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