Chemistry:Parathyroid hormone-related protein

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Short description: Mammalian protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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

References

  1. ↑ "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. doi:10.1159/000495674. PMID 30504697. 
  2. ↑ 2.0 2.1 "Osteoblast-derived PTHrP is a physiological regulator of bone formation". The Journal of Clinical Investigation 115 (9): 2322–2324. September 2005. doi:10.1172/JCI26239. PMID 16138187. 
  3. ↑ "Mechanisms of tooth eruption and orthodontic tooth movement". Journal of Dental Research 87 (5): 414–434. May 2008. doi:10.1177/154405910808700509. PMID 18434571. 
  4. ↑ "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. doi:10.1073/pnas.95.20.11846. PMID 9751753. Bibcode: 1998PNAS...9511846P. 
  5. ↑ "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. doi:10.1242/dev.000182. PMID 17301089. 
  6. ↑ "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. doi:10.1186/bcr1306. PMID 16168142. 
  7. ↑ "Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide". The New England Journal of Medicine 319 (9): 556–563. September 1988. doi:10.1056/NEJM198809013190906. PMID 3043221. 
  8. ↑ "A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide". Science 254 (5034): 1024–1026. November 1991. doi:10.1126/science.1658941. PMID 1658941. Bibcode: 1991Sci...254.1024J. 
  9. ↑ "Clinical practice. Hypercalcemia associated with cancer". The New England Journal of Medicine 352 (4): 373–379. January 2005. doi:10.1056/NEJMcp042806. PMID 15673803. 
  10. ↑ "Parathyroid Hormone". Encyclopedia of Hormones. New York: Academic Press. January 2003. pp. 146–153. doi:10.1016/B0-12-341103-3/00233-3. ISBN 978-0-12-341103-7. https://www.sciencedirect.com/topics/nursing-and-health-professions/sodium-phosphate-cotransporter-2a#:~:text=PTH%20promotes,vitamin%20d. Retrieved 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. ↑ "Entrez Gene: PTHLH parathyroid hormone-like hormone". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5744. 
  13. ↑ "Parathyroid hormone-related protein: biochemistry and molecular biology". Critical Reviews in Biochemistry and Molecular Biology 26 (3–4): 377–395. 1991. doi:10.3109/10409239109114073. PMID 1935171. https://pubmed.ncbi.nlm.nih.gov/1935171/. 
  14. ↑ Martin TJ, Moseley JM, Kemp BE, Wettenhall RE, "Protein active in humoral hypercalcemia of malignancy-PthrP", patent US5460978A, issued October 24, 1995
  15. ↑ "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. doi:10.1172/JCI24918. PMID 16138191. 
  16. ↑ "Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta". Molecular Cell 10 (6): 1345–1353. December 2002. doi:10.1016/S1097-2765(02)00727-X. PMID 12504010. 
  17. ↑ "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. doi:10.1006/bbrc.2001.4607. PMID 11401507. 
  18. ↑ "The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B". FEBS Letters 527 (1–3): 71–75. September 2002. doi:10.1016/S0014-5793(02)03164-2. PMID 12220636. 

Further reading

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



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