Abstract
Parathyroid hormone-related protein (PTHrP) fragments 107–111, 107–138, and 107–139 were all found to be without consistent significant inhibitory effect on the resorptive activity of isolated rat and chick osteoclasts over the dose range 10-13 M-10-9 M. In the rat, these results contrasted with a strong and significant inhibition (100%) by calcitonin. Our results differ from that previously reported for C-terminal fragments of PTHrP by Fenton et al. [1–3], who noted up to a 70% inhibition of resorptive activity of isolated rat or chick osteoclasts at femtomolar doses and greater. It is possible that the lack of response observed in our osteoclast assays is due to unknown variables in the bone slice assay that influence the responsiveness of isolated osteoclasts to these fragments.
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Fenton AJ, Kemp BE, Kent GN, Moseley JM, Zheng M-H, Rowe DJ, Britto JM, Martin TJ, Nicholson GC (1991) A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts. Endocrinology 129:1762–1768
Fenton AJ, Kemp BE, Hammonds RG Jr, Mitchelhill K, Moseley JM, Martin TJ, Nicholson GC (1991) A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein PTHrP(107–111). Endocrinology 129:3424–3426
Fenton AJ, Martin TJ, Nicholson GC (1994) Carboxyl-terminal parathyroid hormone-related protein inhibits bone resorption by isolated chicken osteoclasts. J Bone Miner Res 9:515–519
Martin TJ, Moseley JM, Gillespie MT (1991) Parathyroid hormone-related protein: biochemistry and molecular biology. Crit Rev Biochem Mol Biol 26:377–395
Bergman P, Nijs-DeWolf N, Pepersack T, Corvilain J (1990) Release of parathyroid hormone-like peptides by fetal rat long bones in culture. J Bone Miner Res 5:741–753
Moseley JM, Hayman JA, Danks JA, Alcorn D, Grill V, Southby J, Horton MA (1991) Immunohistochemical detection of parathyroid hormone-related protein in human fetal epithelia. J Clin Endocrinol Metab 73:478–484
Nissenson RA, Diep D, Strewler GJ (1988) 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. J Biol Chem 263:12866–12871
Jüppner H, Abou-Samra A-B, Uneno S, Gu W-X, Potts JT Jr, Segre GV (1988) The parathyroid hormone-like peptide associated with humoral hypercalcemia of malignancy and parathyroid hormone bind to the same receptor on the plasma membrane of ROS 17/2.8 cells. J Biol Chem 263:8557–8560
Shigeno C, Yamamoto I, Kitamura N, Noda T, Lee K, Sone T, Shiomi K, Ohtaka A, Fujii N, Yajima H, Konishi J (1988) Interaction of human parathyroid hormone-related peptide with parathyroid hormone receptors in clonal rat osteosarcoma cells. J Biol Chem 263:18369–18377
Suva LJ, Winslow GA, Wettenhall REH, Hammonds RG, Moseley JM, Diefenbach-Jagger H, Rodda CP, Kemp BE, Rodriguez H, Chen EY, Hudson PJ, Martin TJ, Wood WI (1987) A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237:893–896
Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir EC, Stewart AF, Bander NH, Milstone L, Barton DE, Francke U, Broadus AE (1988) Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc Natl Acad Sci USA 85:597–601
Thiede MA, Strewler GJ, Nissenson RA, Rosenblatt M, Rodan GA (1988) Human renal carcinoma expresses two messages encoding a PTH-like peptide: evidence for alternative splicing of a single copy gene. Proc Natl Acad Sci USA 85:4605–4609
Raisz LG, Simmons HA, Vargas SJ, Kemp BE, Martin TJ (1990) Comparison of the effects of amino-terminal synthetic parathyroid hormone-related peptide (PTHrP) of malignancy and parathyroid hormone on bone resorption of cultured fetal rat bones. Calcif Tissue Int 46:233–238
Murrills RJ, Stein LS, Fey CP, Dempster DW (1990) The effects of PTH and PTHrP on osteoclast resorption of bone slices in vitro: an analysis of pit size and the resorption focus. Endocrinology 127:2648–2653
Murrills RJ, Stein LS, Horbert WR, Dempster DW (1992) Effects of phorbol myristate acetate on rat and chick osteoclasts. J Bone Miner Res 7:415–423
Kukita T, Kukita A, Hata K, Kurisu K (1992) 12-o-tetra-decanoylphorbol-13-acetate inhibits osteoclast-like cell differentiation in rat bone marrow cultures by inducing macrophage polykaryons. Endocrinology 130:577–584
Fenton AJ, Martin TJ, Nicholson GC (1993) Long-term culture of disaggregated rat osteoclasts: inhibition of bone resorption and reduction of osteoclast-like cell number by calcitonin and PTHrP(107–139). J Cell Physiol 155:1–7
Dudley A, King K, Mathias J, Burnier JP, Burdick D, Horton M, Hammonds RG Jr (1992) Effect of human parathyroid hormone-related peptide 107–139 on osteoclast formation and bone resorption in vitro (abstract) J Bone Miner Res 7 (suppl 1):S309
Gamse R, Bauer W, Gombert FO, Feyen JHM (1993) Parathyroid hormone-related peptide fragments (107–111) or (107–139) lack antiresorptive effects in organ culture or in vivo. In: Chistiansen C, Ries B (eds) Proc IVth Int Symp on Osteoporosis (Hong Kong) pp 261–262
Sone T, Kohno H, Ikeda T, Kasai R, Kikuchi Y, Konishi J, Shigeno C (1992) Human parathyroid hormone-related peptide(107–111) does not inhibit bone resorption in neonatal mouse calvariae. Endocrinology 131:2742–2746
Murrills RJ, Dempster DW (1990) The effects of stimulators of intracellular cyclic AMP on rat and chick osteoclast in vitro: validation of a simplified light microscope assay of bone resorption. Bone 11:333–344
Arnett TR, Dempster DW (1987) A comparative study of disaggregated chick and rat osteoclasts in vitro: effects of calcitonin and prostaglandins. Endocrinology 120:602–608
Arnett TR, Dempster DW (1986) Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology 119:119–124
Murrills RJ, Stein LS, Dempster DW (1993) Stimulation of bone resorption and clear zone formation by low pH: a time-course study. J Cell Physiol 154:511–518
Shibutani T, Heersche JNM (1993) Effect of medium pH on osteoclast activity and osteoclast formation in cultures of dispersed rabbit osteoclasts. J Bone Miner Res 8:331–336
Murrills RJ, Shane E, Lindsay R, Dempster DW (1989) Bone resorption by isolated human osteoclasts in vitro: effects of calcitonin. J Bone Miner Res 4:259–268
McSheehy PMJ, Chambers TJ (1986) Osteoblastic cells mediate osteoclastic responsiveness to parathyroid hormone. Endocrinology 118:824–828
McSheehy PMJ, Chambers TJ (1987) 1,25-Dihydroxyvitamin D3 stimulates rat osteoblastic cells to release a soluble factor that increases osteoclastic bone resorption. J Clin Invest 80:425–429
Thompson BM, Saklatvala J, Chambers TJ (1986) Osteoblasts mediate interleukin 1 stimulation of bone resorption by rat osteoclasts. J Exp Med 164:104–112
Thomson BM, Mundy GR, Chambers TJ (1987) Tumor necrosis factors α and β induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol 138:775–779
Tobias JH, Chambers TJ (1991) The effect of sex hormones on bone resorption by rat osteoclasts. Acta Endocrinol (Copenh) 124:121–127
Sahni M, Guenther HL, Fleisch H, Collin P, Martin TJ (1993) Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J Clin Invest 91:2004–2011
Gagnon L, Jouishomme J, Whitfield JF, Durkin JP, MacLean S, Neugebauer W, Willick G, Rixon RH, Chakravarthy B (1993) Protein kinase C-activating domains of parathyroid hormone-related protein. J Bone Miner Res 8:497–503
Blind E, Knappe V, Raue F, Pfeilschifter J, Ziegler R (1992) Tumor necrosis factor alpha inhibits the stimulatory effect of the parathyroid hormone-related protein on cyclic AMP formation in osteoblast-like cells via protein kinase C. Biochem Biophys Res Comm 182:341–347
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Supported in part by NIH grants AR 39191 and AR 41331
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Murrills, R.J., Stein, L.S. & Dempster, D.W. Lack of significant effect of carboxyl-terminal parathyroid hormone-related peptide fragments on isolated rat and chick osteoclasts. Calcif Tissue Int 57, 47–51 (1995). https://doi.org/10.1007/BF00298996
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DOI: https://doi.org/10.1007/BF00298996