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Gene Review

PTHLH  -  parathyroid hormone-like hormone

Homo sapiens

Synonyms: BDE2, HHM, PLP, PTH-rP, PTHR, ...
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Disease relevance of PTHLH

  • PTHLH signalling is absent in osteochondromas, benign tumours arising adjacent to the growth plate, but is reactivated when these tumours undergo malignant transformation towards secondary peripheral chondrosarcoma [1].
  • This is in contrast to osteochondroma, in which PTHLH signalling is downregulated [2].
  • A synthetic peptide corresponding to the first 34 amino acids of the parathyroid hormone-related protein (PTH-rP) produced by a human tumor associated with hypercalcemia was examined for skeletal and renal effects on calcium metabolism in vivo and in vitro [3].
  • These results suggest that proinflammatory cytokine-stimulated production of NH2-terminal PTHrP by synovial tissue directly invading cartilage and bone in RA may mediate joint destruction through direct effects on cartilage or bone, or, indirectly, via the induction of mediators of bone resorption in the tumor-like synovium [4].
  • Previous studies have shown that parathyroid hormone-related protein (PTHrP) is a member of the cascade of proinflammatory cytokines induced in parenchymal organs during lethal endotoxemia [4].

Psychiatry related information on PTHLH

  • HHM is structurally related to the Id family and was highly expressed in brain, pituitary gland, lung, heart, placenta, fetal liver, and bone marrow [5].
  • Furthermore, nude rats bearing LC-6-JCK showed reduced locomotor activity, less eating and drinking and low blood phosphorus; and anti-PTHrP antibody restored them [6].

High impact information on PTHLH


Chemical compound and disease context of PTHLH


Biological context of PTHLH

  • CONCLUSION: These data clearly support the hypothesis that PTHrP is an alternative mechanism associated with bone loss and recovery during and subsequent to lactation [14].
  • RESULTS: Elevated PTHrP values were significantly associated (P<.001) with breast-feeding status, elevated prolactin levels, and lower serum estradiol levels, conditions occurring during lactation [14].
  • Moreover, our data indicate that renal and nonrenal PTHR gene expression are tightly coordinated in humans [15].
  • PTH-rP appears to have similar effects to those of PTH on the skeleton, the kidney, and overall calcium homeostasis [3].
  • We investigated the effect of PTHrP transfection and treatment on production by prostate carcinoma cells of IL (interleukin)-8, which can regulate prostate cancer growth by angiogenic activity and growth-promoting effects [16].

Anatomical context of PTHLH

  • Six prostate cancer cell lines exhibited constitutive expression of PTHrP and IL-8 that were significantly correlated (r = 0.93; P < 0.01) [16].
  • Exposure to a neutralizing antibody to PTHrP increased PPi elaboration by articular chondrocytes [17].
  • Bovine PTH-(1-34) was 6-fold more potent than the PLP peptides in renal membranes, but was 2-fold less potent in UMR-106 cells [10].
  • When expressed in COS-7 cells, zPTH1R bound [Tyr(34)]hPTH-(1-34)-amide (hPTH), [Tyr(36)]hPTHrP-(1-36)-amide (hPTHrP), and [Ala(29),Glu(30), Ala(34),Glu(35), Tyr(36)]fugufish PTHrP-(1-36)-amide (fuguPTHrP) with a high apparent affinity (IC(50): 1.2-3.5 nM), and was efficiently activated by all three peptides (EC(50): 1.1-1.7 nM) [18].
  • PTH was distributed linearly or fine granularly along the cytoplasmic membrane, whereas PTHrP was distributed diffusely or coarse granularly in the cytoplasm [19].

Associations of PTHLH with chemical compounds

  • In the present study, we compared the actions of two synthetic PLP peptides, PLP-(1-34)amide and [Tyr36]PLP-(1-36)amide, with those of bovine parathyroid hormone (bPTH)-(1-34) on receptors and adenylate cyclase in bone cells and in renal membranes [10].
  • Inhibition by PTHrP 1-173, but not by PTHrP 1-146 or PTHrP 1-87, of inorganic pyrophosphate (PPi) elaboration suggested selective functional properties of the 1-173 isoform [17].
  • This effect of PTHrP (107-139), and that of PTHrP (1-34), were abolished by the transcription inhibitor actinomycin D [20].
  • PTHrP (107-139) stimulation of mRNA and protein in hOB cells was abolished by bisindolylmaleimide I, a protein kinase C inhibitor, but not by either adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS), or N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89), two protein kinase A inhibitors [20].
  • Meanwhile, puromycin, a protein synthesis inhibitor, superinduced IL-6 expression in the presence or absence of each PTHrP peptide [20].

Physical interactions of PTHLH


Enzymatic interactions of PTHLH

  • Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments [25].

Co-localisations of PTHLH


Regulatory relationships of PTHLH


Other interactions of PTHLH

  • Phosphorylation of the transcription factor CREB was also necessary but not sufficient for PTHrP-mediated IL-6 promoter activity [21].
  • A competitive PTH receptor antagonist, [Tyr34]bPTH-(7-34)amide, rapidly and fully inhibited adenylate cyclase stimulation by the PLP peptides as well as bPTH-(1-34) [10].
  • The differential properties of specific PTHrP 3'-untranslated sequences encoded by unique exons were examined by creating a series of luciferase-PTHrP fusion genes and examining the contribution of PTHrP sequences to relative luciferase activity after transfection of heterologous cell lines [28].
  • These findings suggest that beta-arrestin 1 acts as an effector for a novel function of PTHrP in cytoplasm [22].
  • Receptor-G-protein interaction increases the receptor binding selectivity of PTHrP and TIP39 [29].

Analytical, diagnostic and therapeutic context of PTHLH


  1. Peripheral chondrosarcoma progression is accompanied by decreased Indian Hedgehog signalling. Hameetman, L., Rozeman, L.B., Lombaerts, M., Oosting, J., Taminiau, A.H., Cleton-Jansen, A.M., Bovée, J.V., Hogendoorn, P.C. J. Pathol. (2006) [Pubmed]
  2. EXT-related pathways are not involved in the pathogenesis of dysplasia epiphysealis hemimelica and metachondromatosis. Bovée, J.V., Hameetman, L., Kroon, H.M., Aigner, T., Hogendoorn, P.C. J. Pathol. (2006) [Pubmed]
  3. Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents. Yates, A.J., Gutierrez, G.E., Smolens, P., Travis, P.S., Katz, M.S., Aufdemorte, T.B., Boyce, B.F., Hymer, T.K., Poser, J.W., Mundy, G.R. J. Clin. Invest. (1988) [Pubmed]
  4. Synovium as a source of increased amino-terminal parathyroid hormone-related protein expression in rheumatoid arthritis. A possible role for locally produced parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis. Funk, J.L., Cordaro, L.A., Wei, H., Benjamin, J.B., Yocum, D.E. J. Clin. Invest. (1998) [Pubmed]
  5. Human homologue of maid: A dominant inhibitory helix-loop-helix protein associated with liver-specific gene expression. Terai, S., Aoki, H., Ashida, K., Thorgeirsson, S.S. Hepatology (2000) [Pubmed]
  6. Parathyroid hormone-related protein (PTHrP) as a causative factor of cancer-associated wasting: possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts. Onuma, E., Tsunenari, T., Saito, H., Sato, K., Yamada-Okabe, H., Ogata, E. Int. J. Cancer (2005) [Pubmed]
  7. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. Schipani, E., Langman, C.B., Parfitt, A.M., Jensen, G.S., Kikuchi, S., Kooh, S.W., Cole, W.G., Jüppner, H. N. Engl. J. Med. (1996) [Pubmed]
  8. Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Waymire, K.G., Mahuren, J.D., Jaje, J.M., Guilarte, T.R., Coburn, S.P., MacGregor, G.R. Nat. Genet. (1995) [Pubmed]
  9. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. Burtis, W.J., Brady, T.G., Orloff, J.J., Ersbak, J.B., Warrell, R.P., Olson, B.R., Wu, T.L., Mitnick, M.E., Broadus, A.E., Stewart, A.F. N. Engl. J. Med. (1990) [Pubmed]
  10. Synthetic peptides comprising the amino-terminal sequence of a parathyroid hormone-like protein from human malignancies. Binding to parathyroid hormone receptors and activation of adenylate cyclase in bone cells and kidney. Nissenson, R.A., Diep, D., Strewler, G.J. J. Biol. Chem. (1988) [Pubmed]
  11. Parathyroid hormone-related protein (PTHrP) does not regulate 1,25-dihydroxyvitamin D serum levels in hypercalcemia of malignancy. Schilling, T., Pecherstorfer, M., Blind, E., Leidig, G., Ziegler, R., Raue, F. J. Clin. Endocrinol. Metab. (1993) [Pubmed]
  12. Bone microenvironment-related growth factors, zoledronic acid and dexamethasone differentially modulate PTHrP expression in PC-3 prostate cancer cells. Tenta, R., Sourla, A., Lembessis, P., Luu-The, V., Koutsilieris, M. Horm. Metab. Res. (2005) [Pubmed]
  13. Effects of parathyroid hormone-related protein on human mesangial cells in culture. Bosch, R.J., Rojo-Linares, P., Torrecillas-Casamayor, G., Iglesias-Cruz, M.C., Rodríguez-Puyol, D., Rodríguez-Puyol, M. Am. J. Physiol. (1999) [Pubmed]
  14. Elevated parathyroid hormone-related peptide associated with lactation and bone density loss. Sowers, M.F., Hollis, B.W., Shapiro, B., Randolph, J., Janney, C.A., Zhang, D., Schork, A., Crutchfield, M., Stanczyk, F., Russell-Aulet, M. JAMA (1996) [Pubmed]
  15. Developmental upregulation of human parathyroid hormone (PTH)/PTH-related peptide receptor gene expression from conserved and human-specific promoters. Bettoun, J.D., Minagawa, M., Hendy, G.N., Alpert, L.C., Goodyer, C.G., Goltzman, D., White, J.H. J. Clin. Invest. (1998) [Pubmed]
  16. Parathyroid hormone-related protein induces interleukin 8 production by prostate cancer cells via a novel intracrine mechanism not mediated by its classical nuclear localization sequence. Gujral, A., Burton, D.W., Terkeltaub, R., Deftos, L.J. Cancer Res. (2001) [Pubmed]
  17. Parathyroid hormone-related proteins is abundant in osteoarthritic cartilage, and the parathyroid hormone-related protein 1-173 isoform is selectively induced by transforming growth factor beta in articular chondrocytes and suppresses generation of extracellular inorganic pyrophosphate. Terkeltaub, R., Lotz, M., Johnson, K., Deng, D., Hashimoto, S., Goldring, M.B., Burton, D., Deftos, L.J. Arthritis Rheum. (1998) [Pubmed]
  18. Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide. Rubin, D.A., Jüppner, H. J. Biol. Chem. (1999) [Pubmed]
  19. Co-secretion of parathyroid hormone and parathyroid-hormone-related protein via a regulated pathway in human parathyroid adenoma cells. Matsushita, H., Usui, M., Hara, M., Shishiba, Y., Nakazawa, H., Honda, K., Torigoe, K., Kohno, K., Kurimoto, M. Am. J. Pathol. (1997) [Pubmed]
  20. Parathyroid hormone-related protein (107-139) stimulates interleukin-6 expression in human osteoblastic cells. De Miguel, F., Martinez-Fernandez, P., Guillen, C., Valin, A., Rodrigo, A., Martinez, M.E., Esbrit, P. J. Am. Soc. Nephrol. (1999) [Pubmed]
  21. Impact of the mitogen-activated protein kinase pathway on parathyroid hormone-related protein actions in osteoblasts. Chen, C., Koh, A.J., Datta, N.S., Zhang, J., Keller, E.T., Xiao, G., Franceschi, R.T., D'Silva, N.J., McCauley, L.K. J. Biol. Chem. (2004) [Pubmed]
  22. The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B. Conlan, L.A., Martin, T.J., Gillespie, M.T. FEBS Lett. (2002) [Pubmed]
  23. Direct mapping of an agonist-binding domain within the parathyroid hormone/parathyroid hormone-related protein receptor by photoaffinity crosslinking. Zhou, A.T., Bessalle, R., Bisello, A., Nakamoto, C., Rosenblatt, M., Suva, L.J., Chorev, M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  24. Regulation of parathyroid hormone-related protein (PTHrP) gene expression. Sp1 binds through an inverted CACCC motif and regulates promoter activity in cooperation with Ets1. Dittmer, J., Gégonne, A., Gitlin, S.D., Ghysdael, J., Brady, J.N. J. Biol. Chem. (1994) [Pubmed]
  25. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Iwamura, M., Hellman, J., Cockett, A.T., Lilja, H., Gershagen, S. Urology (1996) [Pubmed]
  26. Prohormone convertase furin has a role in gastric cancer cell proliferation with parathyroid hormone-related peptide in a reciprocal manner. Nakajima, T., Konda, Y., Kanai, M., Izumi, Y., Kanda, N., Nanakin, A., Kitazawa, S., Chiba, T. Dig. Dis. Sci. (2002) [Pubmed]
  27. Renal vasodilatation and microvessel adenylate cyclase stimulation by synthetic parathyroid hormone-like protein fragments. Musso, M.J., Plante, M., Judes, C., Barthelmebs, M., Helwig, J.J. Eur. J. Pharmacol. (1989) [Pubmed]
  28. Differential expression of RNA transcripts encoding unique carboxy-terminal sequences of human parathyroid hormone-related peptide. Campos, R.V., Zhang, L., Drucker, D.J. Mol. Endocrinol. (1994) [Pubmed]
  29. Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors. Hoare, S.R., Usdin, T.B. Curr. Pharm. Des. (2001) [Pubmed]
  30. Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia. Ratcliffe, W.A., Hutchesson, A.C., Bundred, N.J., Ratcliffe, J.G. Lancet (1992) [Pubmed]
  31. Hyperparathyroidism, humoral hypercalcemia of malignancy, and the anabolic actions of parathyroid hormone and parathyroid hormone-related protein on the skeleton. Stewart, A.F. J. Bone Miner. Res. (2002) [Pubmed]
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