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Nature Reviews. Disease Primers Jul 2020The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and... (Review)
Review
The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and hyperextensible skin, abnormal wound healing and easy bruising. Fourteen different types of EDS are recognized, of which the molecular cause is known for 13 types. These types are caused by variants in 20 different genes, the majority of which encode the fibrillar collagen types I, III and V, modifying or processing enzymes for those proteins, and enzymes that can modify glycosaminoglycan chains of proteoglycans. For the hypermobile type of EDS, the molecular underpinnings remain unknown. As connective tissue is ubiquitously distributed throughout the body, manifestations of the different types of EDS are present, to varying degrees, in virtually every organ system. This can make these disorders particularly challenging to diagnose and manage. Management consists of a care team responsible for surveillance of major and organ-specific complications (for example, arterial aneurysm and dissection), integrated physical medicine and rehabilitation. No specific medical or genetic therapies are available for any type of EDS.
Topics: Ehlers-Danlos Syndrome; Humans; Procollagen
PubMed: 32732924
DOI: 10.1038/s41572-020-0194-9 -
Vitamin C-enriched gelatin supplementation before intermittent activity augments collagen synthesis.The American Journal of Clinical... Jan 2017Musculoskeletal injuries are the most common complaint in active populations. More than 50% of all injuries in sports can be classified as sprains, strains, ruptures, or... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Musculoskeletal injuries are the most common complaint in active populations. More than 50% of all injuries in sports can be classified as sprains, strains, ruptures, or breaks of musculoskeletal tissues. Nutritional and/or exercise interventions that increase collagen synthesis and strengthen these tissues could have an important effect on injury rates.
OBJECTIVE
This study was designed to determine whether gelatin supplementation could increase collagen synthesis.
DESIGN
Eight healthy male subjects completed a randomized, double-blinded, crossover-design study in which they consumed either 5 or 15 g of vitamin C-enriched gelatin or a placebo control. After the initial drink, blood was taken every 30 min to determine amino acid content in the blood. A larger blood sample was taken before and 1 h after consumption of gelatin for treatment of engineered ligaments. One hour after the initial supplement, the subjects completed 6 min of rope-skipping to stimulate collagen synthesis. This pattern of supplementation was repeated 3 times/d with ≥6 h between exercise bouts for 3 d. Blood was drawn before and 4, 24, 48, and 72 h after the first exercise bout for determination of amino-terminal propeptide of collagen I content.
RESULTS
Supplementation with increasing amounts of gelatin increased circulating glycine, proline, hydroxyproline, and hydroxylysine, peaking 1 h after the supplement was given. Engineered ligaments treated for 6 d with serum from samples collected before or 1 h after subjects consumed a placebo or 5 or 15 g gelatin showed increased collagen content and improved mechanics. Subjects who took 15 g gelatin 1 h before exercise showed double the amino-terminal propeptide of collagen I in their blood, indicating increased collagen synthesis.
CONCLUSION
These data suggest that adding gelatin to an intermittent exercise program improves collagen synthesis and could play a beneficial role in injury prevention and tissue repair. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12616001092482.
Topics: Adult; Amino Acids; Ascorbic Acid; Athletic Injuries; Biomechanical Phenomena; Collagen; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Exercise; Gelatin; Humans; Ligaments; Male; Peptide Fragments; Procollagen; Young Adult
PubMed: 27852613
DOI: 10.3945/ajcn.116.138594 -
Clinical Biochemistry 2022The adult bone is continuously being remodelled to repair microdamage, preserve bone strength and mechanical competence as well as maintain calcium homeostasis. Bone... (Review)
Review
The adult bone is continuously being remodelled to repair microdamage, preserve bone strength and mechanical competence as well as maintain calcium homeostasis. Bone turnover markers are products of osteoblasts (bone formation markers) and osteoclasts (bone resorption markers) providing a dynamic assessment of remodelling (turnover). Resorption-specific bone turnover markers are typically degradation products of bone collagen molecules (N- [NTX] and C-telopeptide cross-linked type 1 collagen [CTX]), which are released into the circulation and excreted in urine; or enzymatic activities reflecting osteoclastic resorption, tartrate-resistant acid phosphatase [TRACP]. Formation-specific bone turnover markers embrace different osteoblastic activities: type 1 collagen synthesis (Procollagen type I N- propeptide [PINP]), osteoblast enzymes (bone-specific alkaline phosphatase [BALP]), or bone matrix proteins [osteocalcin]. Among individuals not receiving osteoporosis treatment, resorption and formation markers are tightly linked and highly correlated (r = 0.6-0.8). Significant biological variability was reported in the past, but these issues have been greatly improved with automated assays and attention to pre-analytical and analytical factors that are known to influence bone turnover marker levels. Bone turnover markers are not useful in the diagnosis of osteoporosis, the individual prediction of bone loss, fracture, or rare complications, or in the selection of pharmacological treatment. Despite remaining issues with reference intervals and assays harmonization, bone turnover markers have proven to be useful in elucidating the pharmacodynamics and effectiveness of osteoporosis medications in clinical trials. As an alternative to BMD testing, BTMs may be useful to monitor osteoporosis therapies.
Topics: Adult; Humans; Collagen Type I; Procollagen; Peptide Fragments; Biomarkers; Osteoporosis; Bone Remodeling; Alkaline Phosphatase; Bone Density
PubMed: 36096182
DOI: 10.1016/j.clinbiochem.2022.09.002 -
British Journal of Hospital Medicine... Dec 2018Liver disease is a major cause of mortality both globally and in the UK. The earlier liver fibrosis is detected, the sooner interventions can be implemented, including... (Review)
Review
Liver disease is a major cause of mortality both globally and in the UK. The earlier liver fibrosis is detected, the sooner interventions can be implemented, including lifestyle changes and medications. Non-invasive tests for liver fibrosis are beginning to augment and replace liver biopsy in assessment of liver fibrosis because of their ease of use, lack of complications and reproducibility. The enhanced liver fibrosis (ELF) test is a blood test that measures three molecules involved in liver matrix metabolism to give a score reflecting the severity of liver fibrosis. This article reviews the evidence supporting ELF as a diagnostic test, a prognostic marker and its use in disease monitoring. In doing so it highlights the important role ELF plays in the early recognition of liver fibrosis facilitating timely referral to a liver specialist. The ELF test is useful in primary, secondary and tertiary care, not only allowing earlier diagnosis and more accurate prognosis, but also providing the opportunity to personalize treatment based on the patient's response.
Topics: Algorithms; Biomarkers; Biopsy; Disease Progression; Hematologic Tests; Humans; Hyaluronic Acid; Liver Cirrhosis; Peptide Fragments; Procollagen; Reproducibility of Results; Severity of Illness Index; Tissue Inhibitor of Metalloproteinase-1
PubMed: 30526098
DOI: 10.12968/hmed.2018.79.12.694 -
Annual Review of Biochemistry Jun 2021Collagen is the most abundant protein in mammals. A unique feature of collagen is its triple-helical structure formed by the Gly-Xaa-Yaa repeats. Three single chains of... (Review)
Review
Collagen is the most abundant protein in mammals. A unique feature of collagen is its triple-helical structure formed by the Gly-Xaa-Yaa repeats. Three single chains of procollagen make a trimer, and the triple-helical structure is then folded in the endoplasmic reticulum (ER). This unique structure is essential for collagen's functions in vivo, including imparting bone strength, allowing signal transduction, and forming basement membranes. The triple-helical structure of procollagen is stabilized by posttranslational modifications and intermolecular interactions, but collagen is labile even at normal body temperature. Heat shock protein 47 (Hsp47) is a collagen-specific molecular chaperone residing in the ER that plays a pivotal role in collagen biosynthesis and quality control of procollagen in the ER. Mutations that affect the triple-helical structure or result in loss of Hsp47 activity cause the destabilization of procollagen, which is then degraded by autophagy. In this review, we present the current state of the field regarding quality control of procollagen.
Topics: Animals; Collagen; Endoplasmic Reticulum; Fibrosis; HSP47 Heat-Shock Proteins; Humans; Hydroxylation; Molecular Chaperones; Procollagen; Proline; Protein Conformation; Protein Folding; Protein Processing, Post-Translational
PubMed: 33823651
DOI: 10.1146/annurev-biochem-013118-111603 -
Advanced Science (Weinheim,... Oct 2022Cellular response to protein misfolding underlies multiple diseases. Collagens are the most abundant vertebrate proteins, yet little is known about cellular response to...
Cellular response to protein misfolding underlies multiple diseases. Collagens are the most abundant vertebrate proteins, yet little is known about cellular response to misfolding of their procollagen precursors. Osteoblasts (OBs)-the cells that make bone-produce so much procollagen that it accounts for up to 40% of mRNAs in the cell, which is why bone bears the brunt of mutations causing procollagen misfolding in osteogenesis imperfecta (OI). The present study of a G610C mouse model of OI by multiple transcriptomic techniques provides first solid clues to how OBs respond to misfolded procollagen accumulation in the endoplasmic reticulum (ER) and how this response affects OB function. Surprisingly, misfolded procollagen escapes the quality control in the ER lumen and indirectly triggers the integrated stress response (ISR) through other cell compartments. In G610C OBs, the ISR is regulated by mitochondrial HSP70 (mt-HSP70) and ATF5 instead of their BIP and ATF4 paralogues, which normally activate and regulate ISR to secretory protein misfolding in the ER. The involvement of mt-HSP70 and ATF5 together with other transcriptomic findings suggest that mitochondria might initiate the ISR upon disruption of ER-mitochondria connections or might respond to the ISR activated by a yet unknown sensor.
Topics: Activating Transcription Factors; Animals; Endoplasmic Reticulum; HSP70 Heat-Shock Proteins; Mice; Mitochondria; Osteoblasts; Osteogenesis Imperfecta; Procollagen
PubMed: 35988140
DOI: 10.1002/advs.202201273 -
Essays in Biochemistry Sep 2019The procollagen C-propeptides of the fibrillar collagens play key roles in the intracellular assembly of procollagen molecules from their constituent polypeptides... (Review)
Review
The procollagen C-propeptides of the fibrillar collagens play key roles in the intracellular assembly of procollagen molecules from their constituent polypeptides chains, and in the extracellular assembly of collagen molecules into fibrils. Here we review recent advances in understanding the molecular mechanisms controlling C-propeptide trimerization which have revealed the importance of inter-chain disulphide bonding and a small number of charged amino acids in the stability and specificity of different types of chain association. We also show how the crystal structure of the complex between the C-propeptide trimer of procollagen III and the active fragment of procollagen C-proteinase enhancer-1 leads to a detailed model for accelerating release of the C-propeptides from procollagen by bone morphogenetic protein-1 and related proteinases. We then discuss the effects of disease-related missense mutations in the C-propeptides in relation to the sites of these mutations in the three-dimensional structure. While in general there is a good correlation between disease severity and structure-based predictions, there are notable exceptions, suggesting new interactions involving the C-propeptides yet to be characterized. Mutations affecting proteolytic release of the C-propeptides from procollagen are discussed in detail. Finally, the roles of recently discovered interaction partners for the C-propeptides are considered during fibril assembly and cross-linking.
Topics: Collagen Diseases; Disulfides; Fibrillar Collagens; Humans; Mutation; Peptide Fragments; Procollagen; Protein Multimerization; Protein Structure, Quaternary
PubMed: 31243143
DOI: 10.1042/EBC20180049 -
Journal of Clinical Densitometry : the... 2017Bone turnover markers (BTMs) provide us with a noninvasive approach to studying bone turnover and they can be measured easily and with good precision, especially using... (Review)
Review
Bone turnover markers (BTMs) provide us with a noninvasive approach to studying bone turnover and they can be measured easily and with good precision, especially using automated analyzers. BTMs increase at menopause, and these higher levels are associated with more rapid bone loss. In some but not all studies, they are also associated with greater risk of fracture. However, the evidence base for use as predictors of fracture is not robust, and so BTMs have not been included in fracture prediction models. Further research is needed, and this might include (1) use of reference analytes such as C-telopeptide of type I collagen and procollagen I N-propeptide, measured using automated analyzers in subjects in the fasting state on more than 1 occasion; (2) careful collection of vertebral fractures, which would be the primary endpoint; and (3) common approach to statistical analyses with results expressed as hazard ratio per standard deviation of increase in BTM. We believe that by improving our approach to studying the relationship between BTMs and fracture risk, any association will become clearer and that in the future we might then be able to include BTMs in our fracture prediction models.
Topics: Biomarkers; Bone Remodeling; Collagen Type I; Humans; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Peptide Fragments; Peptides; Predictive Value of Tests; Procollagen; Risk Assessment
PubMed: 28716498
DOI: 10.1016/j.jocd.2017.06.020 -
International Journal of Environmental... Oct 2018Wound healing is a complex process of recovering the forms and functions of injured tissues. The process is tightly regulated by multiple growth factors and cytokines... (Review)
Review
Wound healing is a complex process of recovering the forms and functions of injured tissues. The process is tightly regulated by multiple growth factors and cytokines released at the wound site. Any alterations that disrupt the healing processes would worsen the tissue damage and prolong repair process. Various conditions may contribute to impaired wound healing, including infections, underlying diseases and medications. Numerous studies on the potential of natural products with anti-inflammatory, antioxidant, antibacterial and pro-collagen synthesis properties as wound healing agents have been performed. Their medicinal properties can be contributed by the content of bioactive phytochemical constituents such as alkaloids, essential oils, flavonoids, tannins, saponins, and phenolic compounds in the natural products. This review highlights the in vitro, in vivo and clinical studies on wound healing promotions by the selected natural products and the mechanisms involved.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Biological Products; Humans; Mice; Procollagen; Rats; Wound Healing
PubMed: 30366427
DOI: 10.3390/ijerph15112360 -
Nature Reviews. Disease Primers Jul 2020
Topics: Ehlers-Danlos Syndrome; Humans; Procollagen
PubMed: 32733050
DOI: 10.1038/s41572-020-0206-9