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Journal of Orthopaedic Surgery and... Mar 2024This study examines bone turnover marker (BTM) variations between bone marrow and peripheral blood in osteoporotic and non-osteoporotic patients. BTMs offer insights...
INTRODUCTION
This study examines bone turnover marker (BTM) variations between bone marrow and peripheral blood in osteoporotic and non-osteoporotic patients. BTMs offer insights into bone remodeling, crucial for understanding osteoporosis.
METHODS
A total of 133 patients were categorized into osteoporotic and non-osteoporotic cohorts. BTMs-C-telopeptide cross-linked type 1 collagen (β-CTX), serum osteocalcin (OC), Procollagen type I N-propeptide (P1NP), 25(OH)D-were measured in bone marrow and peripheral blood. Lumbar spine bone mineral density (BMD) was assessed.
RESULTS
Osteoporotic patients exhibited elevated β-CTX and OC levels in peripheral blood, indicating heightened bone resorption and turnover. β-CTX levels in osteoporotic bone marrow were significantly higher. Negative correlations were found between peripheral blood β-CTX and OC levels and lumbar spine BMD, suggesting their potential as osteoporosis severity indicators. No such correlations were observed with bone marrow markers. When analyzing postmenopausal women separately, we obtained consistent results.
CONCLUSIONS
Elevated β-CTX and OC levels in osteoporotic peripheral blood highlight their diagnostic significance. Negative β-CTX and OC-BMD correlations underscore their potential for assessing osteoporosis severity. Discrepancies between peripheral blood and bone marrow markers emphasize the need for further exploration. This research advances our understanding of BTM clinical applications in osteoporosis diagnosis and treatment.
Topics: Humans; Female; Bone Marrow; Procollagen; Biomarkers; Osteoporosis; Bone Remodeling; Osteocalcin
PubMed: 38429649
DOI: 10.1186/s13018-024-04634-x -
Communications Biology Feb 2024Pacak-Zhuang syndrome is caused by mutations in the EPAS1 gene, which encodes for one of the three hypoxia-inducible factor alpha (HIFα) paralogs HIF2α and is...
Pacak-Zhuang syndrome is caused by mutations in the EPAS1 gene, which encodes for one of the three hypoxia-inducible factor alpha (HIFα) paralogs HIF2α and is associated with defined but varied phenotypic presentations including neuroendocrine tumors and polycythemia. However, the mechanisms underlying the complex genotype-phenotype correlations remain incompletely understood. Here, we devised a quantitative method for determining the dissociation constant (K) of the HIF2α peptides containing disease-associated mutations and the catalytic domain of prolyl-hydroxylase (PHD2) using microscale thermophoresis (MST) and showed that neuroendocrine-associated Class 1 HIF2α mutants have distinctly higher K than the exclusively polycythemia-associated Class 2 HIF2α mutants. Based on the co-crystal structure of PHD2/HIF2α peptide complex at 1.8 Å resolution, we showed that the Class 1 mutated residues are localized to the critical interface between HIF2α and PHD2, adjacent to the PHD2 active catalytic site, while Class 2 mutated residues are localized to the more flexible region of HIF2α that makes less contact with PHD2. Concordantly, Class 1 mutations were found to significantly increase HIF2α-mediated transcriptional activation in cellulo compared to Class 2 counterparts. These results reveal a structural mechanism in which the strength of the interaction between HIF2α and PHD2 is at the root of the general genotype-phenotype correlations observed in Pacak-Zhuang syndrome.
Topics: Humans; Prolyl Hydroxylases; Hydroxylation; Polycythemia; Mutation; Procollagen-Proline Dioxygenase
PubMed: 38418569
DOI: 10.1038/s42003-024-05904-4 -
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 -
Biomedicines Jan 2024Bone is a common site of prostate cancer metastasis. Bone turnover markers n-terminal propeptide of type I procollagen (P1NP) and tartrate-resistant acid phosphatase...
Bone Turnover Markers, n-Terminal Propeptide of Type I Procollagen and Tartrate-Resistant Acid Phosphatase Type 5b, for Predicting Castration Resistance in Prostate Cancer.
Bone is a common site of prostate cancer metastasis. Bone turnover markers n-terminal propeptide of type I procollagen (P1NP) and tartrate-resistant acid phosphatase type 5b (TRACP-5b) are highly sensitive to bone remodeling activity. However, their prognostic significance as markers of prostate cancer is unknown. This study retrospectively examined the usefulness of P1NP and TRACP-5b as prognostic biomarkers. Castration-resistant prostate cancer recurrence-free survival (CFS) was estimated using the Kaplan-Meier method. A predictive model for CFS was constructed using multivariate analysis. This study enrolled 255 patients diagnosed with prostate cancer at Kanazawa University Hospital. The median follow-up was 115.1 months. Patients with both high serum P1NP and TRACP-5b levels, defined as having a poor bone turnover category (BTC), had significantly shorter CFS. Multivariate analysis identified Gleason score, metastasis, and BTC poor as predictors for castration resistance in prostate cancer. Using these three factors, a prognostic model was established, categorizing patients into low-risk (no or one factor) and high-risk (two or three factors) groups. In the low-risk group, the median CFS was not reached, contrasting with 19.1 months in the high-risk group (hazard ratio, 32.23, < 0.001). Combining P1NP and TRACP-5b may better predict castration resistance.
PubMed: 38397894
DOI: 10.3390/biomedicines12020292 -
International Journal of Molecular... Feb 2024The interplay between metal ion binding and the activity of thiol proteins, particularly within the protein disulfide isomerase family, remains an area of active...
The interplay between metal ion binding and the activity of thiol proteins, particularly within the protein disulfide isomerase family, remains an area of active investigation due to the critical role that these proteins play in many vital processes. This research investigates the interaction between recombinant human PDIA1 and zinc ions, focusing on the subsequent implications for PDIA1's conformational stability and enzymatic activity. Employing isothermal titration calorimetry and differential scanning calorimetry, we systematically compared the zinc binding capabilities of both oxidized and reduced forms of PDIA1 and assessed the structural consequences of this interaction. Our results demonstrate that PDIA1 can bind zinc both in reduced and oxidized states, but with significantly different stoichiometry and more pronounced conformational effects in the reduced form of PDIA1. Furthermore, zinc binding was observed to inhibit the catalytic activity of reduced-PDIA1, likely due to induced alterations in its conformation. These findings unveil a potential regulatory mechanism in PDIA1, wherein metal ion binding under reductive conditions modulates its activity. Our study highlights the potential role of zinc in regulating the catalytic function of PDIA1 through conformational modulation, suggesting a nuanced interplay between metal binding and protein stability in the broader context of cellular redox regulation.
Topics: Humans; Oxidation-Reduction; Procollagen-Proline Dioxygenase; Protein Binding; Protein Disulfide-Isomerases; Zinc
PubMed: 38396772
DOI: 10.3390/ijms25042095 -
Theranostics 2024Osteosarcoma (OS), a common malignant bone tumor, calls for the investigation of novel treatment strategies. Low-intensity vibration (LIV) presents itself as a...
Osteosarcoma (OS), a common malignant bone tumor, calls for the investigation of novel treatment strategies. Low-intensity vibration (LIV) presents itself as a promising option, given its potential to enhance bone health and decrease cancer susceptibility. This research delves into the effects of LIV on OS cells and mesenchymal stem cells (MSCs), with a primary focus on generating induced tumor-suppressing cells (iTSCs) and tumor-suppressive conditioned medium (CM). To ascertain the influence of vibration frequency, we employed numerical simulations and conducted experiments to determine the most effective LIV conditions. Subsequently, we generated iTSCs and CM through LIV exposure and assessed the impact of CM on OS cells. We also explored the underlying mechanisms of the tumor-suppressive effects of LIV-treated MSC CM, with a specific focus on vinculin (VCL). We employed cytokine array, RNA sequencing, and Western blot techniques to investigate alterations in cytokine profiles, transcriptomes, and tumor suppressor proteins. Numerical simulations validated LIV frequencies within the 10-100 Hz range. LIV induced notable morphological changes in OS cells and MSCs, confirming its dual role in inhibiting OS cell progression and promoting MSC conversion into iTSCs. Upregulated VCL expression enhanced MSC responsiveness to LIV, significantly bolstering CM's efficacy. Notably, we identified tumor suppressor proteins in LIV-treated CM, including procollagen C endopeptidase enhancer (PCOLCE), histone H4 (H4), peptidylprolyl isomerase B (PPIB), and aldolase A (ALDOA). Consistently, cytokine levels decreased significantly in LIV-treated mouse femurs, and oncogenic transcript levels were downregulated in LIV-treated OS cells. Moreover, our study demonstrated that combining LIV-treated MSC CM with chemotherapy drugs yielded additive anti-tumor effects. LIV effectively impeded the progression of OS cells and facilitated the transformation of MSCs into iTSCs. Notably, iTSC-derived CM demonstrated robust anti-tumor properties and the augmentation of MSC responsiveness to LIV via VCL. Furthermore, the enrichment of tumor suppressor proteins within LIV-treated MSC CM and the reduction of cytokines within LIV-treated isolated bone underscore the pivotal tumor-suppressive role of LIV within the bone tumor microenvironment.
Topics: Animals; Mice; Vibration; Mesenchymal Stem Cells; Osteosarcoma; Cytokines; Bone Neoplasms; Tumor Suppressor Proteins; Tumor Microenvironment
PubMed: 38389836
DOI: 10.7150/thno.90945 -
Journal of Microbiology and... Apr 2024Solar UVB irradiation cause skin photoaging by inducing the high expression of matrix metalloproteinase (MMPs) to inhibit the expression of Type1 procollagen synthesis....
Solar UVB irradiation cause skin photoaging by inducing the high expression of matrix metalloproteinase (MMPs) to inhibit the expression of Type1 procollagen synthesis. 1-Kestose, a natural trisaccharide, has been indicated to show a cytoprotective role in UVB radiation-induced-HaCaT cells. However, few studies have confirmed the anti-aging effects. In the present study, we evaluated the anti-photoaging and pathological mechanism of 1-kestose using Human keratinocytes (HaCaT) cells. The results found that 1-kestose pretreatment remarkably reduced UVB-generated reactive oxygen species (ROS) accumulation in HaCaT cells. 1-Kestose suppressed UVB radiation-induced MMPs expressions by blocking MAPK/AP-1 and NF-κB p65 translocation. 1-Kestose pretreatment increased Type 1 procollagen gene expression levels by activating TGF-β/Smad signaling pathway. Taken together, our results demonstrate that 1-kestose may serve as a potent natural trisaccharide for inflammation and photoaging prevention.
Topics: Humans; Collagen Type I; HaCaT Cells; Inflammation; Keratinocytes; Matrix Metalloproteinases; NF-kappa B; Reactive Oxygen Species; Signal Transduction; Skin; Skin Aging; Smad Proteins; Transcription Factor AP-1; Transforming Growth Factor beta; Ultraviolet Rays; Trisaccharides
PubMed: 38379292
DOI: 10.4014/jmb.2311.11020 -
Indian Journal of Endocrinology and... 2023Literature on the treatment of pre-transplant hepatic osteodystrophy (HOD) is limited. The general treatment measures and their timing are currently adopted from the...
PURPOSE
Literature on the treatment of pre-transplant hepatic osteodystrophy (HOD) is limited. The general treatment measures and their timing are currently adopted from the literature on postmenopausal osteoporosis. Therefore, we conducted this randomized study to investigate the effect of zoledronic acid (ZA) on HOD.
METHODS
We randomized 36 male patients with cirrhosis (Child-Pugh class A and B) into 19 to the ZA arm and 17 to the placebo arm, respectively. Patients in the ZA arm received a single infusion of 4 mg ZA dissolved in 100 mL of normal saline at baseline, while patients in the placebo arm received a similar infusion of normal saline at baseline. The primary outcome of the study was the change in lumbar spine bone mineral density (LS-BMD) at 12 months.
RESULTS
Of 36 patients, 28 completed the study (15 in the ZA arm and 13 in the placebo arm). The mean increase in LS-BMD (g/cm) in the ZA and placebo arms was 5.11% (3.50) and 0.72% (4.63) [ = 0.008], respectively. The trabecular bone score (TBS) did not improve significantly in either arm. The incidence of vertebral fractures (VFs) was similar in both arms. There was a significant decrease in plasma beta-C-terminal telopeptide (β-CTX) levels in the ZA arm compared to the placebo arm, while the change in plasma levels of procollagen 1 intact N-terminal propeptide (P1NP) was similar in both arms. Six patients (31.6%) in the ZA arm experienced adverse reactions such as fever and myalgia.
CONCLUSION
ZA improved LS-BMD in male patients with HOD by decreasing bone resorption. However, it may not improve trabecular microarchitecture or prevent morphometric VFs in this population.
PubMed: 38371182
DOI: 10.4103/ijem.ijem_233_23 -
Osteoarthritis and Cartilage May 2024Neutralization of Interleukin (IL)-6-signaling by antibodies is considered a promising tool for the treatment of osteoarthritis (OA). To gain further insight into this...
OBJECTIVE
Neutralization of Interleukin (IL)-6-signaling by antibodies is considered a promising tool for the treatment of osteoarthritis (OA). To gain further insight into this potential treatment, this study investigated the effects of IL-6-signaling and IL-6 neutralization on chondrocyte metabolism and the release of IL-6-signaling-related mediators by human chondrocytes.
DESIGN
Chondrocytes were collected from 49 patients with advanced knee/hip OA or femoral neck fracture. Isolated chondrocytes were stimulated with different mediators to analyze the release of IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130). The effect of IL-6 and IL-6/sIL-6R complex as well as neutralization of IL-6-signaling on the metabolism was analyzed.
RESULTS
OA chondrocytes showed high basal IL-6 production and release, which was strongly negatively correlated with the production of cartilage-matrix-proteins. Chondrocytes produced and released sIL-6R and sgp130. The IL-6/sIL-6R complex significantly increased nitric oxide, prostaglandin E and matrix metalloproteinase 1 production, decreased Pro-Collagen Type II and mitochondrial ATP production, and increased glycolysis in OA chondrocytes. Neutralization of IL-6-signaling by antibodies did not significantly affect the metabolism of OA chondrocytes, but blocking of glycoprotein 130 (gp130)-signaling by SC144 significantly reduced the basal IL-6 release.
CONCLUSION
Although IL-6 trans-signaling induced by IL-6/sIL-6R complex negatively affects OA chondrocytes, antibodies against IL-6 or IL-6R did not affect chondrocyte metabolism. Since inhibition of gp130-signaling reduced the enhanced basal release of IL-6, interfering with gp130-signaling may ameliorate OA progression because high cellular release of IL-6 correlates with reduced production of cartilage-matrix-proteins.
Topics: Humans; Chondrocytes; Cytokine Receptor gp130; Interleukin-6; Receptors, Interleukin-6; Signal Transduction
PubMed: 38369276
DOI: 10.1016/j.joca.2024.02.006 -
Animal Nutrition (Zhongguo Xu Mu Shou... Mar 2024The compromised egg quality and leg abnormality during the end of the laying cycle (after 40 weeks) have been leading to poor animal welfare and substantial economic...
The compromised egg quality and leg abnormality during the end of the laying cycle (after 40 weeks) have been leading to poor animal welfare and substantial economic losses. Therefore, the effects of fermented calcium (Ca) butyrate, produced by fermentation by , on production, eggshell quality, and tibial property of hens were explored. A total of 192 Hy-line brown laying hens at 50-week-old were assigned to a basal diet or the basal diet with 300 mg/kg of the fermented Ca butyrate from 50 to 58 weeks of age. Each treatment had 6 replicates with 16 hens each. The diet supplemented with 300 mg/kg fermented Ca butyrate notably increased egg weight, ovarian follicle number, and eggshell strength ( = 0.072) as compared to the basal diet, which were associated with cytokine secretion, toll-like receptor signaling pathways, and intestinal immunity based on the RNA-seq data from the granulosa. Dietary Ca butyrate inclusion decreased the expression of ileal tumor necrosis factor-alpha and serum pro-inflammatory cytokine concentration, as well as increased the content of serum immunoglobulin A when compared to the basal diet (both < 0.05). The birds that received fermented Ca butyrate diets exhibited higher villus height ( < 0.05) and upregulated expression of tight junction proteins, whereas it did not alter the composition of cecal microbiota ( > 0.05). In addition, the diet with fermented Ca butyrate reduced the number of osteoclasts in the proximal tibia and the level of C-terminal cross-linked telopeptide of type I collagen, a bone resorption marker ( < 0.05), whereas it tended to increase the concentration of the procollagen type I N-terminal propeptide that reflects bone formation marker in serum. Moreover, the layers fed fermented Ca butyrate diets possessed higher ( < 0.05) bone area and trabecular number of the proximal tibia, yield load, and ultimate load than those that consumed basal diets. Collectively, dietary fermented Ca butyrate supplementation in post-peak layer diets improved the ovarian function and tibia quality, which might be related to enhancing intestinal integrity and consequently decreasing inflammation mediated bone resorption.
PubMed: 38362518
DOI: 10.1016/j.aninu.2023.10.008