Age-related trends and reference intervals of cross-linked C-telopeptide of type I collagen and procollagen type I N-propeptide from a reference population of Sri Lankan adult women

It is well established that multinucleation is central for osteoclastic bone resorption. However, our knowledge on the mechanisms regulating how many nuclei an osteoclast will have is limited. The objective of this study was to investigate donor-related variations in the fusion potential of in vitro-generated osteoclasts. Therefore, CD14+ monocytes were isolated from 49 healthy female donors. Donor demographics were compared to the in vivo bone biomarker levels and their monocytes’ ability to differentiate into osteoclasts, showing that: (1) C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels increase with age, (2) the number of nuclei per osteoclast in vitro increases with age, and (3) there is a positive correlation between the number of nuclei per osteoclast in vitro and CTX levels in vivo. Furthermore, the expression levels of the gene encoding dendritic cell-specific transmembrane protein (DCSTAMP) of osteoclasts in vitro correlated positively with the number of nuclei per osteoclast, CTX levels in vivo, and donor age. Our results furthermore suggest that these changes in gene expression may be mediated through age-related changes in DNA methylation levels. We conclude that both intrinsic factors and age-induced increase in fusion potential of osteoclasts could be contributing factors for the enhanced bone resorption in vivo, possibly caused by increased expression levels of DCSTAMP.

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Acute Changes of Bone Turnover and PTH Induced by Insulin and Glucose: Euglycemic and Hypoglycemic Hyperinsulinemic Clamp Studies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.7.8660 ◽

2002 ◽

Vol 87 (7) ◽

pp. 3324-3329 ◽

Cited By ~ 44

Author(s):

Jackie A. Clowes ◽

Robert T. Robinson ◽

Simon R. Heller ◽

Richard Eastell ◽

Aubrey Blumsohn

Keyword(s):

Bone Turnover ◽

Type I Collagen ◽

Oral Glucose ◽

Type I ◽

Double Blind ◽

Euglycemic Clamp ◽

Procollagen Type ◽

Procollagen Type I ◽

Significant Change ◽

Acute Changes

Bone turnover is acutely suppressed after feeding or oral glucose. Insulin infusion suppresses bone turnover and might mediate this effect, but this is confounded by a possible direct effect of hypoglycemia. We examined the effect of euglycemic hyperinsulinemia and hypoglycemic hyperinsulinemia on bone turnover using an insulin clamp. Sixteen men participated in this double-blind crossover study. Clamp induction involved infusion of insulin (80 mU/m2·min) while maintaining euglycemia (5 mmol/liter) for 40 min with a variable rate dextrose infusion. Glucose was lowered to 2.5 mmol/liter (hypoglycemic clamp) or maintained at 5 mmol/liter (euglycemic clamp) for a further 105 min. Nine controls received a matched saline infusion. Measurements included serum C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide, osteocalcin, and PTH. Induction of hyperinsulinemia resulted in a reduction in PTH (27% ± 5; P < 0.01), but no significant change in bone turnover from baseline. Hypoglycemic clamp resulted in suppression of serum C-terminal telopeptide of type I collagen by 34% ± 3, procollagen type I N-terminal propeptide by 15% ± 1, osteocalcin by 5% ± 1, and PTH by a further 12% ± 5 (all P < 0.05). By contrast, there was no significant change in any marker of bone turnover during euglycemic clamp. Postprandial hyperinsulinemia is unlikely to explain the acute suppression of bone turnover with feeding. The reduction in bone turnover during hypoglycemia may be related to hypoglycemia itself, acute changes in PTH, or other hormones released in response to hypoglycemia.

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Molecular and Histological Evidence Detailing Clinically Observed Skin Improvement Following Cryolipolysis

Aesthetic Surgery Journal ◽

10.1093/asj/sjab226 ◽

2021 ◽

Author(s):

W Grant Stevens ◽

Daniel J Gould ◽

Linda D Pham ◽

Joel N Jimenez Lozano

Keyword(s):

Gene Expression ◽

Transforming Growth Factor Beta ◽

Type I Collagen ◽

Transforming Growth Factor ◽

Body Contouring ◽

Fold Increase ◽

Type I ◽

Gene Markers ◽

Procollagen Type ◽

Procollagen Type I

Abstract Background In addition to body contouring, there is anecdotal and supportive clinical evidence of reduced laxity and skin tightening after cryolipolysis. 10,11 Objectives The nature by which cryolipolysis triggers dermal changes has not been established. This study investigated fundamental mechanisms behind clinically observed dermal changes using molecular and immunohistochemistry methods. Methods This feasibility study involved n=7 subjects that received cryolipolysis treatment. Tissue samples were harvested from 3 days to 5 weeks after treatment. RNA-Sequencing examined differential gene expression of major collagens. RNA In Situ Hybridization (RNA-ISH) investigated the distribution of one of the gene markers for collagen Type I (COL1A1). Immunohistochemistry for Procollagen Type I, heat shock protein 47 (HSP47), transforming growth factor beta (TGF-β and Tropoelastin was performed and quantified. Results Gene expression analysis highlighted a gradual upregulation of collagen mRNA genes. RNA-ISH confirmed upregulation of COL1A1 mRNA and showed a homogenous distribution through the dermis. Immunohistochemistry showed increases in protein expression. Quantification revealed 3.62-fold increase of Procollagen Type I (p<0.0071) and 2.91-fold increase of TGF-β (p<0.041); 1.54-fold increase of HSP47 (p<0.007); and 1.57-fold increase of Tropoelastin (p<0.39) compared to untreated areas. Conclusions This study revealed significant induction of molecular and protein markers of Type I collagen, which supports neocollagenesis and may play an essential role in clinically relevant skin improvement. A dermal remodeling process driven by increased TGF-β and higher expression of HSP47 was observed. Overall, these data provide the first evidence of dermal remodeling and clarify the mechanism by which cryolipolysis may induce skin improvement.

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In Vitro Synthesis of Type I Collagen: Quantification of Carboxyterminal Propeptide of Procollagen Type I versus Tritiated Proline Incorporation

Calcified Tissue International ◽

10.1007/s002239900607 ◽

1999 ◽

Vol 64 (3) ◽

pp. 224-228 ◽

Cited By ~ 7

Author(s):

M. Nacher ◽

S. Serrano ◽

M. L. Mariñoso ◽

M. C. García ◽

J. Bosch ◽

...

Keyword(s):

Type I Collagen ◽

Type I ◽

In Vitro Synthesis ◽

Procollagen Type ◽

Proline Incorporation ◽

Procollagen Type I

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Serum levels of procollagen type I carboxyterminal extension peptide in cancer patients with bone metastases

The International Journal of Biological Markers ◽

10.1177/172460089501000207 ◽

1995 ◽

Vol 10 (2) ◽

pp. 107-112 ◽

Cited By ~ 3

Author(s):

I. Santi ◽

M. Monti ◽

A. Viganò ◽

E. D'aprile ◽

E. Rampoldi ◽

...

Keyword(s):

Bone Metastases ◽

Cancer Patients ◽

Type I Collagen ◽

Statistical Significance ◽

Bone Matrix ◽

Serum Levels ◽

Tartrate Resistant Acid Phosphatase ◽

Type I ◽

Procollagen Type ◽

Procollagen Type I

Serum levels of procollagen type I carboxy-terminal extension peptide (PICP) reflect the synthesis of type I collagen. As PICP is produced by osteoblasts and is not incorporated into bone matrix, serum PICP levels have been suggested as a marker of bone formation. In 37 cancer patients (21 men and 16 women; age: 72.4±8.6 (mean±SD) years) with bone metastases and 23 women (age: 77.3+6.64 years) as controls, the following biochemical variables were measured: serum PICP, calcium (Ca), phosphorus, alkaline phosphatase (AP) and tartrate-resistant acid phosphatase (TRAP), and urinary hydroxyproline and calcium corrected for creatinine excretion. Higher serum levels of PICP were observed in cancer patients than in controls (245±177 μg/l vs 121.7±36 μg/l, p<0.01). Cancer patients also had higher AP levels than controls (704±755 U/l vs 216.5±56 U/l, p<0.01). Abnormal PICP and AP serum concentrations (above the mean+2SD of controls) were found in 46% and 51% of patients, respectively. Moreover, patients showed significantly lower serum calcium concentrations (p<0.001), and higher TRAP and hydroxyproline levels although statistical significance was not reached. In the patients, PICP was correlated directly with AP (r=0.50, p<0.01) and TRAP (r=0.34, p<0.05). In conclusion, patients with bone metastases have increased bone turnover as shown by serum markers. Serum PICP may be used as an adjunctive, non-invasive index to assess bone metabolism. However, the clinical usefulness of PICP in cancer patients needs further evaluation.

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Octreotide Abolishes the Acute Decrease in Bone Turnover in Response to Oral Glucose

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-021447 ◽

2003 ◽

Vol 88 (10) ◽

pp. 4867-4873 ◽

Cited By ~ 64

Author(s):

Jackie A. Clowes ◽

Heather C. Allen ◽

Donna M. Prentis ◽

Richard Eastell ◽

Aubrey Blumsohn

Keyword(s):

Bone Turnover ◽

Bone Turnover Markers ◽

Type I Collagen ◽

Gastrointestinal Hormones ◽

Oral Glucose ◽

Type I ◽

Procollagen Type ◽

Procollagen Type I ◽

Turnover Markers

Abstract Feeding or oral intake of glucose results in an acute suppression of bone turnover. This does not appear to be mediated by insulin. Several gastrointestinal hormones modulate bone turnover in vitro and may mediate this response. We examined whether inhibiting the production of gastrointestinal hormones using octreotide could block glucose-mediated suppression of bone turnover. Fifteen subjects were each studied on four occasions in a randomized, single-blind, crossover study after receiving 1) oral placebo, iv saline; 2) oral glucose, iv saline; 3) oral glucose, iv octreotide; or 4) iv octreotide alone. We measured serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen, osteocalcin, procollagen type I N-terminal propeptide, PTH, insulin, ionized calcium, and glucose over 4 h. All bone turnover markers decreased significantly after oral glucose (P < 0.001). At 120 min serum C-terminal telopeptide decreased by 45 ± 2%, urinary N-terminal telopeptide by 31 ± 7%, osteocalcin by 16 ± 1%, and procollagen type I N-terminal propeptide by 8 ± 1%. There was no significant decrease in bone turnover in response to oral glucose during octreotide infusion. Octreotide alone resulted in a significant increase in all bone turnover markers (P < 0.05) and PTH (P < 0.01). We conclude that octreotide completely abolishes the bone turnover response to glucose intake and increases PTH secretion. The apparent bone turnover response to feeding is probably mediated by an octreotide-inhibitable endocrine factor.

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EXPRESS: Assessing bone formation in patients with chronic kidney disease using procollagen type I N-terminal propeptide (PINP): the choice of assay makes a difference

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/00045632211025567 ◽

2021 ◽

pp. 000456322110255

Author(s):

Andreas Tridimas ◽

Anna Milan ◽

Eileen Marks

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Bone Formation ◽

Type I Collagen ◽

Method Comparison ◽

Type I ◽

Positive Bias ◽

Procollagen Type ◽

Metabolic Bone ◽

Procollagen Type I

Background: Measurement of procollagen type I N-terminal propeptide (PINP) concentration in serum reflects the rate of type I collagen synthesis and can therefore be used as a bone formation marker. There are two methods of PINP quantification; the first measures the trimeric propeptide (intact PINP) and the second measures both the trimeric and monomeric propeptides (total PINP). Trimeric PINP is excreted via hepatic endothelial cells whereas monomeric PINP is cleared renally. Therefore in renal failure the total assay has a positive bias with respect to the intact assay, due to monomeric PINP accumulation. The aim of this study was to compare the performance of both assays across all stages of chronic kidney disease (CKD). Methods: Serum was taken from male (n=111) and female (n=105) patients attending a metabolic bone clinic and these were partitioned into stages of CKD 1-5. Each serum sample was analysed using the Roche electrochemiluminescence immunoassay for total PINP and the Immunodiagnostic Systems chemiluminescence immunoassay for intact PINP. Results: Passing-Bablok regression analysis comparing both methods showed that with advancing CKD there was a proportional positive bias affecting the total assay when compared to the intact assay. This proportional positive bias was statistically significant for CKD stages 3b, 4 and 5. Conclusions: Based on this method comparison study, usage of the total PINP assay should be avoided in CKD stages 3b, 4 & 5 (eGFR <u><</u>44 ml/min/1.73m<sup>2</sup>) and instead an intact assay used as the total assay overestimates PINP levels due to monomeric PINP accumulation.

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Development of a Sandwich Chemiluminescence Immunoassay for the Detection of Intact Procollagen Type I N Propeptide with Magnetic Nanosphere Carrier Technology

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3132 ◽

2021 ◽

Vol 17 (8) ◽

pp. 1690-1698

Author(s):

Li Song ◽

Chunmei Xie ◽

Xueke Liu ◽

Zhen Huo ◽

Yinhai Xie ◽

...

Keyword(s):

Type I Collagen ◽

Diagnostic Value ◽

Type I ◽

Chemiluminescence Method ◽

Procollagen Type ◽

Potential Marker ◽

Test Kit ◽

Procollagen Type I ◽

Chemiluminescent Immunoassay ◽

Higher Sensitivity

The metabolic product of type I collagen synthesis, intact procollagen type I N propeptide (intact PINP), is a potential marker of bone formation and osteoporosis, which is not affected by kidney function. We sought to establish a chemiluminescent immunoassay method for the detection of serum intact PINP with previously prepared paired monoclonal antibodies and to evaluate the diagnostic value of the assay in osteoporosis. Using the capture molecule and monoclonal antibody as detection molecule, a diagnostic reagent was developed to detect intact PINP in serum with magnetic nanosphere carriers by the chemiluminescence method, and its analytical performance in the laboratory was evaluated. Serum intact PINP was measured in 142 healthy people and 115 osteoporosis patients. Results were matched with results of a similar test kit, Roche total PINP Elecsys Chemiluminescent Immunoassay Assay. Compared with the performance of the Roche PINP assay product, our method had higher sensitivity (0.02 ng/mL), wider linear range (0.02-1500 ng/mL), and anti-interference. Serum intact PINP values in osteoporosis patients were significantly higher than in healthy subjects (p < 0.001). Our method had good consistency compared with the Roche PINP assay (r = 0.9794). This chemiluminescence method for detecting serum intact PINP (CLIA-intact PINP) with magnetic nanosphere carrier technology meets the requirements of a clinical testing reagent and is expected to have clinical application after further evaluation and can compete with expensive imported kits on the market.

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