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
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPTHLH, BDE2, HHM, PLP, PTHR, PTHRP, parathyroid hormone-like hormone, parathyroid hormone like hormone
External IDsOMIM: 168470 MGI: 97800 HomoloGene: 2113 GeneCards: PTHLH
Orthologs
SpeciesHumanMouse
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 MbChr 6: 147.15 – 147.17 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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

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