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PTH and PTHrP Actions on Bone

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Bone Regulators and Osteoporosis Therapy

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 262))

Abstract

Parathyroid hormone (PTH), PTH-related peptide (PTHrP), PTHR, and their cognate G protein-coupled receptor play defining roles in the regulation of extracellular calcium and phosphate metabolism and in controlling skeletal growth and repair. Acting through complex signaling mechanisms that in many instances proceed in a tissue-specific manner, precise control of these processes is achieved. A variety of direct and indirect disease processes, along with genetic anomalies, can cause these schemes to become dysfunctional. Here, we review the basic components of this regulatory network and present both the well-established elements and emerging findings and concepts with the overall objective to provide a framework for understanding the elementary aspects of how PTH and PTHrP behave and as a call to encourage further investigation that will yield more comprehensive understanding of the physiological and pathological steps at play, with a goal toward novel therapeutic interventions.

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Notes

  1. 1.

    By convention, gene names are italicized. Human genes and their protein products are in uppercase, for other species only the first letter is capitalized.

References

  • Abbas SK et al (1989) Stimulation of ovine placental calcium transport by purified natural and recombinant parathyroid hormone-related protein (PTHrP) preparations. Q J Exp Physiol 74:549–552

    CAS  PubMed  Google Scholar 

  • Abou-Samra AB et al (1992) Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci U S A 89:2732–2736

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alonso V, de Gortazar AR, Ardura JA, Andrade-Zapata I, Alvarez-Arroyo MV, Esbrit P (2008) Parathyroid hormone-related protein (107-139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor-2. J Cell Physiol 217:717–727

    CAS  PubMed  Google Scholar 

  • Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC (1994) Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation. J Cell Biol 126:1611–1623

    CAS  PubMed  Google Scholar 

  • Amizuka N et al (1996) Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. Dev Biol 175:166–176

    CAS  PubMed  Google Scholar 

  • Anderson LJ, Tamayose JM, Garcia JM (2018) Use of growth hormone, IGF-I, and insulin for anabolic purpose: pharmacological basis, methods of detection, and adverse effects. Mol Cell Endocrinol 464:65–74

    CAS  PubMed  Google Scholar 

  • Behar V, Nakamoto C, Greenberg Z, Bisello A, Suva LJ, Rosenblatt M, Chorev M (1996) Histidine at position 5 is the specificity “switch” between two parathyroid hormone receptor subtypes. Endocrinology 137:4217–4224

    CAS  PubMed  Google Scholar 

  • Bilezikian JP, Bandeira L, Khan A, Cusano NE (2018) Hyperparathyroidism. Lancet 391:168–178

    CAS  PubMed  Google Scholar 

  • Bisello A, Chorev M, Rosenblatt M, Monticelli L, Mierke DF, Ferrari SL (2002) Selective ligand-induced stabilization of active and desensitized parathyroid hormone type 1 receptor conformations. J Biol Chem 277:38524–38530

    CAS  PubMed  Google Scholar 

  • Black DM et al (2008) Randomized trial of once-weekly parathyroid hormone (1-84) on bone mineral density and remodeling. J Clin Endocrinol Metab 93:2166–2172

    CAS  PubMed  PubMed Central  Google Scholar 

  • Black DM et al (2013) Improved adherence with PTH(1-84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis. Osteoporos Int 24:1503–1511

    CAS  PubMed  Google Scholar 

  • Blind E, Bambino T, Huang ZM, Bliziotes M, Nissenson RA (1996) Phosphorylation of the cytoplasmic tail of the PTH/PTHrP receptor. J Bone Miner Res 11:578–586

    CAS  PubMed  Google Scholar 

  • Brown EM, Wilson RE, Thatcher JG, Marynick SP (1981) Abnormal calcium-regulated PTH release in normal parathyroid tissue from patients with adenoma. Am J Med 71:565–570

    CAS  PubMed  Google Scholar 

  • Brown EM et al (1993) Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 366:575–580

    CAS  PubMed  Google Scholar 

  • Burtis WJ et al (1990) Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 322:1106–1112

    CAS  PubMed  Google Scholar 

  • Castro M, Dicker F, Vilardaga JP, Krasel C, Bernhardt M, Lohse MJ (2002) Dual regulation of the parathyroid hormone (PTH)/PTH-related peptide receptor signaling by PKC and ß-arrestins. Endocrinology 143:3854–3865

    CAS  PubMed  Google Scholar 

  • Cheloha RW, Gellman SH, Vilardaga JP, Gardella TJ (2015) PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 11:712–724

    CAS  PubMed  PubMed Central  Google Scholar 

  • Civitelli R, Martin TJ, Fausto A, Gunsten SL, Hruska KA, Avioli LV (1989) Parathyroid hormone-related peptide transiently increases cytosolic calcium in osteoblast-like cells: comparison with parathyroid hormone. Endocrinology 125:1204–1210

    CAS  PubMed  Google Scholar 

  • Civitelli R, Hruska KA, Shen V, Avioli LV (1990) Cyclic AMP-dependent and calcium-dependent signals in parathyroid hormone function. Exp Gerontol 25:223–231

    CAS  PubMed  Google Scholar 

  • Cole JA (1999) Parathyroid hormone activates mitogen-activated protein kinase in opossum kidney cells. Endocrinology 140:5771–5779

    CAS  PubMed  Google Scholar 

  • Cornish J, Callon KE, Nicholson GC, Reid IR (1997) Parathyroid hormone-related protein-(107-139) inhibits bone resorption in vivo. Endocrinology 138:1299–1304

    CAS  PubMed  Google Scholar 

  • Cornish J, Callon KE, Lin C, Xiao C, Moseley JM, Reid IR (1999) Stimulation of osteoblast proliferation by C-terminal fragments of parathyroid hormone-related protein. J Bone Miner Res 14:915–922

    CAS  PubMed  Google Scholar 

  • Cramer SD, Chen Z, Peehl DM (1996) Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J Urol 156:526–531

    CAS  PubMed  Google Scholar 

  • Cupp ME, Nayak SK, Adem AS, Thomsen WJ (2013) Parathyroid hormone (PTH) and PTH-related peptide domains contributing to activation of different PTH receptor-mediated signaling pathways. J Pharmacol Exp Ther 345:404–418

    CAS  PubMed  Google Scholar 

  • Datta NS, Samra TA, Abou-Samra AB (2012) Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice. Am J Physiol Endocrinol Metab 302:E1183–E1188

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dean T, Vilardaga JP, Potts JT Jr, Gardella TJ (2008) Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. Mol Endocrinol 22:156–166

    CAS  PubMed  Google Scholar 

  • Dicker F, Quitterer U, Winstel R, Honold K, Lohse MJ (1999) Phosphorylation-independent inhibition of parathyroid hormone receptor signaling by G protein-coupled receptor kinases. Proc Natl Acad Sci U S A 96:5476–5481

    CAS  PubMed  PubMed Central  Google Scholar 

  • Diefenbach-Jagger H, Brenner C, Kemp BE, Baron W, McLean J, Martin TJ, Moseley JM (1995) Arg21 is the preferred kexin cleavage site in parathyroid-hormone-related protein. Eur J Biochem 229:91–98

    CAS  PubMed  Google Scholar 

  • Divieti P, Inomata N, Chapin K, Singh R, Juppner H, Bringhurst FR (2001) Receptors for the carboxyl-terminal region of PTH(1-84) are highly expressed in osteocytic cells. Endocrinology 142:916–925

    CAS  PubMed  Google Scholar 

  • Duvos C, Scutt A, Mayer H (2006) hPTH-fragments (53-84) and (28-48) antagonize the stimulation of calcium release and repression of alkaline phosphatase activity by hPTH-(1-34) in vitro. FEBS Lett 580:1509–1514

    CAS  PubMed  Google Scholar 

  • Everhart-Caye M, Inzucchi SE, Guinness-Henry J, Mitnick MA, Stewart AF (1996) Parathyroid hormone (PTH)-related protein(1-36) is equipotent to PTH(1-34) in humans. J Clin Endocrinol Metab 81:199–208

    CAS  PubMed  Google Scholar 

  • Fenton AJ, Martin TJ, Nicholson GC (1993) Long-term culture of disaggregated rat osteoclasts: inhibition of bone resorption and reduction of osteoclast-like cell number by calcitonin and PTHrP[107-139]. J Cell Physiol 155:1–7

    CAS  PubMed  Google Scholar 

  • Ferrandon S et al (2009) Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol 5:734–742

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ferrari SL, Bisello A (2001) Cellular distribution of constitutively active mutant parathyroid hormone (PTH)/PTH-related protein receptors and regulation of cyclic adenosine 3′,5′-monophosphate signaling by ß-arrestin2. Mol Endocrinol 15:149–163

    CAS  PubMed  Google Scholar 

  • Ferrari SL, Behar V, Chorev M, Rosenblatt M, Bisello A (1999) Endocytosis of ligand-human parathyroid hormone receptor 1 complexes is protein kinase C-dependent and involves ß-arrestin2. Real-time monitoring by fluorescence microscopy. J Biol Chem 274:29968–29975

    CAS  PubMed  Google Scholar 

  • Ferrari S et al (2005) Bone response to intermittent parathyroid hormone is altered in mice null for ß-arrestin2. Endocrinology 146:1854–1862

    CAS  PubMed  Google Scholar 

  • Fiaschi-Taesch NM, Stewart AF (2003) Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences. Endocrinology 144:407–411

    CAS  PubMed  Google Scholar 

  • Flannery PJ, Spurney RF (2001) Domains of the parathyroid hormone (PTH) receptor required for regulation by G protein-coupled receptor kinases (GRKs). Biochem Pharmacol 62:1047–1058

    CAS  PubMed  Google Scholar 

  • Frohner IE, Mudrak I, Kronlachner S, Schuchner S, Ogris E (2020) Antibodies recognizing the C terminus of PP2A catalytic subunit are unsuitable for evaluating PP2A activity and holoenzyme composition. Sci Signal 13

    Google Scholar 

  • Frolik CA, Black EC, Cain RL, Satterwhite JH, Brown-Augsburger PL, Sato M, Hock JM (2003) Anabolic and catabolic bone effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure. Bone 33:372–379

    CAS  PubMed  Google Scholar 

  • Gardella TJ, Vilardaga J-P (2015) International union of basic and clinical pharmacology. XCIII. The parathyroid hormone receptors—family B G protein–coupled receptors. Pharmacol Rev 67:310–337

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gesty-Palmer D et al (2006) Distinct ß-arrestin and G protein dependent pathways for parathyroid hormone receptor stimulated ERK1/2 activation. J Biol Chem 281:10856–10864

    CAS  PubMed  Google Scholar 

  • Gesty-Palmer D, Flannery P, Yuan L, Corsino L, Spurney R, Lefkowitz RJ, Luttrell LM (2009) A β-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci Trans Med 1:1ra1

    Google Scholar 

  • Grundmann M et al (2018) Lack of β-arrestin signaling in the absence of active G proteins. Nat Commun 9:341

    PubMed  PubMed Central  Google Scholar 

  • Hendy GN, Bennett HP, Gibbs BF, Lazure C, Day R, Seidah NG (1995) Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study. J Biol Chem 270:9517–9525

    CAS  PubMed  Google Scholar 

  • Horwitz MJ et al (2006) Safety and tolerability of subcutaneous PTHrP(1-36) in healthy human volunteers: a dose escalation study. Osteoporos Int 17:225–230

    CAS  PubMed  Google Scholar 

  • Horwitz MJ et al (2010) Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose. J Clin Endocrinol Metab 95:1279–1287

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huan J, Olgaard K, Nielsen LB, Lewin E (2006) Parathyroid hormone 7-84 induces Hypocalcemia and inhibits the parathyroid hormone 1-84 secretory response to Hypocalcemia in rats with intact parathyroid glands. J Am Soc Nephrol 17:1923–1930

    CAS  PubMed  Google Scholar 

  • Huang Z, Chen Y, Nissenson RA (1995) The cytoplasmic tail of the G-protein-coupled receptor for parathyroid hormone and parathyroid hormone-related protein contains positive and negative signals for endocytosis. J Biol Chem 270:151–156

    CAS  PubMed  Google Scholar 

  • Jilka RL (2007) Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 40:1434–1446

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC (1999) Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 104:439–446

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson RW, Suva LJ (2018) Hallmarks of bone metastasis. Calcif Tissue Int 102:141–151

    CAS  PubMed  Google Scholar 

  • Jüppner H et al (1991) A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254:1024–1026

    PubMed  Google Scholar 

  • Kamalakar A et al (2017) PTHrP(12-48) modulates the bone marrow microenvironment and suppresses human osteoclast differentiation and lifespan. J Bone Miner Res 32:1421–1431

    CAS  PubMed  PubMed Central  Google Scholar 

  • Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8:277–289

    CAS  PubMed  Google Scholar 

  • Karim Z et al (2008) NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 359:1128–1135

    CAS  PubMed  Google Scholar 

  • Kovacs CS (2017) The skeleton is a storehouse of mineral that is plundered during lactation and (fully?) replenished afterwards. J Bone Miner Res 32:676–680

    CAS  PubMed  Google Scholar 

  • Kronenberg HM (2006) PTHrP and skeletal development. Ann N Y Acad Sci 1068:1–13

    CAS  PubMed  Google Scholar 

  • Lanske B et al (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273:663–666

    CAS  PubMed  Google Scholar 

  • Leder BZ et al (2015) Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 100:697–706

    CAS  PubMed  Google Scholar 

  • Lee S et al (2015) A homozygous [Cys25]PTH(1-84) mutation that impairs PTH/PTHrP receptor activation defines a novel form of hypoparathyroidism. J Bone Miner Res 30:1803–1813

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SH, Park YH, Jin YB, Kim SU, Hur JK (2020) CRISPR diagnosis and therapeutics with single base pair precision. Trends Mol Med 26:337–350

    CAS  PubMed  Google Scholar 

  • Liu L et al (2012) Na+/H+-exchanger regulatory factor-1 (NHERF1) directly regulates osteogenesis. J Biol Chem 287:43312–43321

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mahon MJ, Donowitz M, Yun CC, Segre GV (2002) Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature 417:858–861

    CAS  PubMed  Google Scholar 

  • Malecz N, Bambino T, Bencsik M, Nissenson RA (1998) Identification of phosphorylation sites in the G protein-coupled receptor for parathyroid hormone. Receptor phosphorylation is not required for agonist-induced internalization. Mol Endocrinol 12:1846–1856

    CAS  PubMed  Google Scholar 

  • Mannstadt M, Juppner H, Gardella TJ (1999) Receptors for PTH and PTHrP: their biological importance and functional properties. Am J Phys 277:F665–F675

    CAS  Google Scholar 

  • McCauley LK, Martin TJ (2012) Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res 27:1231–1239

    CAS  PubMed  PubMed Central  Google Scholar 

  • Miao D, Tong XK, Chan GK, Panda D, McPherson PS, Goltzman D (2001) Parathyroid hormone-related peptide stimulates osteogenic cell proliferation through PKC activation of the Ras/mitogen-activated protein kinase signaling pathway. J Biol Chem 276:32204–32213

    CAS  PubMed  Google Scholar 

  • Miao D, Li J, Xue Y, Su H, Karaplis AC, Goltzman D (2004) Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice. Endocrinology 145:3554–3562

    CAS  PubMed  Google Scholar 

  • Miao D et al (2005) Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest 115:2402–2411

    CAS  PubMed  PubMed Central  Google Scholar 

  • Miles RR et al (2000) ADAMTS-1: a cellular disintegrin and metalloprotease with thrombospondin motifs is a target for parathyroid hormone in bone. Endocrinology 141:4533–4542

    CAS  PubMed  Google Scholar 

  • Morales FC, Takahashi Y, Kreimann EL, Georgescu MM (2004) Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Proc Natl Acad Sci U S A 101:17705–17710

    CAS  PubMed  PubMed Central  Google Scholar 

  • Neer RM et al (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441

    CAS  PubMed  Google Scholar 

  • Neville MC, McFadden TB, Forsyth I (2002) Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia 7:49–66

    PubMed  Google Scholar 

  • Orloff JJ, Ganz MB, Ribaudo AE, Burtis WJ, Reiss M, Milstone LM, Stewart AF (1992) Analysis of PTHRP binding and signal transduction mechanisms in benign and malignant squamous cells. Am J Phys 262:E599–E607

    CAS  Google Scholar 

  • Orloff JJ, Reddy D, de Papp AE, Yang KH, Soifer NE, Stewart AF (1994) Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev 15:40–60

    CAS  PubMed  Google Scholar 

  • Pines M et al (1996) Inositol 1-,4-,5-trisphosphate-dependent Ca2+ signaling by the recombinant human PTH/PTHrP receptor stably expressed in a human kidney cell line. Bone 18:381–389

    CAS  PubMed  Google Scholar 

  • Portal-Nunez S, Lozano D, de Castro LF, de Gortazar AR, Nogues X, Esbrit P (2010) Alterations of the Wnt/beta-catenin pathway and its target genes for the N- and C-terminal domains of parathyroid hormone-related protein in bone from diabetic mice. FEBS Lett 584:3095–3100

    CAS  PubMed  Google Scholar 

  • Potts JT Jr et al (1971) Synthesis of a biologically active N-terminal tetratriacontapeptide of parathyroid hormone. Proc Natl Acad Sci U S A 68:63–67

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu T, Crane JL, Xie L, Xian L, Xie H, Cao X (2018) IGF-I induced phosphorylation of PTH receptor enhances osteoblast to osteocyte transition. Bone Res 6:5

    PubMed  PubMed Central  Google Scholar 

  • Rey A, Manen D, Rizzoli R, Caverzasio J, Ferrari SL (2006) Proline-rich motifs in the PTH/PTHrP-receptor C-terminus mediate scaffolding of c-Src with ß-arrestin2 for ERK1/2 activation. J Biol Chem:38181–38188

    Google Scholar 

  • Rodda CP et al (1988) Evidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy. J Endocrinol 117:261–271

    CAS  PubMed  Google Scholar 

  • Sakwe AM, Engstrom A, Larsson M, Rask L (2002) Biosynthesis and secretion of parathyroid hormone are sensitive to proteasome inhibitors in dispersed bovine parathyroid cells. J Biol Chem 277:17687–17695

    CAS  PubMed  Google Scholar 

  • Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ (2002) Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A 99:11470–11475

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shenoy SK et al (2006) β-Arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor. J Biol Chem 281:1261–1273

    CAS  PubMed  Google Scholar 

  • Shimizu M et al (2016) Pharmacodynamic actions of a long-acting PTH analog (LA-PTH) in thyroparathyroidectomized (tptx) rats and normal monkeys. J Bone Miner Res 31:1405–1412

    CAS  PubMed  PubMed Central  Google Scholar 

  • Slatopolsky E et al (2000) A novel mechanism for skeletal resistance in uremia. Kidney Int 58:753–761

    CAS  PubMed  Google Scholar 

  • Sneddon WB, Friedman PA (2007) ß-arrestin-dependent parathyroid hormone-stimulated ERK activation and PTH1R internalization. Endocrinology 148:4073–4079

    CAS  PubMed  Google Scholar 

  • Sneddon WB, Gesek FA, Friedman PA (2000) Obligate MAP kinase activation in parathyroid hormone stimulation of calcium transport but not calcium signaling. Endocrinology 141:4185–4193

    CAS  PubMed  Google Scholar 

  • Sneddon WB et al (2003) Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50). J Biol Chem 278:43787–43796

    CAS  PubMed  Google Scholar 

  • Soifer NE et al (1992) Parathyroid hormone-related protein. Evidence for secretion of a novel mid-region fragment by three different cell types. J Biol Chem 267:18236–18243

    CAS  PubMed  Google Scholar 

  • Spurney RF, Flannery PJ, Garner SC, Athirakul K, Liu S, Guilak F, Quarles LD (2002) Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts. J Clin Invest 109:1361–1371

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suva LJ et al (1987) A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237:893–896

    CAS  PubMed  Google Scholar 

  • Swarthout JT, Doggett TA, Lemker JL, Partridge NC (2001) Stimulation of extracellular signal-regulated kinases and proliferation in rat osteoblastic cells by parathyroid hormone is PKC-dependent. J Biol Chem 276:7586–7592

    CAS  PubMed  Google Scholar 

  • Syme CA, Friedman PA, Bisello A (2005) Parathyroid hormone receptor trafficking contributes to the activation of extracellular signal-regulated kinases but is not required for regulation of cAMP signaling. J Biol Chem 280:11281–11288

    CAS  PubMed  Google Scholar 

  • Thirunavukkarasu K, Halladay DL, Miles RR, Geringer CD, Onyia JE (2002) Analysis of regulator of G-protein signaling-2 (RGS-2) expression and function in osteoblastic cells. J Cell Biochem 85:837–850

    CAS  PubMed  Google Scholar 

  • van der Lee MM et al (2013) ß-Arrestin-biased signalling of PTH analogues of the type 1 parathyroid hormone receptor. Cell Signal 25:527–538

    PubMed  Google Scholar 

  • VanHouten J, Dann P, McGeoch G, Brown EM, Krapcho K, Neville M, Wysolmerski JJ (2004) The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. J Clin Invest 113:598–608

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vilardaga JP, Frank M, Krasel C, Dees C, Nissenson RA, Lohse MJ (2001) Differential conformational requirements for activation of G proteins and the regulatory proteins arrestin and G protein-coupled receptor kinase in the G protein-coupled receptor for parathyroid hormone (PTH)/PTH-related protein. J Biol Chem 276:33435–33443

    CAS  PubMed  Google Scholar 

  • Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ (1996) Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273:613–622

    CAS  PubMed  Google Scholar 

  • Wang HH, Drugge ED, Yen YC, Blumenthal MR, Pang PK (1984) Effects of synthetic parathyroid hormone on hemodynamics and regional blood flows. Eur J Pharmacol 97:209–215

    CAS  PubMed  Google Scholar 

  • Wang L, Liu S, Quarles LD, Spurney RF (2005) Targeted overexpression of G protein-coupled receptor kinase-2 in osteoblasts promotes bone loss. Am J Physiol Endocrinol Metab 288:E826–E834

    CAS  PubMed  Google Scholar 

  • Wang B, Bisello A, Yang Y, Romero GG, Friedman PA (2007) NHERF1 regulates parathyroid hormone receptor membrane retention without affecting recycling. J Biol Chem 282:36214–36222

    CAS  PubMed  Google Scholar 

  • Wang B, Ardura JA, Romero G, Yang Y, Hall RA, Friedman PA (2010) Na/H exchanger regulatory factors control PTH receptor signaling by differential activation of Gα protein subunits. J Biol Chem 285:26976–26986

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang B, Yang Y, Liu L, Blair HC, Friedman PA (2013) NHERF1 regulation of PTH-dependent bimodal pi transport in osteoblasts. Bone 52:268–277

    CAS  PubMed  Google Scholar 

  • Washam CL et al (2013) Identification of PTHrP(12-48) as a plasma biomarker associated with breast cancer bone metastasis. Cancer Epidemiol Biomark Prev 22:972–983

    CAS  Google Scholar 

  • Wehbi VL, Stevenson HP, Feinstein TN, Calero G, Romero G, Vilardaga JP (2013) Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex. Proc Natl Acad Sci U S A 110:1530–1535

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu TL et al (1996) Structural and physiologic characterization of the mid-region secretory species of parathyroid hormone-related protein. J Biol Chem 271:24371–24381

    CAS  PubMed  Google Scholar 

  • Zhang Q et al (2018) Site-specific polyubiquitination differentially regulates parathyroid hormone receptor-initiated MAPK signaling and cell proliferation. J Biol Chem 293:5556–5571

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao LH et al (2019) Structure and dynamics of the active human parathyroid hormone receptor-1. Science 364:148–153

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Original work cited herein was supported by grants DK105811 and DK111427 (PAF) and CA166060 and AA018282 (LJS) from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas Veterinary Medical Center, Texas A&M University, College Station, TX, USA

    Larry J. Suva

  2. Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Peter A. Friedman

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  1. Larry J. Suva
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Correspondence to Peter A. Friedman .

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  1. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Paula H. Stern

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Suva, L.J., Friedman, P.A. (2020). PTH and PTHrP Actions on Bone. In: Stern, P.H. (eds) Bone Regulators and Osteoporosis Therapy. Handbook of Experimental Pharmacology, vol 262. Springer, Cham. https://doi.org/10.1007/164_2020_362

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