Parathyroid hormone-related protein explained

Parathyroid hormone-related protein (PTHrP) is a proteinaceous hormone and a member of the parathyroid hormone family secreted by mesenchymal stem cells. It is occasionally secreted by cancer cells (for example, breast cancer, certain types of lung cancer including squamous-cell lung carcinoma). However, it also has normal functions in bone, teeth, vascular tissues and other tissues.

Function

PTHrP acts as an endocrine, autocrine, paracrine, and intracrine hormone. It regulates endochondral bone development by maintaining the endochondral growth plate at a constant width. It also regulates epithelial–mesenchymal interactions during the formation of the mammary glands. PTHrP plays a major role in regulating calcium homeostasis in vertebrates, including sea bream, chick, and mammals.^[1]

In 2005, Australian pathologist and researcher Thomas John Martin found that PTHrP produced by osteoblasts is a physiological regulator of bone formation.^[2] Martin and Miao et al. demonstrated that osteoblast-specific ablation of PTHrP in mice results in osteoporosis and impaired bone formation both in vivo and ex vivo, which reiterates the phenotype of mice with haploinsufficiency of PTHrP. By these findings, they demonstrated that PTHrP plays a central role in physiological regulation of bone formation by promoting recruitment and survival of osteoblasts. It may also play a role in physiological regulation of bone resorption by enhancing osteoclast formation.^[2]

Tooth eruption

PTHrP is critical in intraosseous phase of tooth eruption where it acts as a signalling molecule to stimulate local bone resorption.^[3] Without PTHrP, the bony crypt surrounding the tooth follicle will not resorb, and therefore the tooth will not erupt. In the context of tooth eruption, PTHrP is secreted by the cells of the reduced enamel epithelium.^[4]

Mammary glands

It aids in normal mammary gland development.^{[5] [6]} It is necessary for maintenance of the mammary bud cells. Loss of PTHrP or its receptor causes the mammary bud cells to change back into epidermal cells. In lactation, it may regulate the mobilization and transfer of calcium to the milk in conjunction with the calcium sensing receptors, as well as placental transfer of calcium.

Humoral hypercalcemia of malignancy

PTHrP is related in function to parathyroid hormone(PTH). When a tumor secretes PTHrP, this can lead to hypercalcemia.^[7] As this is sometimes the first sign of the malignancy, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon. PTHrP is responsible for most cases of humoral hypercalcemia of malignancy.

PTHrP shares the same N-terminal end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor (PTHR1).^[8] PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport. PTHrP lacks the normal feedback inhibition as PTH.^[9]

However, PTHrP has a less sustained action than PTH on PTHR1 activation, which may explain at least in part its reduced ability to stimulate 1,25-dihydroxyvitamin D (1,25(OH)₂ vitamin D) production and indirectly intestinal calcium absorption through an action to increase circulating levels of 1,25(OH)₂ vitamin D.^[10]

Growth Plate

PTHrP is found in the proliferative zone of the growth plate. It is one of the main proteins that regulates mesenchymal stem cell activity. Current research suggests that PTHrP promotes the proliferation of early-phase chondrocytes and inhibits their differentiation into hypertropic chondrocytes. It is involved in a negative feedback loop with Indian Hedgehog (Ihh). ^[11]

Genetics

Four alternatively spliced transcript variants encoding two distinct isoforms have been observed. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, in-frame and downstream of the initiator AUG codon, to give rise to nuclear forms of this hormone.^[12]

Discovery

The protein was first isolated in 1987 by Thomas J. Martin's team at the University of Melbourne.^{[13] [14]} Miao et al. showed that disruption of the PTHrP gene in mice caused a lethal phenotype and distinct bone abnormalities, suggesting that PTHrP has a physiological function.^[15]

Interactions

Parathyroid hormone-related protein has been shown to interact with KPNB1^{[16] [17]} and Arrestin beta 1.^[18]

See also

• Analogs used as pharmaceutical drugs
  • Teriparatide
  • Abaloparatide

Further reading

• Miao D, Li J, Xue Y, Su H, Karaplis AC, Goltzman D . Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice . Endocrinology . 145 . 8 . 3554–3562 . August 2004 . 15090463 . 10.1210/en.2003-1695 . free .
• Casey ML, MacDonald PC . The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta . Human Reproduction . 11 . Suppl 2 . 62–82 . October 1996 . 8982748 . 10.1093/humrep/11.suppl_2.62 .
• Lam MH, Thomas RJ, Martin TJ, Gillespie MT, Jans DA . Nuclear and nucleolar localization of parathyroid hormone-related protein . Immunology and Cell Biology . 78 . 4 . 395–402 . August 2000 . 10947864 . 10.1046/j.1440-1711.2000.00919.x . 23048105 .
• Fiaschi-Taesch NM, Stewart AF . Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences . Endocrinology . 144 . 2 . 407–411 . February 2003 . 12538599 . 10.1210/en.2002-220818 . free .
• Book: Jans DA, Thomas RJ, Gillespie MT . Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles . 66 . 345–84 . 2003 . 12852260 . 10.1016/S0083-6729(03)01010-0 . 978-0-12-709866-1 . Vitamins & Hormones .
• Maioli E, Fortino V, Pacini A . Parathyroid hormone-related protein in preeclampsia: a linkage between maternal and fetal failures . Biology of Reproduction . 71 . 6 . 1779–1784 . December 2004 . 15286039 . 10.1095/biolreprod.104.030932 . 27542199 . free .
• Fenton AJ, Kemp BE, Kent GN, Moseley JM, Zheng MH, Rowe DJ, Britto JM, Martin TJ, Nicholson GC . 6 . A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts . Endocrinology . 129 . 4 . 1762–1768 . October 1991 . 1915066 . 10.1210/endo-129-4-1762 .
• Fenton AJ, Kemp BE, Hammonds RG, Mitchelhill K, Moseley JM, Martin TJ, Nicholson GC . A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP[107-111] . Endocrinology . 129 . 6 . 3424–3426 . December 1991 . 1954916 . 10.1210/endo-129-6-3424 .
• Moniz C, Burton PB, Malik AN, Dixit M, Banga JP, Nicolaides K, Quirke P, Knight DE, McGregor AM . 6 . Parathyroid hormone-related peptide in normal human fetal development . Journal of Molecular Endocrinology . 5 . 3 . 259–266 . December 1990 . 2288637 . 10.1677/jme.0.0050259 .
• Hammonds RG, McKay P, Winslow GA, Diefenbach-Jagger H, Grill V, Glatz J, Rodda CP, Moseley JM, Wood WI, Martin TJ . 6 . Purification and characterization of recombinant human parathyroid hormone-related protein . The Journal of Biological Chemistry . 264 . 25 . 14806–14811 . September 1989 . 2549037 . 10.1016/S0021-9258(18)63771-8 . free .
• Yasuda T, Banville D, Hendy GN, Goltzman D . Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects . The Journal of Biological Chemistry . 264 . 13 . 7720–7725 . May 1989 . 2708388 . 10.1016/S0021-9258(18)83294-X . free .
• Suva LJ, Mather KA, Gillespie MT, Webb GC, Ng KW, Winslow GA, Wood WI, Martin TJ, Hudson PJ . 6 . Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP) . Gene . 77 . 1 . 95–105 . April 1989 . 2744490 . 10.1016/0378-1119(89)90363-6 .
• Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir EC, Stewart AF, Bander NH, Milstone L, Barton DE . 6 . Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy . Proceedings of the National Academy of Sciences of the United States of America . 85 . 2 . 597–601 . January 1988 . 2829195 . 279598 . 10.1073/pnas.85.2.597 . free . 1988PNAS...85..597M .
• Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall RE, Kemp BE, Suva LJ, Rodda CP, Ebeling PR, Hudson PJ, Zajac JD . 6 . Parathyroid hormone-related protein purified from a human lung cancer cell line . Proceedings of the National Academy of Sciences of the United States of America . 84 . 14 . 5048–5052 . July 1987 . 2885845 . 305244 . 10.1073/pnas.84.14.5048 . free . 1987PNAS...84.5048M .
• Mangin M, Ikeda K, Dreyer BE, Broadus AE . Isolation and characterization of the human parathyroid hormone-like peptide gene . Proceedings of the National Academy of Sciences of the United States of America . 86 . 7 . 2408–2412 . April 1989 . 2928340 . 286922 . 10.1073/pnas.86.7.2408 . free . 1989PNAS...86.2408M .
• Thiede MA, Strewler GJ, Nissenson RA, Rosenblatt M, Rodan GA . Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene . Proceedings of the National Academy of Sciences of the United States of America . 85 . 13 . 4605–4609 . July 1988 . 3290897 . 280483 . 10.1073/pnas.85.13.4605 . free . 1988PNAS...85.4605T .
• Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, Rodda CP, Kemp BE, Rodriguez H, Chen EY . 6 . A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression . Science . 237 . 4817 . 893–896 . August 1987 . 3616618 . 10.1126/science.3616618 . 1987Sci...237..893S .
• Campos RV, Zhang L, Drucker DJ . Differential expression of RNA transcripts encoding unique carboxy-terminal sequences of human parathyroid hormone-related peptide . Molecular Endocrinology . 8 . 12 . 1656–1666 . December 1994 . 7708054 . 10.1210/mend.8.12.7708054 . free .
• Holick MF, Ray S, Chen TC, Tian X, Persons KS . A parathyroid hormone antagonist stimulates epidermal proliferation and hair growth in mice . Proceedings of the National Academy of Sciences of the United States of America . 91 . 17 . 8014–8016 . August 1994 . 8058749 . 44535 . 10.1073/pnas.91.17.8014 . free . 1994PNAS...91.8014H .
• Seitz PK, Cooper KM, Ives KL, Ishizuka J, Townsend CM, Rajaraman S, Cooper CW . Parathyroid hormone-related peptide production and action in a myoepithelial cell line derived from normal human breast . Endocrinology . 133 . 3 . 1116–1124 . September 1993 . 8396010 . 10.1210/endo.133.3.8396010 .
• Li H, Seitz PK, Selvanayagam P, Rajaraman S, Cooper CW . Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2) . Endocrinology . 137 . 6 . 2367–2374 . June 1996 . 8641188 . 10.1210/en.137.6.2367 . free .

Notes and References

1. Liu C, Shao G, Lu Y, Xue M, Liang F, Zhang Z, Bai L . Parathyroid Hormone-Related Protein (1-40) Enhances Calcium Uptake in Rat Enterocytes Through PTHR1 Receptor and Protein Kinase Cα/β Signaling . Cellular Physiology and Biochemistry . 51 . 4 . 1695–1709 . 2018 . 30504697 . 10.1159/000495674 . 54474550 . free .
2. Martin TJ . Osteoblast-derived PTHrP is a physiological regulator of bone formation . The Journal of Clinical Investigation . 115 . 9 . 2322–2324 . September 2005 . 16138187 . 1193889 . 10.1172/JCI26239 .
3. Wise GE, King GJ . Mechanisms of tooth eruption and orthodontic tooth movement . Journal of Dental Research . 87 . 5 . 414–434 . May 2008 . 18434571 . 2387248 . 10.1177/154405910808700509 .
4. Philbrick WM, Dreyer BE, Nakchbandi IA, Karaplis AC . Parathyroid hormone-related protein is required for tooth eruption . Proceedings of the National Academy of Sciences of the United States of America . 95 . 20 . 11846–11851 . September 1998 . 9751753 . 21728 . 10.1073/pnas.95.20.11846 . 1998PNAS...9511846P . free .
5. Hens JR, Dann P, Zhang JP, Harris S, Robinson GW, Wysolmerski J . BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction . Development . 134 . 6 . 1221–1230 . March 2007 . 17301089 . 10.1242/dev.000182 . 25109329 .
6. Hens JR, Wysolmerski JJ . Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland . Breast Cancer Research . 7 . 5 . 220–224 . 2005 . 16168142 . 1242158 . 10.1186/bcr1306 . free .
7. Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF . Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide . The New England Journal of Medicine . 319 . 9 . 556–563 . September 1988 . 3043221 . 10.1056/NEJM198809013190906 .
8. Jüppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF, Hock J, Potts JT, Kronenberg HM . 6 . A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide . Science . 254 . 5034 . 1024–1026 . November 1991 . 1658941 . 10.1126/science.1658941 . 1991Sci...254.1024J .
9. Stewart AF . Clinical practice. Hypercalcemia associated with cancer . The New England Journal of Medicine . 352 . 4 . 373–379 . January 2005 . 15673803 . 10.1056/NEJMcp042806 .
10. Book: Nissenson RA . Parathyroid Hormone . January 2003 . Encyclopedia of Hormones . 146–153 . Henry HL, Norman AW . New York . Academic Press . 978-0-12-341103-7 . 10.1016/B0-12-341103-3/00233-3 . 2022-10-12 .
11. Kronenberg, H. M. “PTHrP and Skeletal Development.” Annals of the New York Academy of Sciences 1068, no. 1 (April 1, 2006): 1–13. https://doi.org/10.1196/annals.1346.002.
12. Web site: Entrez Gene: PTHLH parathyroid hormone-like hormone.
13. Martin TJ, Moseley JM, Gillespie MT . Parathyroid hormone-related protein: biochemistry and molecular biology . Critical Reviews in Biochemistry and Molecular Biology . 26 . 3–4 . 377–395 . 1991 . 1935171 . 10.3109/10409239109114073 .
14. US5460978A. Protein active in humoral hypercalcemia of malignancy-PthrP. October 24, 1995. Martin TJ, Moseley JM, Kemp BE, Wettenhall RE .
15. Miao D, He B, Jiang Y, Kobayashi T, Sorocéanu MA, Zhao J, Su H, Tong X, Amizuka N, Gupta A, Genant HK, Kronenberg HM, Goltzman D, Karaplis AC . 6 . Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34 . The Journal of Clinical Investigation . 115 . 9 . 2402–2411 . September 2005 . 16138191 . 1193882 . 10.1172/JCI24918 .
16. Cingolani G, Bednenko J, Gillespie MT, Gerace L . Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta . Molecular Cell . 10 . 6 . 1345–1353 . December 2002 . 12504010 . 10.1016/S1097-2765(02)00727-X . free .
17. Lam MH, Hu W, Xiao CY, Gillespie MT, Jans DA . Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein . Biochemical and Biophysical Research Communications . 282 . 2 . 629–634 . March 2001 . 11401507 . 10.1006/bbrc.2001.4607 .
18. Conlan LA, Martin TJ, Gillespie MT . The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B . FEBS Letters . 527 . 1–3 . 71–75 . September 2002 . 12220636 . 10.1016/S0014-5793(02)03164-2 . 83640616 .