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 The Effect of the Combination of Vitamin K2 and Genistein, Coumestrol and Daidzein on the Osteoblast Differentiation and Bone Matrix Formation

2016 ◽  
Vol 10 (2) ◽  
pp. 12-19
Author(s):  
Sahar S. Karieb ◽  
Mohammed M. Jawad ◽  
Hanady S. Al-Shmgani ◽  
Zahraa H.M. Kadri
Keyword(s):  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Nuclear Factor Kappa B ◽  
Type I Collagen ◽  
Bone Mineralization ◽  
Bone Matrix ◽  
Vitamin K2 ◽  
Type I ◽  
Nuclear Factor ◽  
Effective Factor

Multiple studies have been reported the stimulatory effect of the combinations of nutrients factors on bone formation. One such factor is vitamin K2 which can be associated with bone protective activities. The effect of vitamin K2 alone and in combination with genistein, coumestrol and daidzein on osteoblast differentiation and mineralization were tested. Significantly, vitamin K2 increased bone mineralization in combination with genistein (10-5M), coumestrol (10-7M) and daidzein (10-5M). However, there is no additive effect of this vitamin on alkaline phosphatase (ALP) levels in osteoblasts. By contrast, vitamin K2 enhanced the stimulatory effect of type I collagen and osteocalcin expression. Vitamin K2 alone increased RUNX and OSX expression while there is no synergistic effect with tested compound; this vitamin also did not modulate nuclear factor kappa B ligand (RANKL)/ osteoprotegerin (OPG) ratio expression. These results suggested that vitamin K2 can be more effective factor in the presence of phytoestrogens on the improvement of bone formation after menopause.

scholarly journals Osteogenesis imperfecta: an update on clinical features and therapies

2020 ◽  
Vol 183 (4) ◽  
pp. R95-106 ◽  
Author(s):  
Ronit Marom ◽  
Brien M Rabenhorst ◽  
Roy Morello
Keyword(s):  
Osteogenesis Imperfecta ◽  
Type I Collagen ◽  
Bone Mineralization ◽  
Cardiovascular Complications ◽  
Bone Fragility ◽  
Type I ◽  
Mineral Density ◽  
Multiple Systems ◽  
Pathogenic Variants ◽  
Genes Encoding

Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by bone fragility and skeletal deformities. While the majority of cases are associated with pathogenic variants in COL1A1 and COL1A2, the genes encoding type I collagen, up to 25% of cases are associated with other genes that function within the collagen biosynthesis pathway or are involved in osteoblast differentiation and bone mineralization. Clinically, OI is heterogeneous in features and variable in severity. In addition to the skeletal findings, it can affect multiple systems including dental and craniofacial abnormalities, muscle weakness, hearing loss, respiratory and cardiovascular complications. A multi-disciplinary approach to care is recommended to address not only the fractures, reduced mobility, growth and bone pain but also other extra-skeletal manifestations. While bisphosphonates remain the mainstay of treatment in OI, new strategies are being explored, such as sclerostin inhibitory antibodies and TGF beta inhibition, to address not only the low bone mineral density but also the inherent bone fragility. Studies in animal models have expanded the understanding of pathomechanisms of OI and, along with ongoing clinical trials, will allow to develop better therapeutic approaches for these patients.

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 Serum levels of bone formation and resorption markers in relation to vitamin D status in professional gymnastics and physically active men during upper and lower body high-intensity exercise

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jan Mieszkowski ◽  
Andrzej Kochanowicz ◽  
Elżbieta Piskorska ◽  
Bartłomiej Niespodziński ◽  
Joanna Siódmiak ◽  
...  
Keyword(s):  
Vitamin D ◽  
Bone Formation ◽  
Bone Turnover ◽  
Bone Turnover Markers ◽  
Type I Collagen ◽  
Serum Levels ◽  
Type I ◽  
Vitamin D Metabolites ◽  
Physically Active ◽  
Turnover Markers

Abstract Purpose/introduction To compare serum levels of bone turnover markers in athletes and non-athletes, and to evaluate the relationship between serum levels of vitamin D metabolites and exercise-induced changes in biomarker levels. Methods Sixteen elite male artistic gymnasts (EG; 21.4 ± 0.8 years-old) and 16 physically active men (the control group, PAM; 20.9 ± 1.2 years-old) performed lower and upper body 30-s Wingate anaerobic tests (LBWT and UBWT, respectively). For biomarker analysis, blood samples were collected before, and 5 and 30 min after exercise. Samples for vitamin D levels were collected before exercise. N-terminal propeptide of type I collagen (PINP) was analysed as a marker of bone formation. C-terminal telopeptide of type I collagen (CTX) was analysed as a marker of bone resorption. Results UBWT fitness readings were better in the EG group than in the PAM group, with no difference in LBWT readings between the groups. UBWT mean power was 8.8% higher in subjects with 25(OH)D3 levels over 22.50 ng/ml and in those with 24,25(OH)2D3 levels over 1.27 ng/ml. Serum CTX levels increased after both tests in the PAM group, with no change in the EG group. PINP levels did not change in either group; however, in PAM subjects with 25(OH)D3 levels above the median, they were higher than those in EG subjects. Conclusion Vitamin D metabolites affect the anaerobic performance and bone turnover markers at rest and after exercise. Further, adaptation to physical activity modulates the effect of anaerobic exercise on bone metabolism markers.

Trabecular Bone is Increased in a Rat Model of Polycystic Ovary Syndrome

2020 ◽  
Author(s):  
Lady Katerine Serrano Mujica ◽  
Werner Giehl Glanzner ◽  
Amanda Luiza Prante ◽  
Vitor Braga Rissi ◽  
Gabrielle Rebeca Everling Correa ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Bone Formation ◽  
Type I Collagen ◽  
Polycystic Ovary ◽  
Osteoclast Differentiation ◽  
Bone Volume ◽  
Negative Regulator ◽  
Type I ◽  
Ovary Syndrome ◽  
The Impact

AbstractPolycystic ovary syndrome (PCOS) in an intricate disorder characterized by reproductive and metabolic abnormalities that may affect bone quality and strength along with the lifespan. The present study analysed the impact of postnatal androgenization (of a single dose of testosterone propionate 1.25 mg subcutaneously at day 5 of life) on bone development and markers of bone metabolism in adult female Wistar rats. Compared with healthy controls, the results of measurements of micro-computed tomography (microCT) of the distal femur of androgenized rats indicated an increased cortical bone volume voxel bone volume to total volume (VOX BV/TV) and higher trabecular number (Tb.n) with reduced trabecular separation (Tb.sp). A large magnitude effect size was observed in the levels of circulating bone formation Procollagen I N-terminal propeptide (P1NP) at day 60 of life; reabsorption cross-linked C-telopeptide of type I collagen (CTX) markers were similar between the androgenized and control rats at days 60 and 110 of life. The analysis of gene expression in bone indicated elements for an increased bone mass such as the reduction of the Dickkopf-1 factor (Dkk1) a negative regulator of osteoblast differentiation (bone formation) and the reduction of Interleukin 1-b (Il1b), an activator of osteoclast differentiation (bone reabsorption). Results from this study highlight the possible role of the developmental programming on bone microarchitecture with reference to young women with PCOS.

Tissue Engineering of Bone by Osteoinductive Biomaterials

MRS Bulletin ◽  
1996 ◽  
Vol 21 (11) ◽  
pp. 36-39 ◽  
Author(s):  
Ugo Ripamonti ◽  
Nicolaas Duneas
Keyword(s):  
Tissue Engineering ◽  
Bone Formation ◽  
Type I Collagen ◽  
Demineralized Bone Matrix ◽  
Bone Matrix ◽  
Mesenchymal Cells ◽  
Tissue Response ◽  
Type I ◽  
New Bone Formation ◽  
Demineralized Bone

Recent advances in materials science and biotechnology have given birth to the new and exciting field of tissue engineering, in which the two normally disparate fields are merging into a profitable matrimony. In particular the use of biomaterials capable of initiating new bone formation via a process called osteoinduction is leading to quantum leaps for the tissue engineering of bone.The classic work of Marshall R. Urist and A. Hari Reddi opened the field of osteoinductive biomaterials. Urist discovered that, upon implantation of devitalized, demineralized bone matrix in the muscle of experimental animals, new bone formation occurs within two weeks, a phenomenon he described as bone formation by induction. The tissue response elicited by implantation of demineralized bone matrix in muscle or under the skin includes activation and migration of undifferentiated mesenchymal cells by chemotaxis, anchoragedependent cell attachment to the matrix, mitosis and proliferation of mesenchymal cells, differentiation of cartilage, mineralization of the cartilage, vascular invasion of the cartilage, differentiation of osteoblasts and deposition of bone matrix, and finally mineralization of bone and differentiation of marrow in the newly developed ossicle.The osteoinductive ability of the extracellular matrix of bone is abolished by the dissociative extraction of the demineralized matrix, but is recovered when the extracted component, itself inactive, is reconstituted with the inactive residue—mainly insoluble collagenous bone matrix. This important experiment showed that the osteoinductive signal resides in the solubilized component but needs to be reconstituted with an appropriate carrier to restore the osteoinductive activity. In this case, the carrier is the insoluble collagenous bone matrix—mainly crosslinked type I collagen.

Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by γ-carboxylation-dependent and -independent mechanisms

2009 ◽  
Vol 297 (6) ◽  
pp. C1358-C1367 ◽  
Author(s):  
Gerald J. Atkins ◽  
Katie J. Welldon ◽  
Asiri R. Wijenayaka ◽  
Lynda F. Bonewald ◽  
David M. Findlay
Keyword(s):  
Bone Formation ◽  
Vitamin K ◽  
Type I Collagen ◽  
Vitamin K2 ◽  
Type I ◽  
Vitamin K1 ◽  
Vitamin K3 ◽  
Positive Effect

The vitamin K family members phylloquinone (vitamin K1) and the menaquinones (vitamin K2) are under study for their roles in bone metabolism and as potential therapeutic agents for skeletal diseases. We have investigated the effects of two naturally occurring homologs, phytonadione (vitamin K1) and menatetrenone (vitamin K2), and those of the synthetic vitamin K, menadione (vitamin K3), on human primary osteoblasts. All homologs promoted in vitro mineralization by these cells. Vitamin K1-induced mineralization was highly sensitive to warfarin, whereas that induced by vitamins K2 and K3 was less sensitive, implying that γ-carboxylation and other mechanisms, possibly genomic actions through activation of the steroid xenobiotic receptor, are involved in the effect. The positive effect on mineralization was associated with decreased matrix synthesis, evidenced by a decrease from control in expression of type I collagen mRNA, implying a maturational effect. Incubation in the presence of vitamin K2 or K3 in a three-dimensional type I collagen gel culture system resulted in increased numbers of cells with elongated cytoplasmic processes resembling osteocytes. This effect was not warfarin sensitive. Addition of calcein to vitamin K-treated cells revealed vitamin K-dependent deposition of mineral associated with cell processes. These effects are consistent with vitamin K promoting the osteoblast-to-osteocyte transition in humans. To test whether vitamin K may also act on mature osteocytes, we tested the effects of vitamin K on MLO-Y4 cells. Vitamin K reduced receptor activator of NF-κB ligand expression relative to osteoprotegerin by MLO-Y4 cells, an effect also seen in human cultures. Together, our findings suggest that vitamin K promotes the osteoblast-to-osteocyte transition, at the same time decreasing the osteoclastogenic potential of these cells. These may be mechanisms by which vitamin K optimizes bone formation and integrity in vivo and may help explain the net positive effect of vitamin K on bone formation.

Comparative Analysis of the Proteomic Profile of Cattle Hides that Produce Loose and Tight Leather using In-Gel Tryptic Digestion followed by LC-MS/MS

2020 ◽  
Vol 115 (11) ◽  
pp. 399-408
Author(s):  
Catherine Maidment ◽  
Meekyung Ahn ◽  
Rafea Naffa ◽  
Trevor Loo ◽  
Gillian Norris
Keyword(s):  
Type I Collagen ◽  
Raw Material ◽  
Type I ◽  
Collagen Structure ◽  
Proteomic Profile ◽  
Collagen Network ◽  
Collagen Concentration ◽  
Different Types ◽  
Molecular Components ◽  
First Time

Looseness is a defect found in leather that reduces its quality by causing a wrinkly appearance in the finished product, resulting in a reduction in its value. Earlier studies on loose leather using microscopy and Raman spectroscopy reported a change in the collagen structure of loose leather. In this study, proteomics was used to investigate the possible molecular causes of looseness in the raw material, the first time such a study has been carried out. Proteins extracted from two regions of raw hide using two different methods were analysed; those taken from the distal axilla, an area prone to looseness, and those taken from the backbone which is less prone to looseness. Analyses using 1DE-LC-MS/MS showed that although the overall collagen concentration was similar in both areas of the hide, the distribution of the different types of collagen differed.  Specifically, concentrations of type I collagen, and the collagen-associated proteoglycan decorin were lower in samples taken from the distal axilla, symptomatic of a collagen network with excess space seen for these samples using confocal microscopy. This study suggests a possible link between the molecular components of raw cattle hide and looseness and more importantly between the molecular components of skin and skin defects. There is therefore potential to develop biomarkers for looseness which will enable early preventative action.

scholarly journals Reduced Serum Levels of Bone Formation Marker P1NP in Psoriasis

2021 ◽  
Vol 8 ◽  
Author(s):  
Julia Mentzel ◽  
Tabea Kynast ◽  
Johannes Kohlmann ◽  
Holger Kirsten ◽  
Matthias Blüher ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Metabolism ◽  
Type I Collagen ◽  
Skin Inflammation ◽  
Serum Levels ◽  
Serum Markers ◽  
Chronic Inflammatory Disease ◽  
Type I ◽  
Patient Counseling ◽  
Type I Procollagen

Psoriasis is a chronic inflammatory disease of the skin and joints. More recent data emphasize an association with dysregulated glucose and fatty acid metabolism, obesity, elevated blood pressure and cardiac disease, summarized as metabolic syndrome. TNF-α and IL-17, central players in the pathogenesis of psoriasis, are known to impair bone formation. Therefore, the relation between psoriasis and bone metabolism parameters was investigated. Two serum markers of either bone formation—N-terminal propeptide of type I procollagen (P1NP) or bone resorption—C-terminal telopeptide of type I collagen (CTX-I)—were analyzed in a cohort of patients with psoriasis vulgaris. In patients with psoriasis, P1NP serum levels were reduced compared to gender-, age-, and body mass index-matched healthy controls. CTX-I levels were indistinguishable between patients with psoriasis and controls. Consistently, induction of psoriasis-like skin inflammation in mice decreases bone volume and activity of osteoblasts. Moreover, efficient anti-psoriatic treatment improved psoriasis severity, but did not reverse decreased P1NP level suggesting that independent of efficient skin treatment psoriasis did affect bone metabolism and might favor the development of osteoporosis. Taken together, evidence is provided that bone metabolism might be affected by psoriatic inflammation, which may have consequences for future patient counseling and disease monitoring.

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