Parathyroid hormone-related protein

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.

PTHLH
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3H3G, 1BZG, 1M5N, 3FFD
Identifiers
Aliases	PTHLH, BDE2, HHM, PLP, PTHR, PTHRP, parathyroid hormone-like hormone, parathyroid hormone like hormone
External IDs	OMIM: 168470 MGI: 97800 HomoloGene: 2113 GeneCards: PTHLH
Gene location (Human) Chr. Chromosome 12 (human)^[1] Band 12p11.22 Start 27,958,084 bp^[1] End 27,972,733 bp^[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)^[2] Band 6 G3|6 78.19 cM Start 147,153,599 bp^[2] End 147,165,681 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in periodontal fiber stromal cell of endometrium canal of the cervix endothelial cell vagina ascending aorta gallbladder prefrontal cortex cingulate gyrus minor salivary gland Top expressed in lip semi-lunar valve ankle hair follicle epithelium of stomach corneal stroma aortic valve extraocular muscle sciatic nerve ascending aorta More reference expression data BioGPS More reference expression data
Gene ontology Molecular function peptide hormone receptor binding hormone activity protein binding Cellular component extracellular region nucleus Golgi apparatus nucleoplasm extracellular space cytoplasm cytosol Biological process regulation of gene expression skeletal system development osteoblast development cell-cell signaling female pregnancy negative regulation of chondrocyte differentiation adenylate cyclase-activating G protein-coupled receptor signaling pathway cAMP metabolic process positive regulation of cell population proliferation negative regulation of cell population proliferation epidermis development regulation of signaling receptor activity G protein-coupled receptor signaling pathway bone mineralization negative regulation of chondrocyte development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5744 19227 Ensembl ENSG00000087494 ENSMUSG00000048776 UniProt P12272 P22858 RefSeq (mRNA) NM_002820 NM_198964 NM_198965 NM_198966 NM_008970 RefSeq (protein) NP_002811 NP_945315 NP_945316 NP_945317 n/a Location (UCSC) Chr 12: 27.96 – 27.97 Mb Chr 6: 147.15 – 147.17 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[5]

In 2005, Australian pathologist and researcher Thomas John Martin found that PTHrP produced by osteoblasts is a physiological regulator of bone formation.^[6] 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.^[6]

Tooth eruption

PTHrP is critical in intraosseous phase of tooth eruption where it acts as a signalling molecule to stimulate local bone resorption.^[7] 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.^[8]

Mammary glands

Further information: Breast development and Mammary gland § Development

It aids in normal mammary gland development.^[9][10] 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.^[11] 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).^[12] 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.^[13]

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.^[14]

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). ^[15]

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.^[16]

Discovery

The protein was first isolated in 1987 by Thomas J. Martin's team at the University of Melbourne.^[17][18] 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.^[19]

Interactions

Parathyroid hormone-related protein has been shown to interact with KPNB1^[20][21] and Arrestin beta 1.^[22]

See also

• Analogs used as pharmaceutical drugs
  • Teriparatide
  • Abaloparatide

References

1. GRCh38: Ensembl release 89: ENSG00000087494 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000048776 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Liu C, Shao G, Lu Y, Xue M, Liang F, Zhang Z, Bai L (2018). "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. doi:10.1159/000495674. PMID 30504697. S2CID 54474550.
6. Martin TJ (September 2005). "Osteoblast-derived PTHrP is a physiological regulator of bone formation". The Journal of Clinical Investigation. 115 (9): 2322–2324. doi:10.1172/JCI26239. PMC 1193889. PMID 16138187.
7. Wise GE, King GJ (May 2008). "Mechanisms of tooth eruption and orthodontic tooth movement". Journal of Dental Research. 87 (5): 414–434. doi:10.1177/154405910808700509. PMC 2387248. PMID 18434571.
8. Philbrick WM, Dreyer BE, Nakchbandi IA, Karaplis AC (September 1998). "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. Bibcode:1998PNAS...9511846P. doi:10.1073/pnas.95.20.11846. PMC 21728. PMID 9751753.
9. Hens JR, Dann P, Zhang JP, Harris S, Robinson GW, Wysolmerski J (March 2007). "BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction". Development. 134 (6): 1221–1230. doi:10.1242/dev.000182. PMID 17301089. S2CID 25109329.
10. Hens JR, Wysolmerski JJ (2005). "Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland". Breast Cancer Research. 7 (5): 220–224. doi:10.1186/bcr1306. PMC 1242158. PMID 16168142.
11. Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF (September 1988). "Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide". The New England Journal of Medicine. 319 (9): 556–563. doi:10.1056/NEJM198809013190906. PMID 3043221.
12. Jüppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, et al. (November 1991). "A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide". Science. 254 (5034): 1024–1026. Bibcode:1991Sci...254.1024J. doi:10.1126/science.1658941. PMID 1658941.
13. Stewart AF (January 2005). "Clinical practice. Hypercalcemia associated with cancer". The New England Journal of Medicine. 352 (4): 373–379. doi:10.1056/NEJMcp042806. PMID 15673803.
14. Nissenson RA (January 2003). "Parathyroid Hormone". In Henry HL, Norman AW (eds.). Encyclopedia of Hormones. New York: Academic Press. pp. 146–153. doi:10.1016/B0-12-341103-3/00233-3. ISBN 978-0-12-341103-7. Retrieved October 12, 2022.
15. 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.
16. "Entrez Gene: PTHLH parathyroid hormone-like hormone".
17. Martin TJ, Moseley JM, Gillespie MT (1991). "Parathyroid hormone-related protein: biochemistry and molecular biology". Critical Reviews in Biochemistry and Molecular Biology. 26 (3–4): 377–395. doi:10.3109/10409239109114073. PMID 1935171.
18. US5460978A, Martin TJ, Moseley JM, Kemp BE, Wettenhall RE, "Protein active in humoral hypercalcemia of malignancy-PthrP", issued October 24, 1995 
19. Miao D, He B, Jiang Y, Kobayashi T, Sorocéanu MA, Zhao J, et al. (September 2005). "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. doi:10.1172/JCI24918. PMC 1193882. PMID 16138191.
20. Cingolani G, Bednenko J, Gillespie MT, Gerace L (December 2002). "Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta". Molecular Cell. 10 (6): 1345–1353. doi:10.1016/S1097-2765(02)00727-X. PMID 12504010.
21. Lam MH, Hu W, Xiao CY, Gillespie MT, Jans DA (March 2001). "Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein". Biochemical and Biophysical Research Communications. 282 (2): 629–634. doi:10.1006/bbrc.2001.4607. PMID 11401507.
22. Conlan LA, Martin TJ, Gillespie MT (September 2002). "The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B". FEBS Letters. 527 (1–3): 71–75. doi:10.1016/S0014-5793(02)03164-2. PMID 12220636. S2CID 83640616.

Further reading

• Miao D, Li J, Xue Y, Su H, Karaplis AC, Goltzman D (August 2004). "Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice". Endocrinology. 145 (8): 3554–3562. doi:10.1210/en.2003-1695. PMID 15090463.
• Casey ML, MacDonald PC (October 1996). "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. doi:10.1093/humrep/11.suppl_2.62. PMID 8982748.
• Lam MH, Thomas RJ, Martin TJ, Gillespie MT, Jans DA (August 2000). "Nuclear and nucleolar localization of parathyroid hormone-related protein". Immunology and Cell Biology. 78 (4): 395–402. doi:10.1046/j.1440-1711.2000.00919.x. PMID 10947864. S2CID 23048105.
• Fiaschi-Taesch NM, Stewart AF (February 2003). "Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences". Endocrinology. 144 (2): 407–411. doi:10.1210/en.2002-220818. PMID 12538599.
• Jans DA, Thomas RJ, Gillespie MT (2003). Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles. Vitamins & Hormones. Vol. 66. pp. 345–84. doi:10.1016/S0083-6729(03)01010-0. ISBN 978-0-12-709866-1. PMID 12852260.
• Maioli E, Fortino V, Pacini A (December 2004). "Parathyroid hormone-related protein in preeclampsia: a linkage between maternal and fetal failures". Biology of Reproduction. 71 (6): 1779–1784. doi:10.1095/biolreprod.104.030932. PMID 15286039. S2CID 27542199.
• Fenton AJ, Kemp BE, Kent GN, Moseley JM, Zheng MH, Rowe DJ, et al. (October 1991). "A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts". Endocrinology. 129 (4): 1762–1768. doi:10.1210/endo-129-4-1762. PMID 1915066.
• Fenton AJ, Kemp BE, Hammonds RG, Mitchelhill K, Moseley JM, Martin TJ, Nicholson GC (December 1991). "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. doi:10.1210/endo-129-6-3424. PMID 1954916.
• Moniz C, Burton PB, Malik AN, Dixit M, Banga JP, Nicolaides K, et al. (December 1990). "Parathyroid hormone-related peptide in normal human fetal development". Journal of Molecular Endocrinology. 5 (3): 259–266. doi:10.1677/jme.0.0050259. PMID 2288637.
• Hammonds RG, McKay P, Winslow GA, Diefenbach-Jagger H, Grill V, Glatz J, et al. (September 1989). "Purification and characterization of recombinant human parathyroid hormone-related protein". The Journal of Biological Chemistry. 264 (25): 14806–14811. doi:10.1016/S0021-9258(18)63771-8. PMID 2549037.
• Yasuda T, Banville D, Hendy GN, Goltzman D (May 1989). "Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects". The Journal of Biological Chemistry. 264 (13): 7720–7725. doi:10.1016/S0021-9258(18)83294-X. PMID 2708388.
• Suva LJ, Mather KA, Gillespie MT, Webb GC, Ng KW, Winslow GA, et al. (April 1989). "Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP)". Gene. 77 (1): 95–105. doi:10.1016/0378-1119(89)90363-6. PMID 2744490.
• Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir EC, et al. (January 1988). "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. Bibcode:1988PNAS...85..597M. doi:10.1073/pnas.85.2.597. PMC 279598. PMID 2829195.
• Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall RE, Kemp BE, Suva LJ, et al. (July 1987). "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. Bibcode:1987PNAS...84.5048M. doi:10.1073/pnas.84.14.5048. PMC 305244. PMID 2885845.
• Mangin M, Ikeda K, Dreyer BE, Broadus AE (April 1989). "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. Bibcode:1989PNAS...86.2408M. doi:10.1073/pnas.86.7.2408. PMC 286922. PMID 2928340.
• Thiede MA, Strewler GJ, Nissenson RA, Rosenblatt M, Rodan GA (July 1988). "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. Bibcode:1988PNAS...85.4605T. doi:10.1073/pnas.85.13.4605. PMC 280483. PMID 3290897.
• Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, et al. (August 1987). "A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression". Science. 237 (4817): 893–896. Bibcode:1987Sci...237..893S. doi:10.1126/science.3616618. PMID 3616618.
• Campos RV, Zhang L, Drucker DJ (December 1994). "Differential expression of RNA transcripts encoding unique carboxy-terminal sequences of human parathyroid hormone-related peptide". Molecular Endocrinology. 8 (12): 1656–1666. doi:10.1210/mend.8.12.7708054. PMID 7708054.
• Holick MF, Ray S, Chen TC, Tian X, Persons KS (August 1994). "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. Bibcode:1994PNAS...91.8014H. doi:10.1073/pnas.91.17.8014. PMC 44535. PMID 8058749.
• Seitz PK, Cooper KM, Ives KL, Ishizuka J, Townsend CM, Rajaraman S, Cooper CW (September 1993). "Parathyroid hormone-related peptide production and action in a myoepithelial cell line derived from normal human breast". Endocrinology. 133 (3): 1116–1124. doi:10.1210/endo.133.3.8396010. PMID 8396010.
• Li H, Seitz PK, Selvanayagam P, Rajaraman S, Cooper CW (June 1996). "Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2)". Endocrinology. 137 (6): 2367–2374. doi:10.1210/en.137.6.2367. PMID 8641188.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.