Collagen from the osteogenesis imperfecta mouse model (oim) shows reduced resistance against tensile stress.

Misof, K.; Landis, W J; Klaushofer, Klaus; Fratzl, Peter

doi:10.1172/jci119519

Cited by 150 publications

(84 citation statements)

References 22 publications

(29 reference statements)

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“…One of the most well known genetic diseases is osteogenesis imperfect (brittle bone disease), where tiny single point mutations (i.e. molecular defects at the level of single amino acids, or a few Ångstrom in lengthscale) in the collagen type I gene leads to mechanical weakness at larger scales [82,83] due to a softening of the tropocollagen molecule's stiffness and a significant reduction of the intermolecular adhesion [84,85]. This example shows that under disease conditions, the intrinsic repair and toughening mechanisms of bone can fail to function properly and lead to a rapid breakdown of the tissue [86].…”

Section: Discussionmentioning

confidence: 99%

On the effect of X-ray irradiation on the deformation and fracture behavior of human cortical bone

Barth

Launey

MacDowell

et al. 2010

Bone

178

109

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In situ mechanical testing coupled with imaging using high-energy synchrotron x-ray diffraction or tomography imaging is gaining in popularity as a technique to investigate micrometer and even sub-micrometer deformation and fracture mechanisms in mineralized tissues, such as bone and teeth. However, the role of the irradiation in affecting the nature and properties of the tissue is not always taken into account. Accordingly, we examine here the effect of x-ray synchrotron-source irradiation on the mechanistic aspects of deformation and fracture in human cortical bone. Specifically, the strength, ductility and fracture resistance (both work-of-fracture and resistancecurve fracture toughness) of human femoral bone in the transverse (breaking) orientation were evaluated following exposures to 0.05, 70, 210 and 630 kGy irradiation. Our results show that the radiation typically used in tomography imaging can have a major and deleterious impact on the strength, post-yield behavior and fracture toughness of cortical bone, with the severity of the effect progressively increasing with higher doses of radiation. Plasticity was essentially suppressed after as little as 70 kGy of radiation; the fracture toughness was decreased by a factor of five after 210 kGy of radiation. Mechanistically, the irradiation was found to alter the salient toughening mechanisms, manifest by the progressive elimination of the bone's capacity for plastic deformation which restricts the intrinsic toughening from the formation "plastic zones" around crack-like defects. Deep-ultraviolet Raman spectroscopy indicated that this behavior could be related to degradation in the collagen integrity.

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Section: Discussionmentioning

confidence: 99%

On the effect of X-ray irradiation on the deformation and fracture behavior of human cortical bone

Barth

Launey

MacDowell

et al. 2010

Bone

178

109

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“…Although bone matrix properties and their regulators remain largely uncharacterized, natural and experimental mutations in matrix proteins suggest their importance (5,30). That bone matrix properties are regulated by TGF-␤ also has significant physiological and clinical implications.…”

Section: Discussionmentioning

confidence: 99%

“…Much less is known about the mechanical properties and composition of bone matrix, the unique protein-and mineral-rich extracellular material produced by osteoblasts and osteocytes. However, the importance of bone matrix quality is clinically apparent in bone disorders such as osteogenesis imperfecta and osteopetrosis (4,5). Osteopetrosis patients have increased bone fragility despite elevated bone mass (4).…”

mentioning

confidence: 99%

TGF-β regulates the mechanical properties and composition of bone matrix

Balooch

Nalla

et al. 2005

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

195

191

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The characteristic toughness and strength of bone result from the nature of bone matrix, the mineralized extracellular matrix produced by osteoblasts. The mechanical properties and composition of bone matrix, along with bone mass and architecture, are critical determinants of a bone's ability to resist fracture. Several regulators of bone mass and architecture have been identified, but factors that regulate the mechanical properties and composition of bone matrix are largely unknown. We used a combination of high-resolution approaches, including atomic-force microscopy, x-ray tomography, and Raman microspectroscopy, to assess the properties of bone matrix independently of bone mass and architecture. Properties were evaluated in genetically modified mice with differing levels of TGF-␤ signaling. Bone matrix properties correlated with the level of TGF-␤ signaling. Smad3؉͞؊ mice had increased bone mass and matrix properties, suggesting that the osteopenic Smad3؊͞؊ phenotype may be, in part, secondary to systemic effects of Smad3 deletion. Thus, a reduction in TGF-␤ signaling, through its effector Smad3, enhanced the mechanical properties and mineral concentration of the bone matrix, as well as the bone mass, enabling the bone to better resist fracture. Our results provide evidence that bone matrix properties are controlled by growth factor signaling.osteoblast ͉ Smad3 ͉ atomic force microscopy T he ability of bones to resist fracture is determined by the bone mass and architecture, and the mechanical properties and composition of the bone matrix (1). Bone architecture is determined by cortical bone thickness, trabecular bone volume, and organization. Several signaling pathways, including estrogen, parathyroid hormone, and TGF-␤, have been implicated in the control of bone mass and architecture and its deregulation in metabolic bone diseases such as osteoporosis (2, 3). Much less is known about the mechanical properties and composition of bone matrix, the unique protein-and mineral-rich extracellular material produced by osteoblasts and osteocytes. However, the importance of bone matrix quality is clinically apparent in bone disorders such as osteogenesis imperfecta and osteopetrosis (4, 5). Osteopetrosis patients have increased bone fragility despite elevated bone mass (4). Presumably, bone matrix properties are highly regulated, but the regulators themselves are unknown, partly because of the inaccessibility of methods to define these properties independently of bone mass and architecture. Nevertheless, the regulation of bone matrix properties must be understood to more effectively treat bone disorders.TGF-␤ plays stage-dependent roles in osteoblast and osteoclast differentiation. TGF-␤ inhibits osteoblast differentiation yet stimulates the proliferation of mesenchymal progenitors, thereby expanding the cell population that will differentiate into osteoblasts (6). TGF-␤ signals through a complex of type I and type II transmembrane serine͞threonine kinases (7). Upon ligand binding, the receptor complex phosphorylat...

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“…The increased vulnerability to frac tures might be explained by abnormalities of the miner alized matrix at different levels, affecting structures that normally hinder crack propagation 126 . First, compared with controls, the alignment of collagen fibrils was found to be more disordered and less lamellar in both oim mouse models 124,127 and biopsy samples from patients with osteo genesis imperfecta 128 ; second, the collagenous matrix is not only reduced in amount 129 but also showed more non enzymatic crosslinks 124 ; third, unmineral ized collagen fibrils from the oim mouse model showed reduced strength under tensioning 130 and more affinity to water 131 . By contrast, less tissue water was found in fully mineralized bone of the oim mice 132 and in bone biop sies from patients with osteogenesis imperfecta 121 .…”

Section: Box 2 | Ehlers-danlos Syndromementioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

504

582

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| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

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Collagen from the osteogenesis imperfecta mouse model (oim) shows reduced resistance against tensile stress.

Cited by 150 publications

References 22 publications

On the effect of X-ray irradiation on the deformation and fracture behavior of human cortical bone

On the effect of X-ray irradiation on the deformation and fracture behavior of human cortical bone

TGF-β regulates the mechanical properties and composition of bone matrix

Osteogenesis imperfecta

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