Bone turnover: Biology and assessment tools Szulc, Pawel
Best Practice & Research Clinical Endocrinology & Metabolism,
October 2018, 2018-10-00, 20181001, Letnik:
32, Številka:
5
Journal Article
Recenzirano
Bone turnover includes two processes: resorption (removal of old bone) and formation (laying down of new bone). N-terminal propeptide of type I procollagen (PINP) and C-telopeptide of type I collagen ...(CTX-I) are markers of bone formation and resorption, respectively, that the International Osteoporosis Foundation and the International Federation of Clinical Chemistry recommend for clinical use. Bone turnover markers (BTM) are subject to sources of variability, including feeding (lower resorption) and recent fracture (increased levels of all markers). Controllable patient-related factors should be adapted as much as possible (eg blood collection after an overnight fast) to minimize pre-analytical variability. Uncontrollable factors should be considered in the interpretation of the BTM measurements. BTM do not improve prediction of bone loss or fracture within an individual. In osteoporotic patients, BTM may help to assess the response to anabolic and antiresorptive therapies, to assess compliance to the treatment, or to indicate possible secondary causes of osteoporosis. BTM reflect changes in bone metabolism induced by anti-osteoporotic treatment. Anti-resorptive drugs induce a rapid dose-dependent decrease in bone resorption, whereas bone formation stimulating medications increase the levels of bone formations markers. BTM may be used for monitoring anti-osteoporosis therapy. The expected effect during the anti-resorptive therapy is to decrease the PINP by at least 10 ng/mL and to attain the target level of less than 35 ng/mL. The expected effect during the bone formation-stimulating therapy is to increase the PINP by at least 10 ng/mL and to attain the target level of more than 69 ng/mL.
With metabolic dysfunction-associated fatty liver disease (MAFLD) incidence and prevalence increasing, it is necessary to identify patients with advanced fibrosis (F3-F4 stages). We evaluated the ...performance of new biomarkers and algorithms for diagnosing advanced fibrosis in an Asian population.
Data from two Asian cohorts (including 851 biopsy-proven MAFLD 578 from Wenzhou, 273 from Hong Kong) were studied. The association between N-terminal propeptide of type 3 collagen (PRO-C3) and the histologic stage of liver fibrosis was analyzed by multivariable linear regression. The area under the receiver operating characteristic curve (AUROC) was used to test the diagnostic performance of serum PRO-C3 and the ADAPT score for advanced fibrosis and compared them to other established non-invasive tests.
Serum PRO-C3 levels increased progressively across liver fibrosis stages and correlated with advanced fibrosis (P < 0.001). The ADAPT score had an AUROC of 0.865 (95% confidence interval 0.829–0.901) for advanced fibrosis; the accuracy, sensitivity and negative predictive values were 81.4%, 82.2% and 96.1%, respectively. This result was better compared to that of PRO-C3 alone or other non-invasive fibrosis biomarkers (aspartate aminotransferase-to-platelet ratio index, Fibrosis-4, BARD, and NAFLD fibrosis score). In subgroup analyses (including sex, age, diabetes, NAFLD activity score, body mass index or serum alanine aminotransferase levels), the ADAPT score had good diagnostic performance.
PRO-C3 and the ADAPT score reliably exclude advanced fibrosis in MAFLD patients and reduce the need for liver biopsy.
•The N-terminal propeptide of type 3 collagen can be used for the staging fibrosis.•The ADAPT score has better diagnostic performance for identifying advanced fibrosis.•The ADAPT score can be used as new noninvasive tests for diagnosing advanced fibrosis.
A propeptide is removed from a precursor protein to generate its active or mature form. Propeptides play essential roles in protein folding, transportation, and activation and are present in about ...2.3% of reviewed proteins in the UniProt database. They are often found in secreted or membrane-bound proteins including proteolytic enzymes, hormones, and toxins. We identified a variety of globular and nonglobular Pfam domains in protein sequences designated as propeptides, some of which form intramolecular interactions with other domains in the mature proteins. Propeptide-containing enzymes mostly function as proteases, as they are depleted in other enzyme classes such as hydrolases acting on DNA and RNA, isomerases, and lyases. We applied AlphaFold to generate structural models for over 7000 proteins with propeptides having no less than 20 residues. Analysis of residue contacts in these models revealed conformational changes for over 300 proteins before and after the cleavage of the propeptide. Examples of conformation change occur in several classes of proteolytic enzymes in the families of subtilisins, trypsins, aspartyl proteases, and thermolysin-like metalloproteases. In most of the observed cases, cleavage of the propeptide releases the constraints imposed by the covalent bond between the propeptide and the mature protein, and cleavage enables stronger interactions between the propeptide and the mature protein. These findings suggest that post-cleavage propeptides could play critical roles in regulating the activity of mature proteins.
Summary
The National Bone Health Alliance (NBHA) recommends standardized sample handling and patient preparation for C-terminal telopeptide of type I collagen (CTX-I) and N-terminal propeptide of ...type I procollagen (PINP) measurements to reduce pre-analytical variability. Controllable and uncontrollable patient-related factors are reviewed to facilitate interpretation and minimize pre-analytical variability.
Introduction
The IOF and the International Federation of Clinical Chemistry (IFCC) Bone Marker Standards Working Group have identified PINP and CTX-I in blood to be the reference markers of bone turnover for the fracture risk prediction and monitoring of osteoporosis treatment. Although used in clinical research for many years, bone turnover markers (BTM) have not been widely adopted in clinical practice primarily due to their poor within-subject and between-lab reproducibility. The NBHA Bone Turnover Marker Project team aim to reduce pre-analytical variability of CTX-I and PINP measurements through standardized sample handling and patient preparation.
Methods
Recommendations for sample handling and patient preparations were made based on review of available publications and pragmatic considerations to reduce pre-analytical variability. Controllable and un-controllable patient-related factors were reviewed to facilitate interpretation and sample collection.
Results
Samples for CTX-I must be collected consistently in the morning hours in the fasted state. EDTA plasma is preferred for CTX-I for its greater sample stability. Sample collection conditions for PINP are less critical as PINP has minimal circadian variability and is not affected by food intake. Sample stability limits should be observed. The uncontrollable aspects (age, sex, pregnancy, immobility, recent fracture, co-morbidities, anti-osteoporotic drugs, other medications) should be considered in BTM interpretation.
Conclusion
Adopting standardized sample handling and patient preparation procedures will significantly reduce controllable pre-analytical variability. The successful adoption of such recommendations necessitates the close collaboration of various stakeholders at the global stage, including the laboratories, the medical community, the reagent manufacturers and the regulatory agencies.
Background Peripheral venous pressure (PVP) has been shown to be a reliable surrogate for right atrial pressure in assessing congestion in patients with heart failure (HF). Liver fibrosis markers and ...scores can be useful in assessing organ injury in patients with acute HF. This study aimed to investigate the association of liver fibrosis markers and scores with PVP in patients with acute HF. Methods and Results The 7S domain of the collagen type IV N-terminal propeptide (P4NP 7S), aspartate aminotransferase-to-platelet ratio index, fibrosis-4, and nonalcoholic fatty liver disease fibrosis score were determined along with PVP measurements before discharge in 229 patients with acute HF. The strongest correlation with PVP was found for P4NP 7S (Pearson
=0.40). Patients with high P4NP 7S levels (≥median 6.2 ng/mL) had an increased risk of cardiovascular death or HF hospitalization (adjusted hazard ratio HR, 1.80 95% CI, 1.09-3.04,
=0.02). The concomitant high PVP (≥mean 8 mm Hg)/high P4NP 7S group, in contrast to the high PVP/low P4NP 7S or low PVP/high P4NP 7S group, had a significant risk relative to the low PVP/low P4NP 7S group for cardiovascular death or HF hospitalization (adjusted HR, 2.63 95% CI, 1.43-5.05,
=0.002). A sustained elevation in PVP for 1 month postdischarge was associated with a persistent increase in P4NP 7S. Conclusions The study demonstrated the relationship between the liver fibrosis marker P4NP 7S and congestion. PVP and P4NP 7S could be useful for assessing congestion-related organ injury and predicting prognosis in patients with acute HF.
•The mediators of extracellular matrix deregulation downstream of Insulin-like growth factor II (IGF-II) were investigated.•Levels of pro-Lysyl Oxidase (ProLOX), its cleavage products LOX, and Lysyl ...oxidase propeptide (LOX-PP) as well as the enzymes that cleave ProLOX, Tolloid-like 1 (TLL1) isoforms and bone morphogenetic protein 1 (BMP1), increased in response to IGF-II.•LOX-PP levels were increased in human systemic sclerosis lung tissues and experimental murine lung fibrosis, and LOX-PP increased levels of markers of fibrosis by primary pulmonary fibroblasts.•The class E basic helix-loop-helix protein 40 (BHLHE40) regulates IGF-II-induced LOX-PP and TLL1 isoforms, and its deficiency increases matrix metalloprotease (MMP) 1, and restores MMP3 and cathepsin K levels repressed in response to IGF-II.•Our findings suggest that LOX-PP and BHLHE40 are new potential therapeutic targets in SSc-associated pulmonary fibrosis.
Pulmonary fibrosis (PF) is a clinically severe and commonly fatal complication of Systemic Sclerosis (SSc). Our group has previously reported profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF. We sought to identify downstream regulatory mediators of IGF-II. In the present work, we show that SSc lung tissues have higher baseline levels of the total (N-glycosylated/unglycosylated) LOX-Propeptide (LOX-PP) than control lung tissues. LOX-PP-mediated changes were consistent with the extracellular matrix (ECM) deregulation implicated in SSc-PF progression. Furthermore, Tolloid-like 1 (TLL1) and Bone Morphogenetic Protein 1 (BMP1), enzymes that can cleave ProLOX to release LOX-PP, were increased in SSc lung fibrosis and the bleomycin (BLM)-induced murine lung fibrosis model, respectively. In addition, IGF-II regulated the levels of ProLOX, active LOX, LOX-PP, BMP1, and isoforms of TLL1. The Class E Basic Helix-Loop-Helix protein 40 (BHLHE40) transcription factor localized to the nucleus in response to IGF-II. BHLHE40 silencing downregulated TLL1 isoforms and LOX-PP, and restored features of ECM deregulation triggered by IGF-II. Our findings indicate that IGF-II, BHLHE40, and LOX-PP may serve as targets of therapeutic intervention to halt SSc-PF progression.
Background Biochemical bone turnover markers (BTM) are useful tools to assess bone remodeling at the cellular level. N-terminal propeptide of type I procollagen (PINP) has been recommended as a ...reference marker for bone formation in research studies. Methods We describe the results of a multicenter study for routine clinical laboratory assays for PINP in serum and plasma. Four centers (Athens, Greece GR, Copenhagen, Denmark DK, Liege, Belgium BE and Sheffield, United Kingdom UK) collected serum and plasma (EDTA) samples from 796 patients presenting to osteoporosis clinics. Specimens were analyzed in duplicate with each of the available routine clinical laboratory methods according to the manufacturers' instructions. Passing-Bablok regressions, Bland-Altman plots, V-shape evaluation method and the concordance correlation coefficient for PINP values between serum and plasma specimens and between methods were used to determine the agreement between results. A generalized linear model was employed to identify possible variables that affected the relationship between the methods. Results We showed that both EDTA plasma and serum were suitable for PINP determination. We observed a significant proportional bias between Orion radioimmunoassay and the automated methods for PINP (Roche Cobas and IDS iSYS), which both gave very similar results. The multivariate model did not improve the excellent correlation that was observed between the methods. Conclusions Harmonization of PINP assays is possible by applying a correction factor or correctly assigning the values of the calibrators. This work will benefit from further collaboration between assays manufacturers and clinical laboratory professionals.
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