Andrew F Stewart

Icahn School of Medicine at Mount Sinai, Borough of Manhattan, New York, United States

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Publications (110)1031.02 Total impact

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    ABSTRACT: Pregnancy in rodents is associated with a two- to three-fold increase in beta cell mass, attributable to large increases in beta cell proliferation, complimented by increases in beta cell size, survival and function, mediated mainly by the lactogenic hormones, prolactin (PRL) and placental lactogens (PLs). In humans, however, beta cell mass does not increase as dramatically in pregnancy, and PRL fails to activate proliferation in human islets in vitro. To determine why, we explored the PRL-prolactin receptor (hPRLR)-JAK2-STAT5-cyclin-cdk signaling cascade in human beta cells. Surprisingly, adult human beta cells express little or no PRLR. As expected, restoration of the hPRLR in human beta cells rescued JAK2-STAT5 signaling in response to PRL. However, rescuing hPRLR-STAT5 signaling nevertheless failed to confer proliferative ability on adult human beta cells in response to PRL. Surprisingly, mouse (but not human) Stat5a overexpression led to upregulation of cyclins D1-3 and cdk4, as well as their nuclear translocation, all associated with beta cell cycle entry. Collectively, the findings show that human beta cells fail to proliferate in response to PRL for multiple reasons, one of which is a paucity of functional PRLRs, and that murine Stat5 overexpression is able to bypass these impediments. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    No preview · Article · Jul 2015 · Diabetes
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    ABSTRACT: This is the third in a series of Perspectives on intracellular signaling pathways coupled to proliferation in pancreatic β-cells. We contrast the large knowledge base in rodent β-cells with the more limited human database. With the increasing incidence of type 1 diabetes and the recognition that type 2 diabetes is also due in part to a deficiency of functioning β-cells, there is great urgency to identify therapeutic approaches to expand human β-cell numbers. Therapeutic approaches might include stem cell differentiation, transdifferentiation, or expansion of cadaver islets or residual endogenous β-cells. In these Perspectives, we focus on β-cell proliferation. Past Perspectives reviewed fundamental cell cycle regulation and its upstream regulation by insulin/IGF signaling via phosphatidylinositol-3 kinase/mammalian target of rapamycin signaling, glucose, glycogen synthase kinase-3 and liver kinase B1, protein kinase Cζ, calcium-calcineurin-nuclear factor of activated T cells, epidermal growth factor/platelet-derived growth factor family members, Wnt/β-catenin, leptin, and estrogen and progesterone. Here, we emphasize Janus kinase/signal transducers and activators of transcription, Ras/Raf/extracellular signal-related kinase, cadherins and integrins, G-protein-coupled receptors, and transforming growth factor β signaling. We hope these three Perspectives will serve to introduce these pathways to new researchers and will encourage additional investigators to focus on understanding how to harness key intracellular signaling pathways for therapeutic human β-cell regeneration for diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    No preview · Article · May 2015 · Diabetes
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    ABSTRACT: Types 1 and 2 diabetes affect some 380 million people worldwide. Both ultimately result from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with a peak percentage (∼2%) engaged in the cell cycle in the first year of life. In embryonic life and after early childhood, beta cell replication is barely detectable. Whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, using a high-throughput small-molecule screen (HTS), we find that analogs of the small molecule harmine function as a new class of human beta cell mitogenic compounds. We also define dual-specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine and the nuclear factors of activated T cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation and differentiation. Using three different mouse and human islet in vivo-based models, we show that harmine is able to induce beta cell proliferation, increase islet mass and improve glycemic control. These observations suggest that harmine analogs may have unique therapeutic promise for human diabetes therapy. Enhancing the potency and beta cell specificity of these compounds are important future challenges.
    Full-text · Article · Mar 2015 · Nature Medicine
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    ABSTRACT: The treatment of diabetes mellitus represents one of the greatest medical challenges of our era. Diabetes results from a deficiency or functional impairment of insulin-producing β cells, alone or in combination with insulin resistance. It logically follows that the replacement or regeneration of β cells should reverse the progression of diabetes and, indeed, this seems to be the case in humans and rodents. This concept has prompted attempts in many laboratories to create new human β cells using stem-cell strategies to transdifferentiate or reprogramme non-β cells into β cells or to discover small molecules or other compounds that can induce proliferation of human β cells. This latter approach has shown promise, but has also proven particularly challenging to implement. In this Review, we discuss the physiology of normal human β-cell replication, the molecular mechanisms that regulate the cell cycle in human β cells, the upstream intracellular signalling pathways that connect them to cell surface receptors on β cells, the epigenetic mechanisms that control human β-cell proliferation and unbiased approaches for discovering novel molecules that can drive human β-cell proliferation. Finally, we discuss the potential and challenges of implementing strategies that replace or regenerate β cells.
    No preview · Article · Feb 2015 · Nature Reviews Endocrinology
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    Rohit N Kulkarni · Andrew F Stewart

    Preview · Article · Dec 2014 · Diabetes
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    Adolfo García-Ocaña · Andrew F Stewart
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    ABSTRACT: Adult human pancreatic β cells are refractory to current therapeutic approaches to enhance proliferation. This reluctance to expand is problematic, especially for people with diabetes who lack sufficient numbers of functional insulin-producing β cells and could therefore benefit from therapies for β cell expansion. In this issue of the JCI, Chamberlain et al. describe a surprising series of observations that involve two downstream arms of the RAS signaling pathway, MAPK and RASSF proteins, which also involve the tumor suppressor menin. The findings of this study may help explain the difficulty of inducing β cell proliferation and may provide leads for therapeutic expansion of human β cells.
    Preview · Article · Aug 2014 · Journal of Clinical Investigation
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    Andrew F Stewart

    Preview · Article · Apr 2014 · Diabetes
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    ABSTRACT: Enhancing β-cell proliferation is a major goal for type 1 and type 2 diabetes research. Unraveling the network of β-cell intracellular signaling pathways that promote β-cell replication can provide the tools to address this important task. In a previous Perspectives in Diabetes article, we discussed what was known regarding several important intracellular signaling pathways in rodent β-cells, including the insulin receptor substrate/phosphatidylinositol-3 kinase/Akt (IRS-PI3K-Akt) pathways, glycogen synthase kinase-3 (GSK3) and mammalian target of rapamycin (mTOR) S6 kinase pathways, protein kinase Cζ (PKCζ) pathways, and their downstream cell-cycle molecular targets, and contrasted that ample knowledge to the small amount of complementary data on human β-cell intracellular signaling pathways. In this Perspectives, we summarize additional important information on signaling pathways activated by nutrients, such as glucose; growth factors, such as epidermal growth factor, platelet-derived growth factor, and Wnt; and hormones, such as leptin, estrogen, and progesterone, that are linked to rodent and human β-cell proliferation. With these two Perspectives, we attempt to construct a brief summary of knowledge for β-cell researchers on mitogenic signaling pathways and to emphasize how little is known regarding intracellular events linked to human β-cell replication. This is a critical aspect in the long-term goal of expanding human β-cells for the prevention and/or cure of type 1 and type 2 diabetes.
    Full-text · Article · Mar 2014 · Diabetes
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    ABSTRACT: Parathyroid hormone-related protein (PTHrP)(1-36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but has not been directly compared to parathyroid hormone (PTH)(1-34). We performed a three month, randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis comparing daily subcutaneous injections of PTHrP(1-36) to PTH(1-34). Thirty-five women were randomized to each of three groups: PTHrP(1-36) 400 µg/d; PTHrP(1-36) 600 µg/d; and PTH(1-34) 20 µg/d. The primary outcomes measures were changes in amino-terminal telopeptides of procollagen 1 (PINP) and carboxy-terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)2 vitamin D and BMD. The increase in bone resorption (CTX) by PTH(1-34) (92%) (p < 0.005) was greater than for PTHrP(1-36) (30%) (p < 0.05). PTH(1-34) also increased bone formation (PINP) (171%) (p < 0.0005) more than either dose of PTHrP(1-36) (46 & 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (p < 0.05 for all). Total hip (TH) and femoral neck (FN) BMD increased equivalently in each group but were only significant for the two doses of PTHrP(1-36) (p < 0.05) at the TH, and for PTHrP(1-36) 400 (p < 0.05) at the FN. PTHrP(1-36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1-36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1-34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)2 D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1-36) and PTH(1-34) cause similar increases in LS BMD. PTHrP(1-36) also increased hip BMD. PTH(1-34) induced greater changes in bone turnover than PTHrP(1-36). PTHrP(1-36) was associated with mild transient hypercalcemia. Longer term studies using lower doses of PTHrP(1-36) are needed to define both the optimal dose and full clinical benefits of PTHrP.
    Full-text · Article · Mar 2014 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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    Aaron Bender · Andrew F Stewart

    Preview · Article · Nov 2013 · Diabetologia
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    ABSTRACT: Expansion of pancreatic beta cells is a key goal of diabetes research, yet induction of adult human beta cell replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human beta cell. Here, we provide a comprehensive immunocytochemical "atlas" of G1/S control molecules in the human beta cell. This "atlas" reveals that the majority these molecules, previously known to be present in islets, are actually present in the beta cell. More importantly, and in contrast to anticipated results, the "human beta cell G1/S atlas" reveals that almost all of the critical G1/S cell cycle control molecules are located in the cytoplasm of the quiescent human beta cell. Indeed, the only nuclear G1/S molecules are the cell cycle inhibitors, pRb, p57, and variably, p21: none of the cyclins or cdks necessary to drive human beta cell proliferation are present in the nuclear compartment. This observation may provide an explanation for the refractoriness of human beta cells to proliferation. Thus, in addition to known obstacles to human beta cell proliferation, restriction of G1/S molecules to the cytoplasm of the human beta cell represents an unanticipated obstacle to therapeutic human beta cell expansion.
    Full-text · Article · Mar 2013 · Diabetes
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    ABSTRACT: Harnessing control of human beta cell proliferation has proven frustratingly difficult. Most G1/S control molecules, generally presumed to be nuclear proteins in the human beta cell, are in fact constrained to the cytoplasm. Here, we asked whether G1/S molecules might traffic into and out of the cytoplasmic compartment in association with activation of cell cycle progression. Cdk6 and cyclin D3 were used to drive human beta cell proliferation, and promptly translocated into the nucleus in association with proliferation. In contrast, the cell cycle inhibitors p15, p18 and p19 did not alter their location, remaining cytoplasmic. Conversely, p16, p21, p27 all increased their nuclear frequency. In contrast once again, p57 decreased its nuclear frequency. While proliferating beta cells contained nuclear cyclin D3 and cdk6, proliferation generally did not occur in beta cells that contained nuclear cell cycle inhibitors, except p21. Dynamic cytoplasmic-nuclear trafficking of cdk6 was confirmed using GFP-tagged cdk6 and live-cell imaging. Thus, we provide novel working models describing the control of cell cycle progression in the human beta cell. In addition to known obstacles to beta cell proliferation, cytoplasmic-to-nuclear trafficking of G1/S molecules may represent both an obstacle, as well as a therapeutic opportunity, for human beta cell expansion.
    Full-text · Article · Mar 2013 · Diabetes
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    ABSTRACT: Context:The African-American skeleton is resistant to PTH; whether it is also resistant to PTHrP and the hormonal milieu of lactation is unknown.Objectives:The objective of the study was to assess bone turnover markers in African-Americans during lactation vs Caucasians.Design and Participants:A prospective cohort study with repeated measures of markers of bone turnover in 60 African-American women (3 groups of 20: lactating, bottle feeding, and healthy controls), compared with historic Caucasian women.Setting:The study was conducted at a university medical center.Outcome Measures:Biochemical markers of bone turnover and calcium metabolism were measured.Results:25-Hydroxyvitamin D (25-OHD) and PTH were similar among all 3 African-American groups, but 25-OHD was 30%-50% lower and PTH 2-fold higher compared with Caucasians (P < .001, P < .002), with similar 1,25 dihydroxyvitamin D [1,25(OH)(2)D] values. Formation markers [amino-terminal telopeptide of procollagen-1 (P1NP) and bone-specific alkaline phosphatase (BSAP)] increased significantly (2- to 3-fold) in lactating and bottle-feeding African-American women (P1NP, P < .001; BSAP, P < .001), as did resorption [carboxy-terminal telopeptide of collagen-1 (CTX) and serum amino-terminal telopeptide of collagen 1 (NTX), both P < .001). P1NP and BSAP were comparable in African-American and Caucasian controls, but CTX and NTX were lower in African-American vs Caucasian controls. African-American lactating mothers displayed quantitatively similar increases in markers of bone formation but slightly lower increases in markers of resorption vs Caucasians (P = .036).Conclusions:Despite reported resistance to PTH, lactating African-American women have a significant increase in markers of bone resorption and formation in response the hormonal milieu of lactation. This response is similar to that reported in Caucasian women despite racial differences in 25-OHD and PTH. Whether this is associated with similar bone loss in African-Americans as in Caucasians during lactation is unknown and requires further study.
    No preview · Article · Dec 2012 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: The transcription factor HNF4α (hepatocyte nuclear factor-4α) is required for increased β-cell proliferation during metabolic stress in vivo. We hypothesized that HNF4α could induce proliferation of human β-cells. We employed adenoviral-mediated overexpression of an isoform of HNF4α (HNF4α8) alone, or in combination with cyclin-dependent kinase (Cdk)6 and Cyclin D3, in human islets. Heightened HNF4α8 expression led to a 300-fold increase in the number of β-cells in early S-phase. When we overexpressed HNF4α8 together with Cdk6 and Cyclin D3, β-cell cycle entry was increased even further. However, the punctate manner of bromodeoxyuridine incorporation into HNF4α(High) β-cells indicated an uncoupling of the mechanisms that control the concise timing and execution of each cell cycle phase. Indeed, in HNF4α8-induced bromodeoxyuridine(+,punctate) β-cells we observed signs of dysregulated DNA synthesis, cell cycle arrest, and activation of a double stranded DNA damage-associated cell cycle checkpoint mechanism, leading to the initiation of loss of β-cell lineage fidelity. However, a substantial proportion of β-cells stimulated to enter the cell cycle by Cdk6 and Cyclin D3 alone also exhibited a DNA damage response. HNF4α8 is a mitogenic signal in the human β-cell but is not sufficient for completion of the cell cycle. The DNA damage response is a barrier to efficient β-cell proliferation in vitro, and we suggest its evaluation in all attempts to stimulate β-cell replication as an approach to diabetes treatment.
    No preview · Article · Jul 2012 · Molecular Endocrinology
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    ABSTRACT: A major goal in diabetes research is to find ways to enhance the mass and function of insulin secreting β-cells in the endocrine pancreas to prevent and/or delay the onset or even reverse overt diabetes. In this Perspectives in Diabetes article, we highlight the contrast between the relatively large body of information that is available in regard to signaling pathways, proteins, and mechanisms that together provide a road map for efforts to regenerate β-cells in rodents versus the scant information in human β-cells. To reverse the state of ignorance regarding human β-cell signaling, we suggest a series of questions for consideration by the scientific community to construct a human β-cell proliferation road map. The hope is that the knowledge from the new studies will allow the community to move faster towards developing therapeutic approaches to enhance human β-cell mass in the long-term goal of preventing and/or curing type 1 and type 2 diabetes.
    Preview · Article · Jun 2012 · Diabetes
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    ABSTRACT: Glucose stimulates rodent and human β-cell replication, but the intracellular signaling mechanisms are poorly understood. Carbohydrate response element-binding protein (ChREBP) is a lipogenic glucose-sensing transcription factor with unknown functions in pancreatic β-cells. We tested the hypothesis that ChREBP is required for glucose-stimulated β-cell proliferation. The relative expression of ChREBP was determined in liver and β-cells using quantitative RT-PCR (qRT-PCR), immunoblotting, and immunohistochemistry. Loss- and gain-of-function studies were performed using small interfering RNA and genetic deletion of ChREBP and adenoviral overexpression of ChREBP in rodent and human β-cells. Proliferation was measured by 5-bromo-2'-deoxyuridine incorporation, [(3)H]thymidine incorporation, and fluorescence-activated cell sorter analysis. In addition, the expression of cell cycle regulatory genes was measured by qRT-PCR and immunoblotting. ChREBP expression was comparable with liver in mouse pancreata and in rat and human islets. Depletion of ChREBP decreased glucose-stimulated proliferation in β-cells isolated from ChREBP(-/-) mice, in INS-1-derived 832/13 cells, and in primary rat and human β-cells. Furthermore, depletion of ChREBP decreased the glucose-stimulated expression of cell cycle accelerators. Overexpression of ChREBP amplified glucose-stimulated proliferation in rat and human β-cells, with concomitant increases in cyclin gene expression. In conclusion, ChREBP mediates glucose-stimulated proliferation in pancreatic β-cells.
    Full-text · Article · May 2012 · Diabetes
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    ABSTRACT: Thyroid papillary microcarcinoma (TPMC) is an incidentally discovered papillary carcinoma that measures ≤1.0 cm in size. Most TPMCs are indolent, whereas some behave aggressively. The objective of the study was to evaluate whether the combination of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and specific histopathologic features allows risk stratification of TPMC. A group aggressive TPMCs was selected based on the presence of lymph node metastasis or tumor recurrence. Another group of nonaggressive tumors included TPMCs matched with the first group for age, sex, and tumor size, but with no extrathyroid spread. A molecular analysis was performed, and histologic slides were scored for multiple histopathologic criteria. A separate validation cohort of 40 TPMCs was evaluated. BRAF mutations were detected in 77% of aggressive TPMCs and in 32% of nonaggressive tumors (P = .001). Several histopathologic features differed significantly between the groups. By using multivariate regression analysis, a molecular-pathologic (MP) score was developed that included BRAF status and 3 histopathologic features: superficial tumor location, intraglandular tumor spread/multifocality, and tumor fibrosis. By adding the histologic criteria to BRAF status, sensitivity was increased from 77% to 96%, and specificity was increased from 68% to 80%. In the independent validation cohort, the MP score stratified tumors into low-risk, moderate-risk, and high-risk groups with the probability of lymph node metastases or tumor recurrence in 0%, 20%, and 60% of patients, respectively. BRAF status together with several histopathologic features allowed clinical risk stratification of TPMCs. The combined MP risk stratification model was a better predictor of extrathyroid tumor spread than either mutation or histopathologic findings alone.
    Full-text · Article · Apr 2012 · Cancer
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    ABSTRACT: Induction of proliferation in adult human β-cells is challenging. It can be accomplished by introduction of cell cycle molecules such as cyclin-dependent kinase 6 (cdk6) and cyclin D1, but their continuous overexpression raises oncogenic concerns. We attempted to mimic normal, transient, perinatal human β-cell proliferation by delivering these molecules in a regulated and reversible manner. Adult cadaveric islets were transduced with doxycycline (Dox)-inducible adenoviruses expressing cdk6 or cyclin D1. End points were cdk6/cyclin D1 expression and human β-cell proliferation, survival, and function. Increasing doses of Dox led to marked dose- and time-related increases in cdk6 and cyclin D1, accompanied by a 20-fold increase in β-cell proliferation. Notably, Dox withdrawal resulted in a reversal of both cdk6 and cyclin D1 expression as well as β-cell proliferation. Re-exposure to Dox reinduced both cdk/cyclin expression and proliferation. β-Cell function and survival were not adversely affected. The adenoviral tetracycline (tet)-on system has not been used previously to drive human β-cell proliferation. Human β-cells can be induced to proliferate or arrest in a regulated, reversible manner, temporally and quantitatively mimicking the transient perinatal physiological proliferation that occurs in human β-cells.
    Preview · Article · Dec 2011 · Diabetes
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    ABSTRACT: A small-molecule inducer of beta-cell proliferation in human islets represents a potential regeneration strategy for treating type 1 diabetes. However, the lack of suitable human beta cell lines makes such a discovery a challenge. Here, we adapted an islet cell culture system to high-throughput screening to identify such small molecules. We prepared microtiter plates containing extracellular matrix from a human bladder carcinoma cell line. Dissociated human islets were seeded onto these plates, cultured for up to 7 days, and assessed for proliferation by simultaneous Ki67 and C-peptide immunofluorescence. Importantly, this environment preserved beta-cell physiological function, as measured by glucose-stimulated insulin secretion. Adenoviral overexpression of cdk-6 and cyclin D(1), known inducers of human beta cell proliferation, was used as a positive control in our assay. This induction was inhibited by cotreatment with rapamycin, an immunosuppressant often used in islet transplantation. We then performed a pilot screen of 1280 compounds, observing some phenotypic effects on cells. This high-throughput human islet cell culture method can be used to assess various aspects of beta-cell biology on a relatively large number of compounds.
    Full-text · Article · Dec 2011 · Journal of Biomolecular Screening
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    ABSTRACT: Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7-day continuous-infusion models using human parathyroid hormone(1-34) [hPTH(1-34)] and human parathyroid hormone-related protein(1-36) [hPTHrP(1-36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1-84). The maximal tolerated infused doses over a 7-day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] and tubular maximum for phosphorus (TmP/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone-formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone-resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT.
    Full-text · Article · Sep 2011 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research

Publication Stats

5k Citations
1,031.02 Total Impact Points

Institutions

  • 2013-2015
    • Icahn School of Medicine at Mount Sinai
      • Diabetes, Obesity and Metabolism Institute
      Borough of Manhattan, New York, United States
  • 2001-2013
    • University of Pittsburgh
      • • Department of Medicine
      • • Division of Endocrinology and Metabolism
      • • Division of Pediatric Endocrinology
      Pittsburgh, Pennsylvania, United States
  • 1983-2009
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1990
    • Cornell University
      Итак, New York, United States
  • 1989
    • Saint Francis Hospital And Medical Center, Hartford, Ct
      Hartford, Connecticut, United States
  • 1987
    • West Haven University
      West Haven, Connecticut, United States
    • Albert Einstein College of Medicine
      • Department of Pathology
      New York, New York, United States