scholarly journals Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis

2021 ◽  
Vol 22 (2) ◽  
pp. 625
Author(s):  
Ahmed El-Gazzar ◽  
Wolfgang Högler
Keyword(s):  
Bone Mass ◽  
Type I Collagen ◽  
Mass Matrix ◽  
Medical Knowledge ◽  
Bone Fragility ◽  
Matrix Composition ◽  
Material Strength ◽  
Type I ◽  
Bone Material Strength ◽  
Rank System

Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.

scholarly journals Restoration of Osteogenesis by CRISPR/Cas9 Genome Editing of the Mutated COL1A1 Gene in Osteogenesis Imperfecta

2021 ◽  
Vol 10 (14) ◽  
pp. 3141
Author(s):  
Hyerin Jung ◽  
Yeri Alice Rim ◽  
Narae Park ◽  
Yoojun Nam ◽  
Ji Hyeon Ju
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Disease Modeling ◽  
Bone Fragility ◽  
Osteogenic Potential ◽  
Type I ◽  
Gene Correction ◽  
Col1a1 Gene ◽  
Collagen Formation

Osteogenesis imperfecta (OI) is a genetic disease characterized by bone fragility and repeated fractures. The bone fragility associated with OI is caused by a defect in collagen formation due to mutation of COL1A1 or COL1A2. Current strategies for treating OI are not curative. In this study, we generated induced pluripotent stem cells (iPSCs) from OI patient-derived blood cells harboring a mutation in the COL1A1 gene. Osteoblast (OB) differentiated from OI-iPSCs showed abnormally decreased levels of type I collagen and osteogenic differentiation ability. Gene correction of the COL1A1 gene using CRISPR/Cas9 recovered the decreased type I collagen expression in OBs differentiated from OI-iPSCs. The osteogenic potential of OI-iPSCs was also recovered by the gene correction. This study suggests a new possibility of treatment and in vitro disease modeling using patient-derived iPSCs and gene editing with CRISPR/Cas9.

scholarly journals Early-Onset Osteoporosis

2021 ◽  
Author(s):  
Outi Mäkitie ◽  
M. Carola Zillikens
Keyword(s):  
Young Adults ◽  
Early Onset ◽  
Type I Collagen ◽  
Young Patients ◽  
Fragility Fractures ◽  
Underlying Disease ◽  
Bone Fragility ◽  
Sphingolipid Metabolism ◽  
Type I ◽  
Loss Of Function

AbstractOsteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < − 2.0 in growing children and a Z-score ≤ − 2.0 or a T-score ≤ − 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.

scholarly journals Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

2020 ◽  
Author(s):  
Olga Gewartowska ◽  
Goretti Aranaz Novaliches ◽  
Paweł S Krawczyk ◽  
Seweryn Mroczek ◽  
Monika Kusio-Kobiałka ◽  
...  
Keyword(s):  
Bone Formation ◽  
Type I Collagen ◽  
Bone Mineralization ◽  
Bone Fragility ◽  
Type I ◽  
Human Genetic Disease ◽  
Cytoplasmic Polyadenylation ◽  
Disease Symptoms ◽  
Biologically Relevant ◽  
First Time

AbstractOsteoblasts orchestrate bone formation by secreting dense, highly cross-linked type I collagen and other proteins involved in osteogenesis. Mutations in Col1α1, Col1α2, or collagen biogenesis factors lead to the human genetic disease, osteogenesis imperfecta (OI). Herein, we show that the TENT5A gene, whose mutation is responsible for poorly characterized type XVIII OI, encodes an active cytoplasmic poly(A) polymerase regulating osteogenesis. TENT5A is induced during osteoblast differentiation and TENT5A KO osteoblasts are defective in mineralization. The TENT5A KO mouse recapitulates OI disease symptoms such as bone fragility and hypomineralization. Direct RNA sequencing revealed that TENT5A polyadenylates and increases expression of Col1α1 and Col1α2 RNAs, as well as those of other genes mutated in OI, resulting in lower production and improper folding of collagen chains. Thus, we have identified the specific pathomechanism of XVIII OI and report for the first time a biologically relevant post-transcriptional regulator of collagen production. We further postulate that TENT5A, possibly together with its paralogue TENT5C, is responsible for the wave of cytoplasmic polyadenylation of mRNAs encoding secreted proteins occurring during bone mineralization.

scholarly journals Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 5048-5056 ◽  
Author(s):  
Benoit Detry ◽  
Charlotte Erpicum ◽  
Jenny Paupert ◽  
Silvia Blacher ◽  
Catherine Maillard ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Lymphatic Vessel ◽  
Type I Collagen ◽  
3D Culture ◽  
Matrix Composition ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Vessel Formation

Abstract Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)–2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density, and cross-linking). Transmission electron microscopy and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LECs associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LECs negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis.

Change of cross-linked telopeptide of type I collagen (ICTP) and other bone resorption markers in patients with bone fragility fractures

2007 ◽  
Vol 12 (3) ◽  
pp. 219-226 ◽  
Author(s):  
Kenji Takahara ◽  
Mikio Kamimura ◽  
Hiroyuki Hashidate ◽  
Shigeharu Uchiyama ◽  
Hiroyuki Nakagawa
Keyword(s):  
Bone Resorption ◽  
Type I Collagen ◽  
Fragility Fractures ◽  
Bone Fragility ◽  
Type I ◽  
Bone Resorption Markers

Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy [RETRACTED]

Neurology ◽  
2001 ◽  
Vol 57 (3) ◽  
pp. 445-449 ◽  
Author(s):  
Y. Sato ◽  
I. Kondo ◽  
S. Ishida ◽  
H. Motooka ◽  
K. Takayama ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Mass ◽  
Calcium Metabolism ◽  
Type I Collagen ◽  
Bone Resorption Marker ◽  
Type I ◽  
Serum Concentrations ◽  
Mineral Density ◽  
Z Scores

Background: Bone loss and hypovitaminosis D are reported in patients taking antiepileptic drugs, but little is known about changes in bone and calcium metabolism from valproic acid (VPA).Objective: To assess the relationship of VPA to bone mass and calcium metabolism in 40 adults with epilepsy on long-term VPA monotherapy, 40 age- and sex-matched epileptic patients taking phenytoin (PHT), and 40 healthy control subjects. Bone mineral density (BMD) of the second metacarpal was determined as T- and Z-scores.Results: BMD reduction from control values was 14% (12% in men, 16% in women) with VPA and 13% (12% in men, 15% in women) with PHT. Among patients on VPA, nine (23%) had T-scores below −2.5 SD, suggesting osteoporosis; 15 (37%) had T-scores between −1 and −2.5 SD, suggesting osteopenia. Serum concentrations of calcium were significantly higher with VPA than in PHT or control groups. Serum concentrations of bone Gla protein (a bone formation marker) and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; a bone resorption marker) associated with either drug significantly exceeded control values. Z-scores for BMD in the VPA group correlated negatively with calcium and ICTP. High ICTP correlated positively with ionized calcium, implying that increased bone resorption caused the latter.Conclusion: Long-term VPA monotherapy can increase bone resorption, leading to decreased BMD.

scholarly journals Assessment of Collagen-Based Nanostructured Biomimetic Systems with a Co-Culture of Human Bone-Derived Cells

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 26
Author(s):  
Giorgia Borciani ◽  
Giorgia Montalbano ◽  
Priscila Melo ◽  
Nicola Baldini ◽  
Gabriela Ciapetti ◽  
...  
Keyword(s):  
Type I Collagen ◽  
Osteoporotic Fractures ◽  
Bone Substitutes ◽  
Biological Properties ◽  
Bone Fragility ◽  
Buffy Coat ◽  
Type I ◽  
In Vitro Systems ◽  
Potential Alternative

Osteoporosis is a worldwide disease resulting in the increase of bone fragility and enhanced fracture risk in adults. In the context of osteoporotic fractures, bone tissue engineering (BTE), i.e., the use of bone substitutes combining biomaterials, cells, and other factors, is considered a potential alternative to conventional treatments. Innovative scaffolds need to be tested in in vitro systems where the simultaneous presence of osteoblasts (OBs) and osteoclasts (OCs), the two main players of bone remodeling, is required to mimic their crosstalk and molecular cooperation. To this aim, two composite materials were developed, based on type I collagen, and containing either strontium-enriched mesoporous bioactive glasses or rod-like hydroxyapatite nanoparticles. The developed nanostructured systems underwent genipin chemical crosslinking and were then tested with an indirect co-culture of human trabecular bone-derived OBs and buffy coat-derived OC precursors, for 2–3 weeks. The favorable structural and biological properties of the materials proved to successfully support the viability, adhesion, and differentiation of cells, encouraging a further investigation of the developed bioactive systems as biomaterial inks for the 3D printing of more complex scaffolds for BTE.

scholarly journals Scanning electron microscopy of type I collagen at the dentin-enamel junction of human teeth.

1993 ◽  
Vol 41 (3) ◽  
pp. 381-388 ◽  
Author(s):  
C P Lin ◽  
W H Douglas ◽  
S L Erlandsen
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Type I Collagen ◽  
Immunogold Labeling ◽  
Matrix Composition ◽  
Type I ◽  
Human Teeth ◽  
Dentin Matrix ◽  
Electron Imaging ◽  
Scanning Electron

The dentin-enamel junction constitutes a unique boundary between two highly mineralized tissues with very different matrix composition and physical properties. The nature of the boundary between the ectoderm-derived enamel and mesoderm-derived dentin is not known. This study was undertaken to identify the presence, type, and distribution of collagen at the dentin-enamel junction as an initial step in understanding its structural-functional role in dental occlusion. Sections of human teeth were demineralized with 0.1 M neutral EDTA and examined by high-resolution field-emission scanning electron microscopy at low accelerating voltage. Enamel and dentin were observed to be linked by many parallel 80-120-nm diameter fibrils, which were inserted directly into the enamel mineral and also merged with the interwoven fibrillar network of the dentin matrix. Immunogold labeling for collagen was visualized by secondary electron imaging and backscatter electron imaging at low accelerating voltage. The collagen fibrils at the junctional zone as well as in the dentin matrix were identified as Type I collagen. Collagenase digestion led to loss of the fibrillar structures and prevented immunogold labeling with antibody specific to Type I collagen. Consequently, the dentin-enamel junction can be regarded as a fibril-reinforced bond which is mineralized to a moderate degree.

scholarly journals A Dairy Product to Reconstitute Enriched with Bioactive Nutrients Stops Bone Loss in High-Risk Menopausal Women without Pharmacological Treatment

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2203 ◽  
Author(s):  
Marina Morato-Martínez ◽  
Bricia López-Plaza ◽  
Cristina Santurino ◽  
Samara Palma-Milla ◽  
Carmen Gómez-Candela
Keyword(s):  
At Risk ◽  
Vitamin D ◽  
Bone Mass ◽  
Bone Health ◽  
Pharmacological Treatment ◽  
Type I Collagen ◽  
Dairy Product ◽  
The Other ◽  
Type I ◽  
Menopausal Women

Osteoporosis is a multifactorial disease characterized by the loss of bone mass and deterioration of the internal structure of the bone, increasing the risk of fractures, and is becoming an economic and social problem. The main treatment is pharmacological, however, the population demands other therapies, such as foods with nutrients beneficial to bone health. Seventy-eight healthy menopausal women at risk of osteoporosis or untreated osteopenia were recruited for a randomized, parallel, double-blind clinical trial with two intervention groups: one group consumed a serving a day of the experimental enriched product (experimental group (EG)) and the other group (control group (CG)) consumed the same product without enrichment. The main objective was to compare the effect of consuming a dairy preparation to reconstitute, similar to yogurt when prepared, enriched in calcium, vitamin D, vitamin K, vitamin C, zinc, magnesium, L-leucine and probiotic (Lactobacillus plantarum 3547) on bone metabolism markers for 24 weeks. The EG showed a significantly increased bone mass compared to the CG (0.01 ± 0.03 vs. −0.01 ± 0.03 kg; p < 0.05). In addition, the EG maintained their bone mineral density (BMD) compared to the CG, whose BMD significantly decreased at the end of the study. For biochemical markers, the EG significantly increased the serum levels of the N-terminal propeptide of type I collagen (P1NP) bone formation marker (13.19 ± 25.17 vs. −4.21 ± 15.62 ng/mL; p < 0.05), and decreased the carbo-terminal telopeptide of type I collagen (CTx) bone resorption marker compared to the CG (−0.05 ± 0.19 vs. 0.04 ± 0.14 ng/mL; p < 0.05). On the other hand, the EG exhibited a significantly decreased systolic and diastolic blood pressure compared to the start of the study. Finally, the EG significantly increased their dietary calcium and vitamin D intake compared to the CG. In conclusion, the regular consumption of a dairy product to reconstitute enriched with bioactive nutrients improves bone health markers in menopausal women at risk of osteoporosis without pharmacological treatment.

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