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

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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.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Christov, Marta; Clark, Abbe R; Corbin, Braden et al. (2018) Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities. JCI Insight 3:
Dedic, Christopher; Hung, Tin Shing; Shipley, Alan M et al. (2018) Calcium fluxes at the bone/plasma interface: Acute effects of parathyroid hormone (PTH) and targeted deletion of PTH/PTH-related peptide (PTHrP) receptor in the osteocytes. Bone 116:135-143
Mizuhashi, Koji; Ono, Wanida; Matsushita, Yuki et al. (2018) Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature 563:254-258
Hanna, Patrick; Grybek, Virginie; Perez de Nanclares, Guiomar et al. (2018) Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity. J Bone Miner Res 33:1480-1488
Wein, Marc N; Foretz, Marc; Fisher, David E et al. (2018) Salt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential. Trends Endocrinol Metab 29:723-735
Bastepe, Murat (2018) GNAS mutations and heterotopic ossification. Bone 109:80-85
Roszko, Kelly L; Bi, Ruiye; Gorvin, Caroline M et al. (2017) Knockin mouse with mutant G?11 mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors. JCI Insight 2:e91079
Grigelioniene, Giedre; Nevalainen, Pasi I; Reyes, Monica et al. (2017) A Large Inversion Involving GNAS Exon A/B and All Exons Encoding Gs? Is Associated With Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B). J Bone Miner Res 32:776-783
Balani, Deepak H; Ono, Noriaki; Kronenberg, Henry M (2017) Parathyroid hormone regulates fates of murine osteoblast precursors in vivo. J Clin Invest 127:3327-3338
Cheloha, Ross W; Chen, Bingming; Kumar, Niyanta N et al. (2017) Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad ? Residue Distribution. J Med Chem 60:8816-8833

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