen/matrix assemblies, for example, in tissue engineering 42 .…”

Section: Resultsmentioning

confidence: 99%

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Structural and functional features of a collagen-binding matrix protein from the mussel byssus

et al. 2014

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Blue mussels adhere to surfaces by the byssus, a holdfast structure composed of individual threads representing a collagen fibre reinforced composite. Here, we present the crystal structure and function of one of its matrix proteins, the proximal thread matrix protein 1, which is present in the proximal section of the byssus. The structure reveals two von Willebrand factor type A domains linked by a two-b-stranded linker yielding a novel structural arrangement. In vitro, the protein binds heterologous collagens with high affinity and affects collagen assembly, morphology and arrangement of its fibrils. By providing charged surface clusters as well as insufficiently coordinated metal ions, the proximal thread matrix protein 1 might interconnect other byssal proteins and thereby contribute to the integrity of the byssal threads in vivo. Moreover, the protein could be used for adjusting the mechanical properties of collagen materials, a function likely important in the natural byssus.

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Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Structural and functional features of a collagen-binding matrix protein from the mussel byssus

et al. 2014

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“…Contrary to the mild phenotype MATN3 null mice displayed, mutation of a single base, however, could cause MED. Many studies thus presumed that the pathogenic mechanism of MED might be mediated by a dominant negative effect [19,35,36]. Moreover, multiple growth factors, transcription factors and signal proteins of extracellular matrix, such as BMP2 [12], SOX6 [37] and PTHrp [38], have been proved to be associated with BMD.…”

Section: Discussionmentioning

confidence: 99%

A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study

Zhao

Xia

Nie

et al. 2012

Bone

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The Matrilin3 gene (MATN3) encodes an extracellular matrix protein, which modulates chondrocyte differentiation. The aim of this study was to test for association of MATN3 polymorphisms with bone mineral density (BMD), fracture, vertebral fracture, bone turnover or 25-hydroxyvitamin D [25(OH)D] in postmenopausal women. A community-based population of 1488 postmenopausal women was randomly selected in Beijing. The history of fracture and vertebral fracture was obtained via questionnaire and vertebral X-ray respectively. BMD of lumbar spine (2–4), femoral neck and total hip were measured by dual energy X-ray absorptiometry. Serum N-terminal procollagen of type 1 collagen (P1NP), β-isomerized type I collagen C-telopeptide breakdown products (β-CTX) and 25(OH)D were quantified. Binary logistic regression revealed that Haplotype-4 was significantly associated with vertebral fracture risk in both additive model (p=0.023, OR=1.521) and dominant model (p=0.028, OR=1.623). The significance remained after 10,000 permutation tests to correct multiple testing (p=0.042). Re-selected age matched vertebral fracture case-control groups revealed similar associations in additive model (p=0.014, OR=1.927, 95%CI=1.142–3.253) and in dominant model (p=0.011, OR=2.231, 95%CI=1.200–4.148). However, no significant association was found between MATN3 polymorphisms and serum β-CTX, P1NP, 25(OH)D levels, or BMD. In linear regression, Haplotype-2 approached marginal significance in association with femoral neck BMD T-score (p=0.050), but this would account for only 0.2% of BMD variation in our sample. This study suggests that Haplotype-4 of MATN3 is associated with vertebral fracture risk independent of BMD in Chinese postmenopausal women. Efforts should be made to replicate our finding in other, similar and ethnically diverse, populations.

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“…The effects of the osteoarthritis‐associated p.T303M mutation (in mouse p.T298M models) on the structure of matrilin 3 and on the role of matrilin 3 in extracellular matrix assembly were recently analyzed, and the results revealed that this mutation also allowed normal secretion (38), caused only minor changes in protein structure, and did not affect the affinity for collagens. However, a major impact on collagen fibrillogenesis with the formation of wider cartilage collagen fibrils was observed (39). This example confirms that studies of pathogenic changes in rare forms of cartilage degeneration are likely to provide significant insight into the pathogenetic mechanisms of more common forms of the disease, particularly since the sequence of molecular events seems to be largely independent of the factors that first initiated the disease (40).…”

Section: Discussionmentioning

confidence: 99%

A secreted variant of cartilage oligomeric matrix protein carrying a chondrodysplasia‐causing mutation (p.H587R) disrupts collagen fibrillogenesis

Hansen

Platz

Becker

et al. 2010

Arthritis & Rheumatism

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Objective. Mutations in human cartilage oligomeric matrix protein (COMP) cause multiple epiphyseal dysplasia or pseudoachondroplasia. Electron microscopic analyses of patient biopsy tissue have shown that, in most cases, mutated COMP is retained in granular or lamellar inclusions in the endoplasmic reticulum of chondrocytes. However, some mutations that do not interfere with protein trafficking, resulting in normal secretion of the mutated protein, have been identified. These mutations are likely to cause the chondrodysplasia phenotype, via events that occur after secretion. The aim of the present study was to identify such extracellular mechanisms associated with the pathogenesis of chondrodysplasias.Methods. A mutated but secreted COMP variant, p.H587R, as well as wild-type COMP were recombinantly expressed and purified from cell culture supernatants. Since recent studies have shown that COMP can facilitate collagen fibrillogenesis in vitro, the effect of the p.H587R mutation on this process was determined by analyzing the kinetics of fibrillogenesis in vitro and determining the structure of the collagen fibrils formed by immunogold electron microscopy.Results. Mutated p.H587R COMP accelerated fibril formation by type I collagen in vitro to a slightly greater extent than that with wild-type COMP. However, p.H587R COMP induced aggregation and disorganization of fibril intermediates and end products. Mixtures of cartilage collagens or of type XI collagen alone produced similar results. The addition of p.H587R COMP to preformed fibrils induced aggregation and fusion of the fibrils, whereas wild-type COMP had little effect. Conclusion. The mutant COMP variant p.H587R generally interferes with normal collagen organization during fibrillogenesis. This constitutes a novel pathogenetic mechanism of COMP-associated chondrodysplasias.Cartilage oligomeric matrix protein (COMP), also called thrombospondin 5, is a pentameric protein that, in initial studies, was isolated from cartilage tissue. COMP is predominantly expressed in all types of cartilage (1) but can also be expressed in tendons (2) and, to a lesser extent, by vascular smooth muscle cells (3). The role of COMP in cartilage matrix is not completely understood. COMP-deficient animals do not display any skeletal abnormalities or alterations in tendon structure (4). However, a variety of noncollagenous matrix molecules that interact with COMP have been identified. Binding proteins include types I, II, and IX collagen (5-8) as well as extrafibrillar matrix constituents such as matrilins (9), fibronectin (10), extracellular matrix protein 1 (11), and aggrecan (12).A recent study showed that COMP not only binds to collagens but also acts as an enhancer of collagen fibrillogenesis (13). COMP mediates not only interactions of soluble proteins, but also interactions of cartilage collagen fibrils with matrilin 3 and of type VI Supported in part by the Sonderforschungsbereich (SFB 492

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A matrilin-3 mutation associated with osteoarthritis does not affect collagen affinity but promotes the formation of wider cartilage collagen fibrils

Cited by 22 publications

References 54 publications

Structural and functional features of a collagen-binding matrix protein from the mussel byssus

Structural and functional features of a collagen-binding matrix protein from the mussel byssus

A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study

A secreted variant of cartilage oligomeric matrix protein carrying a chondrodysplasia‐causing mutation (p.H587R) disrupts collagen fibrillogenesis

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