The signaling pathways mediating the phosphaturic actions of PTH are heavily disputed;while many in vitro and ex vivo investigations indicate that the IP3/PKC pathway down-stream of the PTH/PTHrP receptor (PTHR1) is of considerable importance, different forms of pseudohypoparathyroidism (PHP) are clearly caused by abnormal Gas signaling, indicating that the cAMP/PKA signaling pathway has a major role in renal phosphate handling. Consistent with these findings in rare genetic disorders, recent studies in mice have shown that the acute PTH-stimulated excretion of phosphate largely depends on cAMP/PKA signaling. However, mice engineered to express a mutant PTHR1 that fails to increase IP3/PKC formation in response to PTH (D/D mice) develop resistance towards prolonged PTH elevations, indicating that the long-term PTH-dependent regulation of renal phosphate excretion requires intact IP3/PKC signaling. Through signal-selective PTH analogs and genetically manipulated mice, we propose to further dissect the relative contribution of each second messenger pathway to acute and chronic PTH-dependent handling of renal phosphate excretion (Aim 1). We will furthermore determine whether desensitization of the cAMP/PKA pathway occurs with prolonged PTH stimulation, thus explaining the only transient phosphaturic effect of acute PTH injections (Aim 2). Lastly, through the use of PEGylated, signal-selective PTH analogs that are not filtered at the glomerular membrane, we will determine whether PTH acts at the brush-border membrane, at the base-lateral membrane, or at both membranes (Aim 3). Our experiments are expected to help in the development of PTH analogs or PTH mimetics that promote phosphate excretion, ideally without having major effects on calcium homeostasis, thus reducing the risk of extraosseous calcifications in patients with rare genetic disorders or earlier stage of chronic kidney disease (CKD), and lowering the circulating levels of fibroblast growth factor 23 (FGF23), which contribute to kidney disease progression and left ventricular hypertrophy, and probably early mortality in patients with end-stage renal disease

Public Health Relevance

Defining the second messenger pathway at the PTH/PTHrP receptor that enhances urinary phosphate excretion will help in developing PTH analogs or small molecules with sustained phosphaturic properties. Besides allowing dissection of the molecular mechanisms involved in renal phosphate handling, such compounds could help treat hyperphosphatemic disorder, including earlier stages of chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK011794-46
Application #
8659692
Study Section
Special Emphasis Panel (ZDK1-GRB-J (O1))
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
46
Fiscal Year
2014
Total Cost
$435,000
Indirect Cost
$185,000
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Bi, Ruiye; Fan, Yi; Lauter, Kelly et al. (2016) Diphtheria Toxin- and GFP-Based Mouse Models of Acquired Hypoparathyroidism and Treatment With a Long-Acting Parathyroid Hormone Analog. J Bone Miner Res 31:975-84
Stevenson, Hilary P; Lin, Guowu; Barnes, Christopher O et al. (2016) Transmission electron microscopy for the evaluation and optimization of crystal growth. Acta Crystallogr D Struct Biol 72:603-15
Ono, Noriaki; Kronenberg, Henry M (2016) Bone repair and stem cells. Curr Opin Genet Dev 40:103-107
Kim, Sang Wan; Lu, Yanhui; Williams, Elizabeth A et al. (2016) Sclerostin Antibody Administration Converts Bone Lining Cells into Active Osteoblasts. J Bone Miner Res :
Wein, Marc N; Liang, Yanke; Goransson, Olga et al. (2016) SIKs control osteocyte responses to parathyroid hormone. Nat Commun 7:13176
Eda, Homare; Santo, Loredana; Wein, Marc N et al. (2016) Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease. J Bone Miner Res 31:1225-34
Sinha, Partha; Aarnisalo, Piia; Chubb, Rhiannon et al. (2016) Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy. J Biol Chem 291:1631-42
Tenhola, Sirpa; Voutilainen, Raimo; Reyes, Monica et al. (2016) Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation. Eur J Endocrinol 175:211-8
Cheloha, Ross W; Watanabe, Tomoyuki; Dean, Thomas et al. (2016) Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist. ACS Chem Biol 11:2752-2762
Hattersley, Gary; Dean, Thomas; Corbin, Braden A et al. (2016) Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology 157:141-9

Showing the most recent 10 out of 195 publications