HORMONAL CONTROL OF CALCIUM METABOLISM

Summary

Principal Investigator: John T Potts
Abstract: DESCRIPTION OF OVERALL PROGRAM (provided by applicant) This Program Project, "Hormonal Control of Calcium Metabolism," brings together investigators from multiple disciplines to advance understanding of the actions of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). There is a new focus on heterogeneity of ligand/receptor conformations with surprising biological implications, novel cellular systems, and emphasis on genetically modified rodent models that reveal specific cellular controls. Together, these approaches provide insight into previously unappreciated basic mechanisms of PTH action that in turn can lead to changes in therapy of metabolic bone disease and disorders of mineral homeostasis. Project I, "PTH and PTHrP Interaction with PTH Receptors" (Thomas Gardella, PI), will address the divergent mechanisms used by PTH and PTHrP (and related designed analogs) to change the conformation of the PTH/PTHrP receptor in ways that alter signal activation within target cells. Project II, "Genetic Analysis of Second Messengers in PTH Signaling in Bone" (Henry Kronenberg, PI), will use genetically altered mice that permit separate analyses of the roles of activation of adenylate cyclase versus phospholipase C activation by receptors on cells of the osteoblast lineage. Project III, "Second Messengers in PTH Action" (F. Richard Bringhurst, PI), will use genetically altered mice and in vitro studies to address recently identified roles of protein kinase C d and the transcriptiorial co-regulator CITED1 in mediating the actions of PTH on bone. Project IV, "Renal Regulation of Phosphate and Calcium Homeostasis" (Harold Juppner and Matthew Mahon, co-Pis) will use (1) genetically altered mice with selective alteration of mineral ion renal responses of PTH in vivo to determine the mechanisms by which PTH regulates renal mineral ion metabolism;and (2) newly developed selectively modified cell models of renal tubular action in vitro that examine the molecular basis of the phenotypes of the genetically altered mice, with a particular focus on the role of specific components of cellular cytoarchitecture in phosphate homeostasis.
Funding Period: 1997-08-01 - 2013-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Parathyroid hormone activates PKC-delta and regulates osteoblastic differentiation via a PLC-independent pathway
    Dehong Yang
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    Bone 38:485-96. 2006
  2. pmc FGF-23: More than a regulator of renal phosphate handling?
    Harald Juppner
    Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, MA 02114, USA
    J Bone Miner Res 25:2091-7. 2010
  3. pmc Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm
    Jean Pierre Vilardaga
    Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Cell Mol Life Sci 68:1-13. 2011
  4. pmc Vectors bicistronically linking a gene of interest to the SV40 large T antigen in combination with the SV40 origin of replication enhance transient protein expression and luciferase reporter activity
    Matthew J Mahon
    Endocrine Unit, Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, Boston, MA, USA
    Biotechniques 51:119-28. 2011
  5. pmc Visualizing microtubule-dependent vasopressin type 2 receptor trafficking using a new high-affinity fluorescent vasopressin ligand
    Sylvia Chen
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    Endocrinology 152:3893-904. 2011
  6. pmc Constitutively active PTH/PTHrP receptor specifically expressed in osteoblasts enhances bone formation induced by bone marrow ablation
    Noriaki Ono
    Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
    J Cell Physiol 227:408-15. 2012
  7. pmc Intermittent parathyroid hormone administration converts quiescent lining cells to active osteoblasts
    Sang Wan Kim
    Department of Internal Medicine, Boramae Hospital, Seoul National University, Seoul, Korea
    J Bone Miner Res 27:2075-84. 2012
  8. pmc Loss of wnt/β-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes
    Lige Song
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    J Bone Miner Res 27:2344-58. 2012
  9. pmc αKlotho: FGF23 coreceptor and FGF23-regulating hormone
    Harald Juppner
    Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    J Clin Invest 122:4336-9. 2012
  10. pmc Heterologous downregulation of vasopressin type 2 receptor is induced by transferrin
    Richard Bouley
    1Nephrology Division, MGH Center for Systems Biology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Am J Physiol Renal Physiol 304:F553-64. 2013

Detail Information

Publications39

  1. ncbi Parathyroid hormone activates PKC-delta and regulates osteoblastic differentiation via a PLC-independent pathway
    Dehong Yang
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    Bone 38:485-96. 2006
    ..We conclude that PTH1Rs activate PKC-delta by a PLC-independent, PTH(29-34)-dependent mechanism that promotes osteoblastic differentiation...
  2. pmc FGF-23: More than a regulator of renal phosphate handling?
    Harald Juppner
    Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, MA 02114, USA
    J Bone Miner Res 25:2091-7. 2010
    ..Nonetheless, reducing the production and/or the biologic activity of FGF-23 may be an important therapeutic goal for this patient population...
  3. pmc Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm
    Jean Pierre Vilardaga
    Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Cell Mol Life Sci 68:1-13. 2011
    ....
  4. pmc Vectors bicistronically linking a gene of interest to the SV40 large T antigen in combination with the SV40 origin of replication enhance transient protein expression and luciferase reporter activity
    Matthew J Mahon
    Endocrine Unit, Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, Boston, MA, USA
    Biotechniques 51:119-28. 2011
    ....
  5. pmc Visualizing microtubule-dependent vasopressin type 2 receptor trafficking using a new high-affinity fluorescent vasopressin ligand
    Sylvia Chen
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
    Endocrinology 152:3893-904. 2011
    ..We conclude that the new VP(TMR) ligand is suitable for dissecting V2R and VP internalization and trafficking in cells, and that V2R trafficking and down-regulation is an MT-dependent mechanism...
  6. pmc Constitutively active PTH/PTHrP receptor specifically expressed in osteoblasts enhances bone formation induced by bone marrow ablation
    Noriaki Ono
    Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
    J Cell Physiol 227:408-15. 2012
    ..These results indicate that constitutive activation of PTH/PTHrP receptor in differentiated osteoblasts enhances bone marrow ablation-induced recruitment, proliferation, and differentiation of osteoprogenitors...
  7. pmc Intermittent parathyroid hormone administration converts quiescent lining cells to active osteoblasts
    Sang Wan Kim
    Department of Internal Medicine, Boramae Hospital, Seoul National University, Seoul, Korea
    J Bone Miner Res 27:2075-84. 2012
    ..These data support the hypothesis that intermittent PTH treatment can increase osteoblast number by converting lining cells to mature osteoblasts in vivo...
  8. pmc Loss of wnt/β-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes
    Lige Song
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    J Bone Miner Res 27:2344-58. 2012
    ....
  9. pmc αKlotho: FGF23 coreceptor and FGF23-regulating hormone
    Harald Juppner
    Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    J Clin Invest 122:4336-9. 2012
    ..show that the cleaved form of αKlotho, the membrane-bound form of which is an FGF23 coreceptor, serves as a novel endocrine regulator of phosphate homeostasis, capable of inducing FGF23 production in osteocytes...
  10. pmc Heterologous downregulation of vasopressin type 2 receptor is induced by transferrin
    Richard Bouley
    1Nephrology Division, MGH Center for Systems Biology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Am J Physiol Renal Physiol 304:F553-64. 2013
    ..It also provides new insights into urine-concentrating defects observed in rat models of hemochromatosis...
  11. pmc Oncogenic osteomalacia due to FGF23-expressing colon adenocarcinoma
    David E Leaf
    Division of Renal Medicine, Brigham and Women s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA
    J Clin Endocrinol Metab 98:887-91. 2013
    ..Most cases of oncogenic osteomalacia have been associated with benign tumors of bone or soft tissue; however, whether malignant neoplasms can also produce and secrete FGF23 is currently unknown...
  12. pmc Insights from genetic disorders of phosphate homeostasis
    Marta Christov
    Renal Unit, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
    Semin Nephrol 33:143-57. 2013
    ..Thus, we are able to leverage our knowledge of rare human disorders affecting only a few individuals, to understand and potentially treat disease processes that affect millions of patients...
  13. pmc Activation of a non-cAMP/PKA signaling pathway downstream of the PTH/PTHrP receptor is essential for a sustained hypophosphatemic response to PTH infusion in male mice
    Jun Guo
    Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Endocrinology 154:1680-9. 2013
    ..Our data indicate that PLC signaling at the PPR contributes to the long-term effect of PTH on Pi homeostasis but not to the regulation of 1,25 dihydroxyvitamin D3, fibroblast growth factor 23, or blood Ca(2+)...
  14. pmc Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH
    Akira Maeda
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    Proc Natl Acad Sci U S A 110:5864-9. 2013
    ....
  15. pmc FGF23 and mineral metabolism in the early post-renal transplantation period
    Katherine Wesseling-Perry
    Department of Pediatrics, David Geffen School of Medicine at UCLA, A2 383 MDCC, 650 Charles Young Drive, Los Angeles, 90095, CA, USA
    Pediatr Nephrol 28:2207-15. 2013
    ..The relationship between fibroblast growth factor 23 (FGF23) and vitamin D production and catabolism post-renal transplantation has not been characterized...
  16. pmc Disordered FGF23 and mineral metabolism in children with CKD
    Anthony A Portale
    Department of Pediatrics, University of California, San Francisco, California, Department of Medicine and, Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, Department of Pediatrics, Weill Cornell Medical College, New York, New York, Department of Pediatrics, University of California, Los Angeles, California, Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York, Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, Department of Pediatrics, University of Missouri Kansas City School of Medicine, Kansas City, Missouri
    Clin J Am Soc Nephrol 9:344-53. 2014
    ....
  17. pmc Phospholipase C signaling via the parathyroid hormone (PTH)/PTH-related peptide receptor is essential for normal bone responses to PTH
    Jun Guo
    Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Endocrinology 151:3502-13. 2010
    ..Furthermore, PTH stimulated proliferation and increased mRNAs encoding cyclin D1 in primary osteoblasts derived from Wt but not from DSEL mice. Our data indicate that PLC signaling through the PTHR is required for skeletal homeostasis...
  18. pmc Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active
    Takashi Shimada
    Endocrine Unit, Thier 10, 50 Blossum Street, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    J Clin Endocrinol Metab 95:578-85. 2010
    ....
  19. pmc Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis
    Clemens Bergwitz
    Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    J Clin Endocrinol Metab 94:4267-74. 2009
    ..However, it remained unclear to date how these mutations lead to loss of biologically active FGF23 in the circulation...
  20. pmc Mechanisms of ligand binding to the parathyroid hormone (PTH)/PTH-related protein receptor: selectivity of a modified PTH(1-15) radioligand for GalphaS-coupled receptor conformations
    Thomas Dean
    Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    Mol Endocrinol 20:931-43. 2006
    ..Thus, (125)I-[Aib(1,3),M]PTH(1-15) appears to function as a selective probe of Galpha(S)-coupled, active-state PTHR conformations...
  21. ncbi Role of amino acid side chains in region 17-31 of parathyroid hormone (PTH) in binding to the PTH receptor
    Thomas Dean
    Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School, 50 Blossom Street, Boston, MA 02114, USA
    J Biol Chem 281:32485-95. 2006
    ..The data help define the roles that side chains in the binding domain of PTH play in the PTH-PTHR interaction process and provide new clues for understanding the overall topology of the bimolecular complex...
  22. ncbi Alix (AIP1) is a vasopressin receptor (V2R)-interacting protein that increases lysosomal degradation of the V2R
    Xianhua Yi
    Cellular Biophysics Laboratory, Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas, USA
    Am J Physiol Renal Physiol 292:F1303-13. 2007
    ..These data suggest that Alix increases the rate of lysosomal degradation of V2R and may play an important regulatory role in the VP response by modulating V2R downregulation...
  23. pmc Contributions of parathyroid hormone (PTH)/PTH-related peptide receptor signaling pathways to the anabolic effect of PTH on bone
    D Yang
    Endocrine Unit, Thier 11, Massachusetts General Hospital, Boston, MA 02114, USA
    Bone 40:1453-61. 2007
    ..PTH1R PLC signaling pathway is not required for an anabolic effect of intermittent PTH(1-34) on bone...
  24. ncbi Continuous activation of G alpha q in osteoblasts results in osteopenia through impaired osteoblast differentiation
    Naoshi Ogata
    Endocrine Unit and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
    J Biol Chem 282:35757-64. 2007
    ..We propose that continuous activation of the G alpha(q) signal in osteoblasts plays a crucial, previously unrecognized role in bone formation...
  25. pmc Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor
    Thomas Dean
    Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    Mol Endocrinol 22:156-66. 2008
    ..paracrine, and may help explain reported differences in the effects that the ligands have on calcium and bone metabolism when administered to humans...
  26. ncbi Ezrin promotes functional expression and parathyroid hormone-mediated regulation of the sodium-phosphate cotransporter 2a in LLC-PK1 cells
    Matthew J Mahon
    Department of Medicine, Harvard Medical School and Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA
    Am J Physiol Renal Physiol 294:F667-75. 2008
    ..Instead, PTH perhaps initiates NPT2a endocytosis by inducing reorganization of the actin-containing microvilli in a process that is blocked by the actin-stabilizing compound jasplakinolide...
  27. pmc CBP/p300-interacting protein CITED1 modulates parathyroid hormone regulation of osteoblastic differentiation
    Dehong Yang
    Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    Endocrinology 149:1728-35. 2008
    ..We conclude also that PTH receptor signaling pathways independent of cAMP restrain osteoblastic differentiation, an effect normally obscured in the presence of CITED1 but revealed in its absence...
  28. pmc Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation
    Matthew J Hilton
    Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA
    Nat Med 14:306-14. 2008
    ..Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway...
  29. pmc A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc
    Graciana Jaureguiberry
    Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
    Am J Physiol Renal Physiol 295:F371-9. 2008
    ..M137 thus may uncouple sodium-phosphate cotransport, suggesting that this amino acid residue has an important functional role in human NaPi-IIc...
  30. pmc Eliminating phosphorylation sites of the parathyroid hormone receptor type 1 differentially affects stimulation of phospholipase C and receptor internalization
    Susanne U Miedlich
    Massachusetts General Hospital Harvard Medical School, Boston, MA 02114, USA
    Am J Physiol Endocrinol Metab 295:E665-71. 2008
    ..In addition, we show that G protein-coupled receptor kinase 2 interferes with pd PTH1R signaling to G(q/11) proteins at least partially by direct binding to G(q/11) proteins...
  31. pmc Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation
    Makoto Okazaki
    Endocrine Unit and Center for Systems Biology, Massachusetts General Hospital, and Orthopedic Biomechanic Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02114, USA
    Proc Natl Acad Sci U S A 105:16525-30. 2008
    ..Controlling, via ligand analog design, the selectivity with which a PTH ligand binds to R(0), versus RG, may be a strategy for optimizing signaling duration time, and hence therapeutic efficacy, of PTHR agonist ligands...
  32. pmc NHERF1 regulates parathyroid hormone receptor desensitization: interference with beta-arrestin binding
    Bin Wang
    Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Mol Pharmacol 75:1189-97. 2009
    ..NHERF1 inhibited beta-arrestin2 binding to wtPTH1R but had no effect on beta-arrestin2 association with pdPTH1R. Such an effect may protect against PTH resistance or PTH1R down-regulation in cells harboring NHERF1...
  33. pmc Disorders of phosphate homeostasis and tissue mineralisation
    Clemens Bergwitz
    Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA
    Endocr Dev 16:133-56. 2009
    ..This chapter will provide an update on the current knowledge of the pathophysiology, the clinical presentation, diagnostic evaluation and therapy of the disorders of phosphate homeostasis and tissue mineralisation...
  34. pmc Growth hormone protects against ovariectomy-induced bone loss in states of low circulating insulin-like growth factor (IGF-1)
    J Christopher Fritton
    Leni and Peter W May Department of Orthopaedics, Mount Sinai School of Medicine, New York, NY 10029, USA
    J Bone Miner Res 25:235-46. 2010
    ..Interactions between estrogen and the GH/IGF-1 system as related to bone remodeling provide a pathway to minimize degeneration of bone tissue structure and osteoporotic fracture...
  35. pmc Life impact of urologic pain syndromes
    Lena Hatchett
    Department of Preventive Medicine, Loyola University Medical Center, Maywood, IL 60153, USA
    J Health Psychol 14:741-50. 2009
    ..Fatigue emerged as a newly recognized symptom that may benefit from treatment. Role limitations are mediated by potentially modifiable personal and interpersonal effects currently not addressed in urologic pain treatment paradigms...
  36. pmc TIP39/parathyroid hormone type 2 receptor signaling is a potent inhibitor of chondrocyte proliferation and differentiation
    Dibiyendu Panda
    Div of Endocrinology, Dept of Medicine, Sir Mortimer B Davis Jewish General Hosp, 3755 Cote Ste Catherine Road, Montreal, QC, Canada H3T 1E2
    Am J Physiol Endocrinol Metab 297:E1125-36. 2009
    ....
  37. pmc Caffey disease: new perspectives on old questions
    Harikiran Nistala
    Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    Bone 60:246-51. 2014
    ....