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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 -
Indian Journal of Orthopaedics Dec 2023Osteoporosis is characterized by microarchitectural disruption of the bone, decrease in bone mineral density, and increased skeletal fragility and risk of fracture.... (Review)
Review
BACKGROUND
Osteoporosis is characterized by microarchitectural disruption of the bone, decrease in bone mineral density, and increased skeletal fragility and risk of fracture. Osteoporosis occurs due to the decoupling of bone formation and bone resorption, with a significant increase in resorption. This review article focuses on the role of laboratory investigations in the diagnosis and monitoring of treatment in patients with osteoporosis.
METHODS
This review article collected literature from various databases using keywords such as 'Laboratory investigations', 'Osteoporosis', 'Diagnosis', 'Monitoring', and 'Bone turnover markers'.
RESULTS AND DISCUSSION
Laboratory investigations, including serum calcium, alkaline phosphatase, vitamin D, and parathormone, are commonly performed tests to exclude secondary causes of osteoporosis and monitor the response to therapy. The biochemical markers of bone turnover are newly emerged tests for monitoring individual patients with osteoporosis. These markers are classified as bone formation and resorption markers, measurable in both serum and urine. The use of these markers is limited by biological and analytical variability. The International Federation of Clinical Chemistry and Laboratory Medicine and the International Osteoporosis Foundation recommend serum procollagen type 1 amino-terminal propeptide as the bone formation marker and β-form of C-terminal cross-linked telopeptide of type I collagen (β-CTx-1/β-CrossLaps) as the marker of choice, using standardized procedures. However, in specific cases, such as patients with chronic renal disease, CTx-1 is replaced by the resorption marker tartrate-resistant acid phosphatase 5b, as its levels are not affected by renal excretion.
CONCLUSION
Bone turnover markers have emerged as tools for the assessment of osteoporosis, using standardized procedures, and are useful in monitoring therapy and treatment compliance.
PubMed: 38107808
DOI: 10.1007/s43465-023-01019-w -
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 -
Biochemical and Biophysical Research... Dec 2023Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent type of liver disease and a worldwide disease threatening human health. This study aims to...
PURPOSE
Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent type of liver disease and a worldwide disease threatening human health. This study aims to identify the novel diagnostic biomarkers of NAFLD by comprehensive bioinformatics and machine learning, and to validate our results in hepatocyte and animal models.
METHODS
We used Gene Expression Omnibus (GEO) databases on NAFLD patients for differential gene expression analyses. Intersections were taken with genes from the key modules of WGCNA and differentially expressed genes (DEGs). Machine learning algorithms like LASSO regression analysis, SVM-RFE, and RandomForest were used to screen hub genes. In addition, a nomogram model and calibration curves were built in order to forecast the probability of NAFLD occurrence. Then, the relationship between hub genes and immune cells was verified using Spearman analysis. Finally, we further verified the expression of key genes by constructing a steatosis hepatocyte model and animal model.
RESULTS
Key genes (INHBE and P4HA1) were identified by comprehensive bioinformatics analysis and machine learning. INHBE and P4HA1 were up-regulated and down-regulated in the steatosis hepatocyte model, respectively. Animal experiments also showed that INHBE was up-regulated in the liver of mice fed with high fat diet (HFD).
CONCLUSION
INHBE and P4HA1 are the hub genes of NAFLD. Our findings may contribute to a greater understanding of the occurrence and development of NAFLD and provide potential biomarkers and possible therapeutic targets for future clinical diagnosis and treatment.
Topics: Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; Hepatocytes; Algorithms; Biomarkers; Inhibin-beta Subunits; Procollagen-Proline Dioxygenase
PubMed: 37922570
DOI: 10.1016/j.bbrc.2023.149180 -
Cannabis and Cannabinoid Research Sep 2023Cannabidiol (CBD), a nonintoxicating cannabinoid, may be involved in bone remodeling, but human studies are limited. In this case series, we explored the effects of... (Randomized Controlled Trial)
Randomized Controlled Trial
Cannabidiol (CBD), a nonintoxicating cannabinoid, may be involved in bone remodeling, but human studies are limited. In this case series, we explored the effects of oral CBD administration on bone turnover. Two postmenopausal women with osteopenia (T-score=-1 to -2.5) were randomized to receive 100 or 300 mg CBD daily (oral, [twice per day]) for 12 weeks. Serum markers of bone resorption (carboxyl-terminal collagen crosslinks [CTx]) and bone formation (procollagen type 1 N-terminal propeptide [P1NP], bone-specific alkaline phosphatase [BSAP], and osteocalcin [OC]); safety measures; plasma concentrations of CBD and metabolites; sleep disturbance; symptoms of depression, anxiety, and stress; and quality of life, were assessed. CBD was well tolerated, with no clinically significant change in vital signs, hematology, chemistry, or urinalysis, and no adverse events reported. Reductions (% change vs. baseline) in CTx (-8.5%, -28.1%), P1NP (-9.9%, -39.5%), BSAP (-12.7%, -74.8%), and OC (-16.0%, -6.7%) were observed after 12 weeks of oral administration of 100 or 300 mg CBD daily, respectively. The two participants self-reported consuming 95.3% and 98.8% of CBD doses, respectively. CBD and select metabolites were measurable in plasma after 4 and 12 weeks of CBD treatment. No notable changes in sleep disturbance, depression, anxiety, stress, or quality of life were observed. CBD was well tolerated after 12 weeks of twice-daily oral administration and was associated with reduction in measured markers of bone turnover. Compliance with CBD treatment was good. Large-scale randomized clinical trials into the bone protective effects of CBD in postmenopausal women are warranted.
Topics: Humans; Female; Cannabidiol; Postmenopause; Quality of Life; Bone Diseases, Metabolic; Administration, Oral; Alkaline Phosphatase; Osteocalcin
PubMed: 37721991
DOI: 10.1089/can.2023.0060 -
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 -
Calcified Tissue International Aug 2023Romosozumab can increase bone mineral density (BMD) in patients with osteoporosis, but some patients do not respond to it. This study aimed to identify risk factors for... (Observational Study)
Observational Study
Romosozumab can increase bone mineral density (BMD) in patients with osteoporosis, but some patients do not respond to it. This study aimed to identify risk factors for being a nonresponder to romosozumab treatment. This retrospective observational study included 92 patients. Romosozumab (210 mg) was subcutaneously administered to the participants every 4 weeks over 12 months. We excluded patients who previously underwent treatment for osteoporosis to assess the impact of romosozumab alone. We evaluated the proportion of patients who did not respond to romosozumab treatment to the lumbar spine and hip with increased BMD. Nonresponders were defined as those with a bone density change of < 3% after 12 months of treatment. We compared demographics and biochemical markers between responders and nonresponders. We found that 11.5% of patients were nonresponders at the lumbar spine, and 56.8% were nonresponders at the hip. A risk factor for nonresponse at the spine was low type I procollagen N-terminal propeptide (P1NP) values at 1 month. The cutoff value for P1NP at month 1 was 50 ng/ml. We found that 11.5% and 56.8% of patients experienced no significant improvement in the lumbar spine and hip BMD, respectively. Clinicians should use nonresponse risk factors to inform decisions about romosozumab treatment for patients with osteoporosis.
Topics: Humans; Female; Bone Density Conservation Agents; Osteoporosis; Bone Density; Lumbar Vertebrae; Osteoporosis, Postmenopausal
PubMed: 37138124
DOI: 10.1007/s00223-023-01087-y -
ELife Jul 2023Hypoxia requires metabolic adaptations to sustain energetically demanding cellular activities. While the metabolic consequences of hypoxia have been studied extensively...
Hypoxia requires metabolic adaptations to sustain energetically demanding cellular activities. While the metabolic consequences of hypoxia have been studied extensively in cancer cell models, comparatively little is known about how primary cell metabolism responds to hypoxia. Thus, we developed metabolic flux models for human lung fibroblast and pulmonary artery smooth muscle cells proliferating in hypoxia. Unexpectedly, we found that hypoxia decreased glycolysis despite activation of hypoxia-inducible factor 1α (HIF-1α) and increased glycolytic enzyme expression. While HIF-1α activation in normoxia by prolyl hydroxylase (PHD) inhibition did increase glycolysis, hypoxia blocked this effect. Multi-omic profiling revealed distinct molecular responses to hypoxia and PHD inhibition, and suggested a critical role for MYC in modulating HIF-1α responses to hypoxia. Consistent with this hypothesis, MYC knockdown in hypoxia increased glycolysis and MYC over-expression in normoxia decreased glycolysis stimulated by PHD inhibition. These data suggest that MYC signaling in hypoxia uncouples an increase in HIF-dependent glycolytic gene transcription from glycolytic flux.
Topics: Humans; Cell Hypoxia; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lung; Procollagen-Proline Dioxygenase; Proto-Oncogene Proteins c-myc; Signal Transduction
PubMed: 37428010
DOI: 10.7554/eLife.82597