Procollagen Type Research Articles

Changes in Bone Metabolism in Patients with Rheumatoid Arthritis during Tumor Necrosis Factor Inhibitor Therapy.

Tumor necrosis factor alpha (TNF-α), which enhances osteoclast activity and bone resorption, is one of the key inflammation mediators in rheumatoid arthritis (RA). The aim of this study was to assess the influence of yearlong TNF-α inhibitor application on bone metabolism. The study sample comprised 50 female patients with RA. Analyses involved the osteodensitometry measurements obtained using a "Lunar" type apparatus and the following biochemical markers from serum: procollagen type 1 N-terminal propeptide (P1NP), beta crosslaps C-terminal telopeptide of collagen type I (b-CTX) by ECLIA method, total and ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone and vitamin D. Analyses revealed changes in bone mineral density (BMD) at L1-L4 and the femoral neck, with the difference in mean BMD (g/cm2) not exceeding the threshold of statistical significance (p = 0.180; p = 0.502). Upon completion of 12-month therapy, a significant increase (p < 0.001) in P1NP was observed relative to b-CTX, with mean total calcium and phosphorus values following a decreasing trend, while vitamin D levels increased. These results suggest that yearlong application of TNF inhibitors has the capacity to positively impact bone metabolism, as indicated by an increase in bone-forming markers and relatively stable BMD (g/cm2).

Abstract P101: Effect of an Intensive Lifestyle Intervention on Biomarkers of Atrial Fibrillation-Related Pathways Among Overweight Adults: The PREDIMED-PLUS Trial

Background: Lifestyles influence atrial fibrillation (AF) risk. Blood biomarkers can characterize the atrial substrate that facilitates the development of AF. Therefore, determining the effect of lifestyle interventions on blood concentrations of biomarkers of AF-related pathways could help understand AF pathophysiology and contribute to AF prevention. Methods: The PREDIMED-PLUS study is a Spanish multicenter randomized trial in adults (55-75 years) with metabolic syndrome and body mass index between 27-40 kg/m 2 . Participants were randomized 1:1 to an intensive lifestyle intervention (ILI) program, emphasizing physical activity, weight loss, and adherence to the Mediterranean diet, or a control intervention. In a sub-sample, serum biomarkers including carboxy-terminal propeptide of procollagen type I (PICP), high-sensitivity troponin T (hsTnT), high-sensitivity C reactive protein (hsCRP), N-terminal propeptide of B-type natriuretic peptide (NT-proBNP), and 3-nitrotyrosine (3-NT) were measured at baseline and years 3 and 5 after randomization. Mixed models were used to evaluate the effect of ILI on changes in biomarkers through years 3 and 5. Follow-up time was modeled as a categorical and continuous variable. Results: Of 481 participants (65 mean age, 40% female, 49% assigned to ILI), 453 (94%) and 442 (92%) had available samples at years 3 and 5. After 5 years, mean changes in log-transformed biomarkers were -0.01 (PICP), 0.20 (hsTnT), -0.17 (hsCRP), 0.12 (3-NT), and 0.25 (NT-proBNP). Participants in the ILI group experienced greater decreases in hsCRP or smaller increases in 3-NT, NT-proBNP, and in hsTnT to a lesser extent, as compared to the control group (Table). The ILI did not affect PICP concentrations. Results were consistent when modeling follow-up time as a continuous variable. Conclusion: Over five years, an ILI favorably affected concentrations of hsCRP, 3-NT, and NT-proBNP, and of hs-TnT to a lesser degree, pointing to specific mechanisms in the pathways linking lifestyles and AF.

Effect of Intravenous Iron Administration on Bone Mineral and Iron Homeostasis in Patients with Inflammatory Bowel Disease-Results of a Prospective Single-Centre Study.

Anaemia and bone metabolism alterations are common in inflammatory bowel disease (IBD), which is a heterogeneous group of diseases that include Crohn's disease (CD) and ulcerative colitis (UC) with a rich intestinal and extraintestinal symptomatology. All these make the diagnostic procedures complicated and difficult. The aim of this study was to assess the effect of parenteral iron administration on biomarkers of mineral and bone homeostasis over time. The study was a single-centre non-randomised prospective study. It was carried out between 2016 and 2020 in a group of patients in the Department of Internal Medicine and Gastroenterology Subunit of Inflammatory Bowel Diseases at the National Institute of Medicine of the Ministry of the Interior and Administration in Warsaw. At the first examination, the baseline disease severity, initial evaluation of anaemia (morphology, iron (Fe), total iron binding capacity (TIBC), ferritin, vitamin B12, folic acid) and bone mineral metabolism including C-reactive protein (CRP), albumins, alkaline phosphatase (ALP), Calcium, osteocalcin, phosphate in serum and in urine, parathyroid hormone (PTH), vitamin D3, fibroblast growth factor (iFGF23) and procollagen type 1N propeptide (P1NP) C-terminal telopeptide (CTX), was initially assessed. On the basis of peripheral blood counts, an appropriate dose of iron (iron derisomaltose or caboxymaltose) was administered. During the subsequent appointments on week 1, 4, and 12 morphology, iron (Fe), total iron binding capacity (TIBC), ferritin, vitamin B12, folic acid, C-reactive protein (CRP), albumins, alkaline phosphatase (ALP), Calcium, osteocalcin, phosphate in serum and in urine, parathyroid hormone (PTH), vitamin D3, fibroblast growth factor (iFGF23) and procollagen type 1N propeptide (P1NP) C-terminal telopeptide (CTX), were evaluated. A total of 56 patients were enrolled into the study: 24 women and 32 men. In the group, 32 patients had Crohn's disease (CD) and 24 had ulcerative colitis (UC). We found a statistically significant increase in the concentration of albumin (p = 0.031), haemoglobin (p < 0.001), haematocrit (p < 0.001), MCV (p < 0.001), MCHC (p = 0.001), iron (p < 0.001) and ferritin (p < 0.001) after the administration of parenteral iron. The influence of individual iron formulations on the analysed parameters (phosphate concentration in serum and in the urine, iFGF23, P1NP, PTH, vitamin D, haemoglobin and ferritin) was similar. Interestingly, an inverse correlation was found between the concentration of phosphorus in the blood and iFGF23 at certain time-points; however, in the study group they did not significantly affect the disturbances of calcium and phosphate metabolism. In the study group, transient and non-significant disorders of phosphate metabolism were found, which does not constitute a contraindication to treatment with parenteral iron in inflammatory bowel disease patients, which was safe and efficient.

In vitro and in vivo synergistic wound healing and anti-methicillin-resistant Staphylococcus aureus (MRSA) evaluation of liquorice-decorated silver nanoparticles.

The multi-drug resistant Staph. aureus strain, Methicillin-resistant Staphylococcus aureus (MRSA), is an emerging pathogen that could penetrate skin cuts and wounds, causing a life-threatening condition. The green biosynthesis of silver nanoparticles with liquorice extract has been demonstrated over several years for anticancer and antioxidant effects, as well as antibacterial effect against bothGram-positive and Gram-negative bacteria. The study was designed to evaluate the synergistic in vivo and in vitro wound healing and anti-MRSA activity of decorated liquorice silver nanoparticles (LD-AgNPs). The LD-AgNPs were prepared by thoroughly mixing diluted liquorice extract with AgNO3 at room temperature. The prepared nanoparticles were characterized by size measurement, IR spectroscopy, TEM imaging, and X-ray diffraction. The in vitro and in vivo antibacterial and wound healing testing were also performed. The obtained LD-AgNPs were spherical in shape and had a hydrodynamic size of about 50.16 ± 5.37 nm. Moreover, they showed potent antibacterial activity againstGram-positive and Gram-negative resistant bacteria, produced a significantly higher level of procollagen type I compared to either liquorice extract or standard silver sulfadiazine, and promoted the wound healing process in rabbits. The formulation of silver nanoparticles with liquorice extract showed synergetic effects in enhancing the treatment of wounds, with significant antibacterial activity against E. coli and MRSA.

Predictive Value of Collagen Biomarkers in Advanced Chronic Kidney Disease Patients.

Patients with chronic kidney disease have an increased risk of all-cause death. The value of collagen biomarkers such as procollagen type I carboxy-terminal propeptide (PICP) and procollagen type III N-terminal peptide (P3NP), in end-stage renal disease (ESRD), has not yet been defined (in the literature and in clinics). The purpose of this study was to determine the potential value of these new biomarkers in the prediction of mortality in this population. Plasma PICP and P3NP levels were determined in 140 patients with ESRD, not yet on dialysis, who were followed up for 36 ± 5.3 months. During follow-up, 58 deaths were recorded (41.4%), with the majority of them being cardiovascular deaths (43, 74.13%). Using the ROC curve, the cut-off value for the prediction of mortality for PICP was 297.31 µg/L, while for P3NP, the cut-off value was 126.67 µg/L. In univariate analysis, a value of PICP above the cut-off point was associated with a fivefold increased risk of mortality (hazard ratio (HR) 5.071, 95% confidence interval 1.935-13.29, p = 0.001) and a value of P3NP above the cut-off point was associated with a twofold increased risk of mortality (HR 2.089, 95% CI 1.044-4.178, p = 0.002). In a multivariable Cox proportional hazards model, PICP values remained independent predictors of mortality (HR 1.22, 95% CI 1.1-1.31, p < 0.0001). Our data suggest that the collagen biomarker PICP is an independent predictor of mortality in ESRD patients who are not yet on dialysis.

Calcium carbonate-enriched pumpkin affects calcium status in ovariectomized rats

Calcium carbonate (CaCO3)-enriched pumpkin may serve as a good source of calcium for patients diagnosed with osteoporosis. In this study, we aimed to determine the effect of CaCO3-enriched pumpkin on Ca status in ovariectomized rats. The study included 40 female Wistar rats divided into five groups (n = 8). One group was fed with a standard diet (control group), while the other four groups were ovariectomized and received a standard diet (control ovariectomized group), or a diet containing CaCO3-enriched pumpkin, alendronate, or both. The nutritional intervention lasted 12 weeks, and then the rats were euthanized. Tissue and blood samples were collected and assessed for the levels of total Ca, estradiol, parathyroid hormone, and procollagen type I N propeptide. In addition, a histological analysis was performed on femurs. The results of the study suggest that CaCO3-enriched pumpkin can increase Ca content in femurs and improve bone recovery in ovariectomized rats. Furthermore, enriched pumpkin contributes to Ca accumulation in the kidneys, and this effect is more pronounced in combination with alendronate.

Impact of Vitamin D Supplementation on the Clinical Outcomes and Epigenetic Markers in Patients with Acute Coronary Syndrome.

Vitamin D has recently been found to influence the renin-angiotensin system (RAS); it can reduce the effects of renin-angiotensin system inhibitors (RASI) by decreasing plasma renin. This study examines the effect of vitamin D supplements on cardiac fibrosis markers, echocardiographic parameters, and epigenetic markers in patients with established acute coronary syndrome (ACS). It also looks at the incidence of vitamin D receptor (VDR) gene polymorphisms Apa I (rs7975232), Bsm I (rs1544410), Taq I (rs731236), and Fok I (rs2228570) and its association with the development of secondary major acute cardiovascular events (MACE) and heart failure (HF). A randomized controlled trial in which patients were divided into two groups was performed. Group 1 comprised of 125 ACS patients who received ACS standard therapy alone, while Group 2 consisted of 125 ACS patients who received ACS standard therapy plus vitamin D according to their vitamin D levels. Patients were monitored for 24 months to find subsequent MACE and HF. Vitamin D therapy for ACS patients resulted in a substantial decline in end systolic and end diastolic volumes (p = 0.0075 and 0.002, respectively), procollagen type III N-terminal peptide (PIIINP) and soluble ST2 levels (p = 0.007 and 0.001, respectively), as well as in ejection fraction and vitamin D level (p = 0.0001 and 0.008, respectively). In addition, vitamin D treatment was linked to a significant decline in the levels of noncoding RNA, such as mir361, lncRNA MEG3, and lncRNA Chaer (p = 2.9 × 10-4, 2.2 × 10-6, and 1.2 × 10-5, respectively). Furthermore, patients who suffered MACE had significantly higher levels of the Bsm I CC and Fok I GG genotypes (p = 4.8 × 10-4 and 0.003, respectively), while patients with HF had significantly higher levels of the Taq I AA genotype (p = 4.2 × 10-7). Supplementing ACS patients with vitamin D has been demonstrated to limit cardiac fibrosis and echocardiographic parameters, as well as epigenetic markers. Additionally, MACE and HF among ACS patients may be related to genetic variations among VDR gene polymorphisms.

Replacement substance P reduces cardiac fibrosis in monkeys with type 2 diabetes

BackgroundType 2 diabetes mellitus (T2DM)-associated cardiac fibrosis contributes to heart failure. We previously showed that diabetic mice with cardiomyopathy, including cardiac fibrosis, exhibit low levels of the neuropeptide substance P; exogenous replacement of substance P reversed cardiac fibrosis, independent of body weight, blood glucose and blood pressure. We sought to elucidate the effectiveness and safety of replacement substance P to ameliorate or reverse cardiac fibrosis in type 2 diabetic monkeys. MethodsFour female T2DM African Green monkeys receive substance P (0.5 mg/Kg/day S.Q. injection) for 8 weeks. We obtained cardiac magnetic resonance imaging and blood samples to assess left ventricular function and fibrosis by T1 map-derived extracellular volume as well as circulating procollagen type I C-terminal propeptide. Hematological parameters for toxicities were also assessed in these monkeys and compared with three female T2DM monkeys receiving saline S.Q. as a safety comparison group. ResultsDiabetic monkeys receiving replacement substance P exhibited a ∼20% decrease in extracellular volume (p = 0.01), concomitant with ∼25% decrease procollagen type I C-terminal propeptide levels (p = 0.008). Left ventricular ejection fraction was unchanged with substance P (p = 0.42); however, circumferential strain was improved (p < 0.01). Complete blood counts, glycosylated hemoglobin A1c, lipids, liver and pancreatic enzymes, and inflammation markers were unchanged (p > 0.05). ConclusionsReplacement substance P reversed cardiac fibrosis in a large preclinical model of type 2 diabetes, independent of glycemic control. No hematological or organ-related toxicity was associated with replacement substance P. These results strongly support a potential application for replacement substance P as safe therapy for diabetic cardiac fibrosis.

Antisclerostin Effect on Osseointegration and Bone Remodeling.

Objective: This study reviewed the literature on local or systemic administration of antisclerostin, presenting results associated with osseointegration of dental/orthopedic implants and stimulation of bone remodeling. Materials and Methods: An extensive electronic search was conducted through MED-LINE/PubMed, PubMed Central, Web of Science databases and specific peer-reviewed journals to identify case reports, case series, randomized controlled trials, clinical trials and animal studies comparing either the systemic or local administration of antisclerostin and its effect in osseointegration and bone remodeling. Articles in English and with no restriction on period were included. Results: Twenty articles were selected for a full-text, and one was excluded. Finally, 19 articles were included in the study (16 animal studies and 3 randomized control trials). These studies were divided into two groups, which evaluated (i) osseointegration and (ii) bone remodeling potential. Initially 4560 humans and 1191 animals were identified. At least 1017 were excluded from the studies (981 humans and 36 animals), totaling 4724 subjects who completed (3579 humans and 1145 animals). (a) Osseointegration: 7 studies described this phenomenon; 4 reported bone-implant contact, which increased in all included studies. Similar results were found for bone mineral density, bone area/volume and bone thickness. (b) Bone remodeling: 13 studies were used for description. The studies reported an increase in BMD with sclerostin antibody treatment. A similar effect was found for bone mineral density/area/volume, trabecular bone and bone formation. Three biomarkers of bone formation were identified: bone-specific alkaline phosphatase (BSAP), osteocalcin and procollagen type 1 N-terminal Pro-peptide (P1NP); and markers for bone resorption were: serum C-telopeptide (sCTX), C-terminal telopeptides of type I collagen (CTX-1), β-isomer of C-terminal telopeptides of type I collagen (β-CTX) and tartrate-resistant acid phosphatase 5b (TRACP-5b). There were limitations: low number of human studies identified; high divergence in the model used (animal or human); the variance in the type of Scl-Ab and doses of administration; and the lack of reference quantitative values in the parameters analyzed by authors' studies (many articles only reported qualitative information). Conclusion: Within the limitations of this review and carefully observing all data, due to the number of articles included and the heterogeneity existing, more studies must be carried out to better evaluate the action of the antisclerostin on the osseointegration of dental implants. Otherwise, these findings can accelerate and stimulate bone remodeling and neoformation.

Empagliflozin suppressed cardiac fibrogenesis through sodium-hydrogen exchanger inhibition and modulation of the calcium homeostasis

BackgroundThe novel sodium-glucose co-transporter 2 inhibitor (SGLT2i) potentially ameliorates heart failure and reduces cardiac arrhythmia. Cardiac fibrosis plays a pivotal role in the pathophysiology of HF and atrial myopathy, but the effect of SGLT2i on fibrogenesis remains to be elucidated. This study investigated whether SGLT2i directly modulates fibroblast activities and its underlying mechanisms.Methods and resultsMigration, proliferation analyses, intracellular pH assay, intracellular inositol triphosphate (IP3) assay, Ca2+ fluorescence imaging, and Western blotting were applied to human atrial fibroblasts. Empagliflozin (an SGLT2i, 1, or 5 μmol/L) reduced migration capability and collagen type I, and III production. Compared with control cells, empagliflozin (1 μmol/L)- treated atrial fibroblasts exhibited lower endoplasmic reticulum (ER) Ca2+ leakage, Ca2+ entry, inositol trisphosphate (IP3), lower expression of phosphorylated phospholipase C (PLC), and lower intracellular pH. In the presence of cariporide (an Na+-H+ exchanger (NHE) inhibitor, 10 μmol/L), control and empagliflozin (1 μmol/L)-treated atrial fibroblasts revealed similar intracellular pH, ER Ca2+ leakage, Ca2+ entry, phosphorylated PLC, pro-collagen type I, type III protein expression, and migration capability. Moreover, empagliflozin (10 mg/kg/day orally for 28 consecutive days) significantly increased left ventricle systolic function, ß-hydroxybutyrate and decreased atrial fibrosis, in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats.ConclusionsBy inhibiting NHE, empagliflozin decreases the expression of phosphorylated PLC and IP3 production, thereby reducing ER Ca2+ release, extracellular Ca2+ entry and the profibrotic activities of atrial fibroblasts.

Spironolactone effect on circulating procollagen type I carboxy-terminal propeptide: Pooled analysis of three randomized trials

BackgroundSpironolactone might improve the prognosis of patients with heart failure with preserved left ventricular ejection fraction (HFpEF), but the mechanisms by which it acts are uncertain. Serum concentrations of procollagen type I carboxy-terminal propeptide (PICP) reflect the synthesis of type I collagen and correlate well with histologically proven cardiac fibrosis. AimsTo investigate the effect of spironolactone on serum PICP concentration in patients with stage B and C HFpEF across three trials (HOMAGE, ALDO-DHF, and TOPCAT) for which measurements of serum PICP were available. MethodsRandom-effects meta-analysis. ResultsA total of 1038 patients with PICP measurements available both at baseline and 9–12 months were included in this analysis: 488 (47.0%) from HOMAGE, 386 (37.2%) from ALDO-DHF, and 164 (15.8%) from TOPCAT. The median (percentile25–75) serum PICP was 98 (76–128) ng/mL. Compared to placebo or usual care, administration of spironolactone for 9 to 12 months reduced serum PICP by −7.4 ng/mL, 95%CI -13.9 to −0.9, P-value =0.02. The effect was moderately heterogeneous (I2 = 64%) with the most pronounced effect seen in TOPCAT where PICP was reduced by −27.0 ng/mL, followed by HOMAGE where PICP was reduced by −8.1 ng/mL, and was least marked in ALDO-DHF where PICP changed by −2.9 ng/mL. The association between spironolactone and serum PICP was not mediated substantially by blood pressure. ConclusionsSpironolactone reduced serum concentrations of PICP in patients with HFpEF with different severity and stages of disease. These findings are consistent with spironolactone having an anti-fibrotic effect.

Associations Between Inflammatory Mediators and Bone Outcomes in Postmenopausal Women: A Cross-Sectional Analysis of Baseline Data from the Prune Study.

Hypoestrogenism triggers increased production of inflammatory mediators, which contribute to bone loss during postmenopausal osteoporosis. This study aimed to investigate the association between circulating inflammatory markers and bone outcomes in postmenopausal women. We conducted a cross-sectional, secondary analysis of baseline data from participants who completed a 12-month randomized controlled trial, The Prune Study (NCT02822378), which included healthy postmenopausal women (n=183, 55-75 years old) with bone mineral density (BMD) T-score between 0.0 and -3.0 at any site. BMD was measured using dual-energy X-ray absorptiometry, and bone geometry and strength were measured using peripheral quantitative computed tomography. Blood was collected at baseline to measure (1) serum biomarkers of bone turnover, including procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide and (2) inflammatory markers, including serum high-sensitivity C-reactive protein (hs-CRP) and plasma pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1, using enzyme-linked immunosorbent assay. The associations between bone and inflammatory outcomes at baseline were analyzed using correlation and regression analyses. Serum hs-CRP negatively correlated with P1NP (r=-0.197, p=0.042). Plasma IL-1β, IL-6, IL-8, and TNF-α negatively correlated with trabecular bone score at the lumbar spine (all p<0.05). In normal-weight women, plasma IL-1β, IL-6, and IL-8 negatively correlated (p<0.05) with trabecular and cortical bone area, content, and density at various sites in the tibia and radius. Serum hs-CRP positively predicted lumbar spine BMD (β=0.078, p=0.028). Plasma IL-6 negatively predicted BMD at the total body (β=-0.131, p=0.027) and lumbar spine (β=-0.151, p=0.036), whereas plasma TNF-α negatively predicted total hip BMD (β=-0.114, p=0.028). At baseline, inflammatory markers were inversely associated with various estimates of bone density, geometry, and strength in postmenopausal women. These findings suggest that inflammatory markers may be an important mediator for postmenopausal bone loss.

Anti-Photoaging Effect of Phaseolus angularis L. Extract on UVB-Exposed HaCaT Keratinocytes and Possibilities as Cosmetic Materials.

Phaseolus angularis L. is widely cultivated and is considered a superfood because of its nutritious protein and starch contents. Nevertheless, P. angularis's effects on skin photoaging are unknown. The aim of this study was to research the effects of P. angularis seed extract (PASE) on photoaging in human keratinocytes (HaCaT) damaged by UVB radiation so as to find out whether PASE can be used as an effective anti-photoaging ingredient in cosmetic products. The antioxidant activities were assessed using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) radical scavenging, and reactive oxygen species (ROS) assays. Enzyme-linked immunosorbent assay (ELISA) analysis was used to determine the change in matrix metalloproteinase (MMP)-1, and MMP-3. The protein levels of mitogen-activated protein kinase (MAPK)/activator protein (AP)-1, transforming growth factor beta (TGF)-β/suppressor of mothers against decapentaplegic (Smad), and NF-E2-related factor (Nrf)2/antioxidant response element (ARE) were measured by western blot. As a result, PASE increased DPPH and ABTS antioxidant activities in a dose-dependent manner. Additionally, PASE treatment (100 µg/mL) significantly reverted the damage induced by UVB (125 mJ/cm2) irradiation by downregulating ROS, matrix metalloproteinase (MMP)-1, and MMP-3 secretion and expression and increasing procollagen type I production. To suppress MMP-1 and MMP-3 secretion, PASE significantly decreased UVB-induced p38 and JNK phosphorylation and phosphorylated c-Fos and c-Jun nuclear translocation. PASE promoted collagen I production by inhibiting UVB-induced TGF-β activation and Smad7 overexpression; antioxidant properties also arose from the stimulation of the Nrf2-dependent expression of the antioxidant enzymes heme oxygenase (HO)-1 and quinone oxidoreductase (NQO)-1. Our data demonstrated that PASE has the potential to prevent ROS formation induced by UVB exposure by targeting specific pathways. Thus, PASE might be a potent anti-photoaging component to exploit in developing anti-aging products.

Determinition of Bone Strength by Using Procollagen Type 1 N-Terminal Propeptide (P1NP) as a Predictive Marker in Native Population of Pakistan.

Due to better health facilities, food and living facilities the life expectancy is increasing which is leading towards Osteopenia and Osteoporosis in the whole world. Despites of its prevalence it is ignored in Pakistan due to which it is causing a burden on Pakistan economy. It is therefore necessary to find some suitable methods for the quick identification of the problems so that people will be safe from the cost of treatment of the fractured bones and they are treated before going to worse situation. Vigorous physical activity in adults have a great impact bone mass and bone turnover. The effects of moderate activity (physical) remain tentative. Bone formation marker propertied of type 1 Procollagen (P1NP) is related to physical activity and its levels. The relationship between P1NP and physical activity remained significant after the adjustment of data by two factors, age and BMI (body mass index). In Pakistan, use of P1NP for the early identification of bone strength is not implemented yet.

Low Bone Turnover Associates With Lower Insulin Sensitivity in Newly Diagnosed Drug-Naïve Persons With Type 2 Diabetes.

Bone turnover markers (BTMs) are lower in type 2 diabetes mellitus (T2D). The relationships between bone turnover, β-cell function, and insulin sensitivity in T2D are uncertain. To investigate if fasting levels of BTMs in persons with T2D are associated with β-cell function or insulin sensitivity. We defined three T2D phenotypes, the insulinopenic (low β-cell function, high insulin sensitivity), the classical (low β-cell function, low insulin sensitivity), and the hyperinsulinemic (high β-cell function, low insulin sensitivity) phenotypes, in the Danish Centre for Strategic Research T2D cohort using the homeostatic model assessment. We selected age- and gender-matched subgroups to represent the three T2D phenotypes, yielding 326 glucose-lowering treatment-naïve persons with T2D. Median values of BTMs between the three T2D phenotypes were compared. Regression models were applied to assess the association between BTMs, β-cell function, and insulin sensitivity adjusted for potential confounders. Median serum levels of procollagen type I N-terminal propeptide, C-terminal telopeptide of type I collagen, and osteocalcin were higher in the insulinopenic phenotype (52.3 μg/L, IQR 41.6, 63.3; 259.4 ng/L, IQR 163.4, 347.7; and 18.0 μg/L, IQR 14.4, 25.2, respectively) compared with the classical (41.4, IQR 31.0, 51.4; 150.4 IQR 103.5, 265.1; 13.1, IQR 10.0, 17.6, respectively) and the hyperinsulinemic (43.7, IQR 32.3, 57.3; 163.3, IQR 98.9, 273.1; 15.7 IQR 10.2, 20.8, respectively) phenotypes (all P < .01). These differences persisted after adjustment for age, sex, waist to hip ratio, or fasting plasma glucose (P < .01). BTMs are lower in newly diagnosed persons with T2D characterized by low insulin sensitivity.

Sequential treatment of teriparatide and alendronate versus alendronate alone for elevation of bone mineral density and prevention of refracture after percutaneous vertebroplasty in osteoporosis: a prospective study

BackgroundPercutaneous vertebroplasty was the most common strategy for osteoporotic vertebral compression fracture. However, refracture after vertebroplasty also occurred and bone mineral density (BMD) was one of the main factors associated with refracture after percutaneous vertebroplasty.AimsTo investigate the efficacy of a short-sequential treatment of teriparatide followed by alendronate on prevention of refracture after percutaneous vertebroplasty in osteoporotic patients, and compare it with the therapy of alendronate alone.MethodsFrom January 2018 to January 2020, we recruited 165 female osteoporosis patients after percutaneous vertebroplasty who were assigned into sequential treatment of teriparatide followed by alendronate group (TPTD + ALN group) and alendronate alone group (ALN group). The vertebral fracture occurred during this process was also recorded in both the groups. A total of 105 participants completed the 1-year follow-up. Furthermore, BMD and serum procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were compared between the two groups during 1-year follow-up.ResultsThe 105 patients were finally included, with 59 in ALN group and 46 in TPTD + ALN group. During 1-year follow-up, the vertebral refracture rate in TPTD + ALN group was much lower than that in ALN group (2.2% vs. 13.6%, p < 0.05). At 12 months, the BMDs at lumbar in TPTD + ALN group were significantly elevated when compared to the ALN group (0.65 ± 0.10 vs. 0.57 ± 0.07, p < 0.001).Discussion and conclusionA short-sequential administration of teriparatide followed by alendronate was more effective in elevating the BMD and decreasing the refracture rate at 12-month follow-up, compared to the counterpart with alendronate alone.

340 Dupilumab treatment of children with moderate-to-severe atopic dermatitis increases bone alkaline phosphatase, a marker of bone mineralization

Abstract Children with atopic dermatitis (AD) are at risk for low bone mineral density (BMD), which is associated with an increased prevalence of osteopenia, osteoporosis, and fracture risk.1,2 Factors such as restricted nutrition, vitamin D deficiency, poor sleep and corticosteroid use contribute to lower bone alkaline phosphatase (BALP) levels, a marker of bone mineralization, seen in children with moderate-to-severe AD compared with healthy children.3 A major determinant for the lifetime risk of fractures and osteoporosis is the magnitude of peak bone mass achieved during prepubescent years. Low BALP and BMD in children with moderate-to-severe AD could contribute to a higher prevalence of osteopenia and osteoporosis. The objective of this analysis is to report the impact of dupilumab treatment on markers of bone formation in children aged ≥ 6 to &amp;lt; 12 years with moderate-to-severe AD. The analysis was performed retrospectively on sera from participants in LIBERTY AD PEDS (NCT03345914) and LIBERTY AD PED-OLE (NCT02612454). In LIBERTY AD PEDS, a double-blind, 16-week, phase 3 trial, children aged 6 to &amp;lt; 12 years were randomized 1 : 1 : 1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w for patients with baseline weight &amp;lt;30 kg, and 200 mg q2w for those with baseline weight ≥30 kg), or placebo; with concomitant medium-potency topical corticosteroids (TCS). After the initial 16-week trial, children aged 6 to &amp;lt;12 years were enrolled in the open-label extension study LIBERTY AD PED-OLE. Patients received dupilumab 300 mg q4w, which could be titrated up in case of inadequate clinical response at week 16 (200 mg q2w for patients with baseline weight &amp;lt;60 kg, and 300 mg q2w for those with baseline weight ≥60 kg); with concomitant medium-potency TCS. Bone biomarkers including BALP, procollagen type 1 N-terminal propeptide, C-terminal crosslinking telopeptide of type 1 collagen, osteocalcin, and insulin-like growth factor 1 were analysed at baseline, 8, 12, 16 and BALP only at 52 weeks. Dupilumab treatment led to a rapid and significant increase in geometric mean (standard error) levels of BALP in children with moderate-to-severe AD at 16 weeks compared with patients in the placebo group (77.7(1.02) μgL−1 vs. 65.0(1.04) μgL−1; P &amp;lt; 0.0001). As well as a rapid and significant increase in BALP levels in children from the placebo group once they joined the OLE trial. BALP levels increased over 52 weeks in all treated children, reaching a level of 78–84 μgL−1 which constitutes a significant improvement compared with baseline, and is comparable to healthy reference intervals. An increasing trend from baseline to 16 weeks of dupilumab treatment was observed for other biomarkers, however, there was a limited number of data points due to insufficient volumes of serum available for analysis. These placebo-controlled results show, for the first time, a rapid and significant increase in BALP, and a possible trend in other biomarkers, in children with AD during treatment with dupilumab. These results suggest increased bone mineralization during the treatment period.

Stiff substrates inhibit collagen accumulation via integrin α2β1, FAK and Src kinases in human atrial fibroblast and myofibroblast cultures derived from patients with aortal stenosis

The aim of the study was to confirm whether cell substrate stiffness may participate in the regulation of fibrosis. The involvement of integrin α2β1, focal adhesion kinase (FAK) and Src kinase in signal transmission was investigated. Human atrial fibroblasts and myofibroblasts were cultured in both soft (2.23 ± 0.8 kPa) and stiff (8.28 ± 1.06 kPa) polyacrylamide gels. The cells were derived from the right atrium of patients with aortal stenosis undergoing surgery. The isolated cells, identified as fibroblasts or myofibroblasts, were stained positively with α smooth muscle actin, vimentin and desmin. The cultures settled on stiff gel demonstrated lower intracellular collagen and collagen type I telopeptide (PICP) levels; however, no changes in α1 chain of procollagen type I and III expression were noted. Inhibition of α2β1 integrin by TC-I 15 (10−7 and 10−8 M) or α2 integrin subunit silencing augmented intracellular collagen level. Moreover, FAK or Src kinase inhibitors increased collagen content within the culture. Lower TIMP4 secretion was reported within the stiff gel cultures but neither MMP 2 nor TIMP-1, 2 or 3 release was altered. The stiff substrate cultures also demonstrated lower interleukin-6 release. Substrate stiffness modified collagen deposition within the atrial fibroblast and myofibroblast cultures. The elasticity of the cellular environment exerts a regulatory influence on both synthesis and breakdown of collagen. Integrin α2β1, FAK and Src kinase activity participates in signal transmission, which may influence fibrosis in the atria of the human heart.

G‑CSF delays tooth extraction socket bone healing via the inhibition of bone turnover in mice.

Granulocyte colony-stimulating factor (G-CSF) regulates the survival, proliferation and differentiation of all cells in the neutrophil lineage, and is consequently used for neutropenic conditions. Upon G-CSF administration, osteoblasts and osteocytes are suppressed, and the support system allowing hematopoietic stem cells to remain in the microenvironment is diminished. The present study focused on and investigated G-CSF as a regulatory factor of bone remodeling. The aim of the present study was to investigate the effect of G-CSF administration on the bone healing of tooth extraction sockets. Significant differences in the bone volume fraction, and trabecular separation of the proximal femurs and alveolar septa were observed between the G-CSF and control (saline-treated) groups. The trabecular bone of the femur and alveolar septa was reduced in the G-CSF group compared with that in the control group. In addition, serum procollagen type 1 N-terminal propeptide levels, a marker of bone formation, were lower in the G-CSF group compared with in the control group. Fibrous connective tissues and immature bone were observed in the extraction socket, and bone healing was delayed in the G-CSF group compared with that in the control group. The bone area in the extraction socket 6 days after tooth extraction was significantly smaller in the G-CSF group (23.6%) than that in the control group (45.1%). Furthermore, G-CSF administration reduced the number of canaliculi per osteocyte and inhibited the connection of osteocyte networks. Consequently, osteoblast activation was inhibited and bone remodeling changed to a state of low bone turnover in the G-CSG group. Analysis of bone formation parameters revealed that the G-CSF group exhibited a lower mineral apposition rate compared with in the control group. In conclusion, these findings indicated that G-CSF may delay bone healing of the socket after tooth extraction.

Biophotonic Effects of Low-Level Laser Therapy on Adipose-Derived Stem Cells for Soft Tissue Deficiency.

The objectives of this study are to use diode lasers for low-level laser therapy (LLLT) and to assess its applicability and effects in adipose-derived stem cell (ADSC) growth processes. Studies were conducted on the diode laser with wavelengths of 622.7, 527.1, and 467.3 nm. The mechanism of action of LLL illumination was studied on ADSCs, isolated from human tissue, and then cultured by examining different wavelengths to determine the relevant light parameters for optimal responses. We used enzyme-linked immunosorbent assay and real-time polymerase chain to determine the percentages of fibroblast-mediated procollagen type 1 and matrix metallopeptidase 1 (MMP-1), MMP-2, and MMP-9 production at different wavelengths. The levels of lactate dehydrogenase produced by ADSCs after LLL illumination were assessed as well. Clinical results from 20 patients treated for soft tissue deficiency were collected for assessment of ADSC-assisted lipotransfer. Low-level laser (622.7 nm) illumination on cell cultures in vitro increased ADSCs proliferation, type 1 procollagen expression, collagen production, as well as MMP-1, MMP-2, and MMP-9 relative expression. Statistical analysis demonstrated a significant difference in red light (622.7 nm) versus green light (527.1 nm) and blue light (467.3 nm, P < 0.05). No significant differences were noted between the effects of green and blue lights. In clinical application, all patients attained significant improvement with treatment in the final outcome assessment after 6 months. Low-level laser illumination may affect ADSCs growth processes and ADSC-assisted lipotransfer for soft tissue deformity, scar treatment, wound healing, and other reconstructive surgery.