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Circulation Research Feb 2024Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular aging. Sox9 (SRY-box transcription factor 9) has been implicated in...
BACKGROUND
Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular aging. Sox9 (SRY-box transcription factor 9) has been implicated in vascular smooth muscle cell (VSMC) osteo/chondrogenic conversion; however, its relationship with aging and calcification has not been studied.
METHODS
Immunohistochemistry was performed on human aortic samples from young and aged patients. Young and senescent primary human VSMCs were induced to produce ECM, and Sox9 expression was manipulated using adenoviral overexpression and depletion. ECM properties were characterized using atomic force microscopy and proteomics, and VSMC phenotype on hydrogels and the ECM were examined using confocal microscopy.
RESULTS
In vivo, Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16 (cyclin-dependent kinase inhibitor 2A). In vitro Sox9 showed mechanosensitive responses with increased expression and nuclear translocation in senescent cells and on stiff matrices. Sox9 was found to regulate ECM stiffness and organization by orchestrating changes in collagen (Col) expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs, whereby senescent cells plated on ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. LH3 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3) was identified as an Sox9 target and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles and Sox9 promotes extracellular vesicle secretion, leading to increased LH3 deposition within the ECM.
CONCLUSIONS
These findings highlight the crucial role of ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle, whereby cellular senescence and increased ECM stiffening promote Sox9 expression, which, in turn, drives further ECM modifications to further accelerate stiffening and senescence.
Topics: Aged; Humans; Aging; Cells, Cultured; Extracellular Matrix; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Vascular Calcification
PubMed: 38179698
DOI: 10.1161/CIRCRESAHA.123.323365 -
Biomedicines Aug 2023Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by a progressive decline in lung function and poor prognosis. The deposition of the... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by a progressive decline in lung function and poor prognosis. The deposition of the extracellular matrix (ECM) by myofibroblasts contributes to the stiffening of lung tissue and impaired oxygen exchange in IPF. Type I collagen is the major ECM component and predominant collagen protein deposited in chronic fibrosis, suggesting that type I collagen could be a target of drugs for fibrosis treatment. Heat shock protein 47 (HSP47), encoded by the serpin peptidase inhibitor clade H, member 1 gene, is a stress-inducible collagen-binding protein. It is an endoplasmic reticulum-resident molecular chaperone essential for the correct folding of procollagen. HSP47 expression is increased in cellular and animal models of pulmonary fibrosis and correlates with pathological manifestations in human interstitial lung diseases. Various factors affect HSP47 expression directly or indirectly in pulmonary fibrosis models. Overall, understanding the relationship between HSP47 expression and pulmonary fibrosis may contribute to the development of novel therapeutic strategies.
PubMed: 37760828
DOI: 10.3390/biomedicines11092387 -
Annals of Laboratory Medicine Mar 2024Bone-turnover marker (BTM) measurements in the blood or urine reflect the bone-remodeling rate and may be useful for studying and clinically managing metabolic bone... (Review)
Review
Bone-turnover marker (BTM) measurements in the blood or urine reflect the bone-remodeling rate and may be useful for studying and clinically managing metabolic bone diseases. Substantial evidence supporting the diagnostic use of BTMs has accumulated in recent years, together with the publication of several guidelines. Most clinical trials and observational and reference-interval studies have been performed in the Northern Hemisphere and have mainly involved Caucasian populations. This review focuses on the available data for populations from the Asia-Pacific region and offers guidance for using BTMs as diagnostic biomarkers in these populations. The procollagen I N-terminal propeptide and β-isomerized C-terminal telopeptide of type-I collagen (measured in plasma) are reference BTMs used for investigating osteoporosis in clinical settings. Premenopausal reference intervals (established for use with Asia-Pacific populations) and reference change values and treatment targets (used to monitor osteoporosis treatment) help guide the management of osteoporosis. Measuring BTMs that are not affected by renal failure, such as the bone-specific isoenzyme alkaline phosphatase and tartrate-resistant acid phosphatase 5b, may be advantageous for patients with advanced chronic kidney disease. Further studies of the use of BTMs in individuals with metabolic bone disease, coupled with the harmonization of commercial assays to provide equivalent results, will further enhance their clinical applications.
Topics: Humans; Bone Density; Osteoporosis; Alkaline Phosphatase; Asia; Biomarkers; Peptide Fragments
PubMed: 37869778
DOI: 10.3343/alm.2023.0214 -
ELife Jul 2023The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor... (Review)
Review
The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor is the oxygen-dependent enzyme PHD: hypoxia inhibits its ability to hydroxylate the transcription factor HIF, causing HIF to accumulate and trigger the classic HIF-dependent hypoxia response. A small handful of other oxygen sensors are known, all of which are oxygen-dependent enzymes. However, hundreds of oxygen-dependent enzymes exist among aerobic organisms, raising the possibility that additional sensors remain to be discovered. This review summarizes known and potential hypoxia sensors among human O-dependent enzymes and highlights their possible roles in hypoxia-related adaptation and diseases.
Topics: Humans; Hypoxia; Oxygen; Gene Expression Regulation; Transcription Factors; Procollagen-Proline Dioxygenase; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia
PubMed: 37494095
DOI: 10.7554/eLife.87705 -
Cell Reports Aug 2023Circular RNAs are generated by backsplicing and control cellular signaling and phenotypes. Pericytes stabilize capillary structures and play important roles in the...
Circular RNAs are generated by backsplicing and control cellular signaling and phenotypes. Pericytes stabilize capillary structures and play important roles in the formation and maintenance of blood vessels. Here, we characterize hypoxia-regulated circular RNAs (circRNAs) in human pericytes and show that the circular RNA of procollagen-lysine,2-oxoglutarate 5-dioxygenase-2 (circPLOD2) is induced by hypoxia and regulates pericyte functions. Silencing of circPLOD2 affects pericytes and increases proliferation, migration, and secretion of soluble angiogenic proteins, thereby enhancing endothelial migration and network capability. Transcriptional and epigenomic profiling of circPLOD2-depleted cells reveals widespread changes in gene expression and identifies the transcription factor krüppel-like factor 4 (KLF4) as a key effector of the circPLOD2-mediated changes. KLF4 depletion mimics circPLOD2 silencing, whereas KLF4 overexpression reverses the effects of circPLOD2 depletion on proliferation and endothelial-pericyte interactions. Together, these data reveal an important function of circPLOD2 in controlling pericyte proliferation and capillary formation and show that the circPLOD2-mediated regulation of KLF4 significantly contributes to the transcriptional response to hypoxia.
Topics: Humans; Hypoxia; Pericytes; RNA, Circular
PubMed: 37481725
DOI: 10.1016/j.celrep.2023.112824 -
Journal of Clinical Medicine Feb 2024Sarcopenia is a chronic, progressive skeletal muscle disease characterised by low muscle strength and quantity or quality, leading to low physical performance. Patients... (Review)
Review
Sarcopenia is a chronic, progressive skeletal muscle disease characterised by low muscle strength and quantity or quality, leading to low physical performance. Patients with type 2 diabetes mellitus (T2DM) are more at risk of sarcopenia than euglycemic individuals. Because of several shared pathways between the two diseases, sarcopenia is also a risk factor for developing T2DM in older patients. Various biomarkers are under investigation as potentially valuable for sarcopenia diagnosis and treatment monitoring. Biomarkers related to sarcopenia can be divided into markers evaluating musculoskeletal status (biomarkers specific to muscle mass, markers of the neuromuscular junction, or myokines) and markers assuming causal factors (adipokines, hormones, and inflammatory markers). This paper reviews the current knowledge about how diabetes and T2DM complications affect potential sarcopenia biomarker concentrations. This review includes markers recently proposed by the expert group of the European Society for the Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) as those that may currently be useful in phase II and III clinical trials of sarcopenia: myostatin (MSTN); follistatin (FST); irisin; brain-derived neurotrophic factor (BDNF); procollagen type III N-terminal peptide (PIIINP; P3NP); sarcopenia index (serum creatinine to serum cystatin C ratio); adiponectin; leptin; insulin-like growth factor-1 (IGF-1); dehydroepiandrosterone sulphate (DHEAS); C-reactive protein (CRP); interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). A better understanding of factors influencing these biomarkers' levels, including diabetes and diabetic complications, may lead to designing future studies and implementing results in clinical practice.
PubMed: 38398421
DOI: 10.3390/jcm13041107 -
Frontiers in Nutrition 2023The free hormone hypothesis suggests that free and bioavailable 25-hydroxyvitamin D [25(OH)D] may better reflect vitamin D bioactivity. This study aimed to determine the...
OBJECTIVE
The free hormone hypothesis suggests that free and bioavailable 25-hydroxyvitamin D [25(OH)D] may better reflect vitamin D bioactivity. This study aimed to determine the free and bioavailable 25(OH)D characteristics, estimate their thresholds based on parathyroid hormone (PTH) and bone turnover markers (BTMs), assess their associations with the risk of metabolic syndrome (MetS), and evaluate their potential advantages.
METHODS
A cross-sectional study was conducted using a nationally representative database ( = 1,505, female, 18-45 years). Serum total 25(OH)D, vitamin D-binding protein, albumin, PTH, and BTMs [osteocalcin, β-CrossLaps of type 1 collagen containing cross-linked C-telopeptide (β-CTX), and procollagen type 1 N-terminal propeptide (P1NP)] were measured. Free 25(OH)D and bioavailable 25(OH)D were calculated. The threshold associations of 25(OH)D with PTH and BTMs were analyzed. The relationship between 25(OH)D and MetS risk was examined. An intervention study was then performed in 39 women (18-47 years) to assess the associations of increasing 25(OH)D with PTH and BTMs after vitamin D supplementation.
RESULTS
In the cross-sectional study, the three forms of 25(OH)D were found to have similar distribution characteristics. Free and bioavailable 25(OH)D correlated well with total 25(OH)D. Significant total 25(OH)D cutoffs were observed for PTH (14.19 ng/mL and 18.03 ng/mL), osteocalcin (15.14 ng/mL), β-CTX (14.79 ng/mL), and P1NP (15.08 ng/mL). Free and bioavailable 25(OH)D cutoffs were only found for P1NP (3.47 pg/mL and 1.66 ng/mL, respectively). A total 25(OH)D of <15.14 ng/mL was marginally associated with a higher risk of reduced high-density lipoprotein cholesterol (HDL-C) [odd ratios (OR) = 1.371 (0.991-1.899)]. The ORs of higher versus lower free and bioavailable 25(OH)D levels for reduced HDL-C were 0.770 (0.621-0.956) and 0.772 (0.622-0.958), respectively. The results of the intervention study indicated that PTH and BTMs responded more sensitively to total 25(OH)D than to free or bioavailable 25(OH)D.
CONCLUSION
Free and bioavailable 25(OH)D only had a threshold effect on P1NP. The active 25(OH)D thresholds could be used for risk assessment of reduced HDL-C. However, no superiority of free or bioavailable 25(OH)D was found based on the response of PTH and BTMs to changes in 25(OH)D in Chinese women of childbearing age following vitamin D supplementation.
CLINICAL TRIAL REGISTRATION
http://www.chictr.org.cn, ChiCTR2200058290.
PubMed: 37736136
DOI: 10.3389/fnut.2023.1131140 -
Journal of Bone and Mineral Research :... Oct 2023Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy... (Randomized Controlled Trial)
Randomized Controlled Trial
Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy and safety of the abaloparatide microstructured transdermal system (abaloparatide-sMTS) as an alternative to the SC formulation. This phase 3, noninferiority study (NCT04064411) randomly assigned postmenopausal women with osteoporosis (N = 511) 1:1 to open-label abaloparatide administered daily via abaloparatide-sMTS or SC injection for 12 months. The primary comparison between treatment groups was the percentage change in lumbar spine bone mineral density (BMD) at 12 months, with a noninferiority margin of 2.0%. Secondary endpoints included percentage change in total hip and femoral neck BMD, bone turnover markers, dermatologic safety, and new clinical fracture incidence. At 12 months, percentage increase from baseline in lumbar spine BMD was 7.14% (SE: 0.46%) for abaloparatide-sMTS and 10.86% (SE: 0.48%) for abaloparatide-SC (treatment difference: -3.72% [95% confidence interval: -5.01%, -2.43%]). Percentage change in total hip BMD was 1.97% for abaloparatide-sMTS and 3.70% for abaloparatide-SC. Median changes from baseline at 12 months in serum procollagen type I N-terminal propeptide (s-PINP) were 52.6% for abaloparatide-sMTS and 74.5% for abaloparatide-SC. Administration site reactions were the most frequently reported adverse events (abaloparatide-sMTS, 94.4%; abaloparatide-SC, 70.5%). Incidence of serious adverse events was similar between groups. Mild or moderate skin reactions occurred with abaloparatide-sMTS with no identifiable risk factors for sensitization reactions. Few new clinical fractures occurred in either group. Noninferiority of abaloparatide-sMTS to abaloparatide-SC for percentage change in spine BMD at 12 months was not demonstrated; however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed in both treatment groups. © 2023 Radius Health, Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Female; Osteoporosis, Postmenopausal; Bone Density Conservation Agents; Postmenopause; Osteoporosis; Bone Density; Osteoporotic Fractures; Lumbar Vertebrae; Minerals
PubMed: 37417725
DOI: 10.1002/jbmr.4877