Publications by authors named "Jolaine M Hines"

9 Publications

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Short carboxyl terminal parathyroid hormone peptides modulate human parathyroid hormone signaling in mouse osteoblasts.

Biochem Biophys Res Commun 2021 Oct 28;572:15-19. Epub 2021 Jul 28.

Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic Rochester, 200 First Street Southwest, Rochester, MN, 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic Rochester, 200 First Street Southwest, Rochester, MN, 55905, USA. Electronic address:

Background: Novel human parathyroid hormone (hPTH) peptides of unknown biological activity have recently been identified in the serum of subjects with normal renal function, chronic renal failure, and end-stage renal disease through the application of liquid chromatography-high resolution mass spectrometry.

Purpose: of experiments: To determine the bioactivity of these peptides, we synthesized hPTH28-84, hPTH38-84, and hPTH45-84 peptides by solid phase peptide synthesis and tested their bioactivity in MC3T3-E1 mouse osteoblasts, either individually or together with the native hormone, hPTH1-84, by assessing the accumulation of 3´,5´-cyclic adenosine monophosphate (cAMP) and the induction of alkaline phosphatase activity.

Results: Increasing doses of hPTH1-84 (1-100 nM) increased the accumulation of cAMP and alkaline phosphatase activity in osteoblasts. hPTH28-84, hPTH38-84, and hPTH45-84 in concentrations of 1-100 nM were biologically inert. Surprisingly, 100 nM hPTH38-84 and hPTH45-84 increased the accumulation of cAMP in osteoblasts treated with increasing amounts of hPTH1-84. Human PTH28-84 had no effects on cAMP activity alone or in combination with hPTH1-84. Conversely, 100 nM hPTH38-84, hPTH45-84, and hPTH28-84 blocked the activation of alkaline phosphatase activity by hPTH1-84.

Conclusions: The data show that the short carboxyl-terminal hPTH peptides, hPTH38-84 and hPTH45-84, increase the amount of cellular cAMP generated in cultured osteoblasts in response to treatment with full-length hPTH1-84 when compared to full-length hPTH1-84 alone. Human PTH28-84 had no effect on cAMP activity alone or in combination with hPTH1-84. Human PTH28-84, hPTH38-84 and hPTH45-84 reduced the effects of hPTH1-84 in osteoblasts with respect to the induction of alkaline phosphatase activity compared to hPTH1-84 alone. Short carboxyl peptides of human PTH are biologically inert but when administered together with full-length hPTH1-84 modulate the bioactivity of hPTH1-84 in osteoblasts.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380684PMC
October 2021

Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)D and normal FGF7 concentrations characterize patients with CKD.

BMC Nephrol 2021 Mar 30;22(1):114. Epub 2021 Mar 30.

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 1st Street SW, MN, 55905, Rochester, USA.

Background: Hyperphosphatemia confers adverse cardiovascular outcomes, and commonly occurs in late-stage CKD. Fibroblast growth factor 7 (FGF7) is a phosphaturic peptide which decreases renal phosphate transport in vitro and in vivo. Serum FGF7 concentrations are reduced in hyperphosphatemic patients with hypophosphatasia and are elevated in some hypophosphatemic patients with tumor-induced osteomalacia. No data, however, are available on whether circulating FGF7 concentrations increase to compensate for phosphate retention in CKD patients.

Methods: This was a cross-sectional study performed among 85 adult patients with varying estimated glomerular filtration rates (eGFR). We measured serum intact FGF7 (iFGF7) concentration using an iFGF7 immunoassay and determined its associated factors. Relationships between eGFR and mineral metabolism biomarkers [phosphate, iFGF7, iFGF23, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25(OH)D)] were explored.

Results: For eGFRs of ≥ 60 (n = 31), 45-59 (n = 16), 30-44 (n = 11), 15-29 (n = 15), and < 15 mL/min/1.73 m (n = 12), median (IQ25-75) iFGF7 concentrations were 46.1 (39.2-56.9), 43.1 (39.0-51.5), 47.3 (38.3-66.5), 47.7 (37.7-55.8), and 49.6 (42.5-65.6) pg/mL, respectively (P = 0.62). Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m (95 % CI, 19.25-25.51), respectively, while significant decreases in serum 1,25(OH)D were observed at an eGFR of < 52 mL/min/1.73 m (95 % CI, 42.57-61.43). No significant correlation was found between serum iFGF7 and phosphate, iFGF23, PTH or 1,25(OH)D. In multivariable analyses, body mass index (per 5 kg/m increase) was independently associated with the highest quartile of serum iFGF7 concentration (OR, 1.20; 95 % CI, 1.12-1.55).

Conclusions: Compensatory decreases in circulating 1,25(OH)D and increases in circulating iFGF23 and PTH, but not iFGF7, facilitate normalization of serum phosphate concentration in early stages of CKD. Whether other circulating phosphaturic peptides change in response to phosphate retention in CKD patients deserves further study.
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http://dx.doi.org/10.1186/s12882-021-02311-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011073PMC
March 2021

Chemical Characterization and Quantification of Circulating Intact PTH and PTH Fragments by High-Resolution Mass Spectrometry in Chronic Renal Failure.

Clin Chem 2021 Jun;67(6):843-853

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Background: The precise concentrations of full-length parathyroid hormone (PTH1-84) and the identity and concentrations of PTH fragments in patients with various stages of chronic renal failure are unknown.

Methods: We developed a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method to characterize and quantify PTH1-84 and PTH fragments in serum of 221 patients with progressive renal dysfunction. Following capture by matrix-bound amino-terminal or carboxyl-terminal region-specific antibodies and elution from matrix, PTH1-84 and PTH fragments were identified and quantitated using LC-HRMS. PTH was simultaneously measured using an intact PTH (iPTH) immunoassay.

Results: Full-length PTH1-84 and 8 PTH fragments (PTH28-84, 34-77, 34-84, 37-77, 37-84, 38-77, 38-84, and 45-84) were unequivocally identified and were shown to increase significantly when an eGFR declined to ≤17-23 mL/min/1.73m2. Serum concentrations of PTH1-84 were similar when measured by LC-HRMS following capture by amino-terminal or carboxyl-terminal immunocapture methods. In patients with an eGFR of <30 mL/min/1.73 m2, serum PTH concentrations measured using LC-HRMS were significantly lower than PTH measured using an iPTH immunoassay. PTH7-84 and oxidized forms of PTH1-84 were below the limit of detection (30 and 50 pg/mL, respectively).

Conclusions: LC-HRMS identifies circulating PTH1-84, carboxyl-terminal PTH fragments, and mid-region PTH fragments, in patients with progressive renal failure. Serum PTH1-84 and its fragments markedly rise when an eGFR decreases to ≤17-23 mL/min/1.73 m2. PTH concentrations measured using LC-HRMS tend to be lower than those measured using an iPTH immunoassay, particularly in severe chronic renal failure. Our data do not support the existence of circulating PTH7-84 and oxidized PTH1-84.
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http://dx.doi.org/10.1093/clinchem/hvab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167341PMC
June 2021

Development and Application of Mass Spectroscopy Assays for Nε-(1-Carboxymethyl)-L-Lysine and Pentosidine in Renal Failure and Diabetes.

J Appl Lab Med 2020 05;5(3):558-568

Mayo Clinic College of Medicine, Rochester, MN.

Background: Advanced glycation end products (AGEs) are formed via the nonenzymatic glycation of sugars with amino acids. Two AGEs, Nε-(1-carboxymethyl)-L-Lysine (CML) and pentosidine, have been observed to be elevated in subjects suffering from a multitude of chronic disease states, and accumulation of these compounds may be related to the pathophysiology of disease progression and aging.

Methods: We describe here the development and validation of a specific and reproducible LC-MS/MS method to quantify CML and pentosidine in human serum with lower limits of quantitation of 75 ng/mL and 5 ng/mL, respectively. The analyte calibration curve exhibited excellent linearity at a range of 0-10 900 ng/mL for CML and 0-800 ng/mL for pentosidine. High-low linearity of 5 serum pairs was assessed, with a mean recovery of 103% (range 94-116%) for CML, and 104% (range 97-116%) for pentosidine.

Results: Serum concentrations of CML and pentosidine were quantified in 30 control and 30 subjects with chronic renal insufficiency. A significant increase in both analytes was observed in renal failure compared to control subjects (2.1-fold and 8.4-fold, respectively; P < 0.001 for both). In a separate cohort of 49 control versus 95 subjects with type 2 diabetes mellitus (T2DM), serum CML but not serum pentosidine, was significantly elevated in the T2DM patients, and CML was also correlated with glycemic control, as assessed by hemoglobin A1c (r = 0.34, P < 0.001).

Conclusions: These mass spectroscopy-based assays for serum CML and pentosidine should be useful in accurately evaluating circulating levels of these key AGEs in various disease states.
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http://dx.doi.org/10.1093/jalm/jfaa023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192546PMC
May 2020

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes.

JCI Insight 2020 05 7;5(9). Epub 2020 May 7.

Division of Endocrinology.

The worldwide prevalence of type 2 diabetes (T2D) is increasing. Despite normal to higher bone density, patients with T2D paradoxically have elevated fracture risk resulting, in part, from poor bone quality. Advanced glycation endproducts (AGEs) and inflammation as a consequence of enhanced receptor for AGE (RAGE) signaling are hypothesized culprits, although the exact mechanisms underlying skeletal dysfunction in T2D are unclear. Lack of inducible models that permit environmental (in obesity) and temporal (after skeletal maturity) control of T2D onset has hampered progress. Here, we show in C57BL/6 mice that a onetime pharmacological intervention (streptozotocin, STZ) initiated in adulthood combined with high-fat diet-induced (HFD-induced) obesity caused hallmark features of human adult-onset T2D, including prolonged hyperglycemia, insulin resistance, and pancreatic β cell dysfunction, but not complete destruction. In addition, HFD/STZ (i.e., T2D) resulted in several changes in bone quality that closely mirror those observed in humans, including compromised bone microarchitecture, reduced biomechanical strength, impaired bone material properties, altered bone turnover, and elevated levels of the AGE CML in bone and blood. Furthermore, T2D led to the premature accumulation of senescent osteocytes with a unique proinflammatory signature. These findings highlight the RAGE pathway and senescent cells as potential targets to treat diabetic skeletal fragility.
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http://dx.doi.org/10.1172/jci.insight.135236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253018PMC
May 2020

Adrenal Cortical Carcinoma Associated With Lynch Syndrome: A Case Report and Review of Literature.

J Endocr Soc 2019 Apr 5;3(4):784-790. Epub 2019 Mar 5.

Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.

Objective: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. ACC was reported in 3.2% patients with Lynch syndrome (LS), however no particular case-detection strategies have been recommended.

Participants: We report a case of a 65-year-old woman who was incidentally discovered with a large adrenal mass during work-up of postmenopausal uterine bleeding. She was recently diagnosed with germline mutation after her sister presented with uterine carcinoma in the setting of LS.

Results: Whereas the patient was asymptomatic for overt hormonal excess, biochemical work-up confirmed glucocorticoid autonomy and androgen and estrogen excess. Urine steroid profiling was suggestive of ACC. Adrenalectomy confirmed an oncocytic ACC with focal extracapsular extension into the periadrenal adipose tissue with a Ki-67 of 15% and a peak mitotic count of 40/50 high-power fields.

Conclusion: ACC can be the only manifestation of LS. A best case-detection approach for ACC in the asymptomatic patient with LS is unclear, however urine steroid profiling could be considered.
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http://dx.doi.org/10.1210/js.2019-00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446885PMC
April 2019

Over-the-Counter "Adrenal Support" Supplements Contain Thyroid and Steroid-Based Adrenal Hormones.

Mayo Clin Proc 2018 03;93(3):284-290

Department of Endocrinology, Mayo Clinic, Jacksonville, FL; American Thyroid Association, Falls Church, VA Dr Akturk is now with the University of Colorado, Barbara Davis Center for Diabetes, Aurora, CO.

Objective: To assess whether dietary supplements that are herbal and/or animal-derived products, marketed for enhancing metabolism or promoting energy, "adrenal fatigue," or "adrenal support," contain thyroid or steroid hormones.

Methods: Twelve dietary adrenal support supplements were purchased. Pregnenolone, androstenedione, 17-hydroxyprogesterone, cortisol, cortisone, dehydroepiandrosterone sulfate, synthetic glucocorticoids (betamethasone, dexamethasone, fludrocortisone, megestrol acetate, methylprednisolone, prednisolone, prednisone, budesonide, and triamcinolone acetonide) levels were measured twice in samples in a blinded fashion. This study was conducted between February 1, 2016, and November 1, 2016.

Results: Among steroids, pregnenolone was the most common hormone in the samples. Budesonide, 17-hydroxyprogesterone, androstenedione, cortisol, and cortisone were the others in order of prevalence. All the supplements revealed a detectable amount of triiodothyronine (T3) (63-394.9 ng/tablet), 42% contained pregnenolone (66.12-205.2 ng/tablet), 25% contained budesonide (119.5-610 ng/tablet), 17% contained androstenedione (1.27-7.25 ng/tablet), 8% contained 17-OH progesterone (30.09 ng/tablet), 8% contained cortisone (79.66 ng/tablet), and 8% contained cortisol (138.5 ng/tablet). Per label recommended doses daily exposure was up to 1322 ng for T3, 1231.2 ng for pregnenolone, 1276.4 ng for budesonide, 29 ng for androstenedione, 60.18 ng for 17-OH progesterone, 277 ng for cortisol, and 159.32 ng for cortisone.

Conclusion: All the supplements studied contained a small amount of thyroid hormone and most contained at least 1 steroid hormone. This is the first study that measured thyroid and steroid hormones in over-the-counter dietary "adrenal support" supplements in the United States. These results may highlight potential risks of hidden ingredients in unregulated supplements.
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http://dx.doi.org/10.1016/j.mayocp.2017.10.019DOI Listing
March 2018

High-Resolution, Accurate-Mass (HRAM) Mass Spectrometry Urine Steroid Profiling in the Diagnosis of Adrenal Disorders.

Clin Chem 2017 Dec 16;63(12):1824-1835. Epub 2017 Aug 16.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Background: Steroid profiling is a promising diagnostic tool with adrenal tumors, Cushing syndrome (CS), and disorders of steroidogenesis. Our objective was to develop a multiple-steroid assay using liquid-chromatography, high-resolution, accurate-mass mass spectrometry (HRAM LC-MS) and to validate the assay in patients with various adrenal disorders.

Methods: We collected 24-h urine samples from 114 controls and 71 patients with adrenal diseases. An HRAM LC-MS method was validated for quantitative analysis of 26 steroid metabolites in hydrolyzed urine samples. Differences in steroid excretion between patients were analyzed based on -score deviation from control reference intervals.

Results: Limits of quantification were 20 ng/mL. Dilution linearity ranged from 80% to 120% with means of 93% to 110% for all but 2 analytes. Intraassay and interassay imprecision ranged from 3% to 18% for all but 1 analyte. Control women had lower excretion of androgen and glucocorticoid precursors/metabolites than men ( < 0.001), but no difference in mineralocorticoids was seen ( = 0.06). Androgens decreased with age in both sexes ( < 0.001). Compared with patients with adrenocortical adenoma (ACA), patients with adrenocortical carcinoma (ACC) had 11 steroids with increased scores, especially tetrahydro-11-deoxycortisol (14 vs 0.5, < 0.001), pregnanetriol (7.5 vs -0.4, = 0.001), and 5-pregnenetriol (5.4 vs -0.4, = 0.01). Steroid profiling also demonstrated metabolite abnormalities consistent with enzymatic defects in congenital adrenal hyperplasia and differences in pituitary vs adrenal CS.

Conclusions: Our HRAM LC-MS assay successfully quantifies 26 steroids in urine. The statistically significant differences in steroid production of ACC vs ACA, adrenal vs pituitary CS, and in congenital adrenal hyperplasia should allow for improved diagnosis of patients with these diseases.
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http://dx.doi.org/10.1373/clinchem.2017.271106DOI Listing
December 2017

Mass spectrometric immunoassay raises doubt for the existence of parathyroid hormone fragment 7-84.

Clin Chem 2015 Mar 16;61(3):558-60. Epub 2015 Jan 16.

Departments of Laboratory Medicine and Medicine University of Washington Seattle, WA.

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http://dx.doi.org/10.1373/clinchem.2014.235440DOI Listing
March 2015
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