This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ma, Y. L. Articles by Onyia, J. E. Search for Related Content PubMed PubMed Citation Articles by Ma, Y. L. Articles by Onyia, J. E.

Catabolic Effects of Continuous Human PTH (1–38) in Vivo Is Associated with Sustained Stimulation of RANKL and Inhibition of Osteoprotegerin and Gene-Associated Bone Formation

Gene Regulation, Bone and Inflammation Research Division (Y.L.M., R.L.C., D.L.H., X.Y., Q.Z., S.C., T.J.M., J.E.O.), Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285; and St. Vincent’s Institute of Medical Research (T.J.M.), Fitzroy, Victoria 3065, Australia

Address all correspondence and request for reprints to: Dr. Yanfei. L. Ma, Gene Regulation, Bone and Inflammation Research Division, Building 98C/B, DC 0403, Lilly Research Labs, Indianapolis, Indiana 46285. E-mail: ma_linda{at}lilly.com

Continuous infusion of PTH in vivo results in active bone resorption. To investigate the molecular basis of the catabolic effect of PTH in vivo, we evaluated the role of OPG and RANKL, which are known to influence osteoclast formation and function. Weanling rats fed a calcium-free diet were parathyroidectomized and infused with PTH via an Alzet pump to examine: 1) the changes of serum-ionized calcium and osteoclast number, 2) the expression of OPG/RANKL mRNA and protein, and 3) the expression of osteoblast phenotype bone formation-associated genes such as osteoblast specific transcription factor, osteocalcin, bone sialoprotein, and type I collagen. PTH (1–38) (0.01–20 µg/100 g) continuous infusion for 1–24 h resulted in a dose-dependent increase in serum-ionized calcium in parathyroidectomized rats and a corresponding dose-dependent increase in osteoclast number, indicating an increased bone resorption. At 20 µg/100 g PTH dose level, serum-ionized calcium was 2.1-fold of the vehicle control and not different from the Sham-parathyroidectomized rats, and osteoclast number was 3-fold of the vehicle control and 1.7-fold of the Sham-parathyroidectomized rats. In the distal femur, RANKL mRNA expression was increased (27-fold) and OPG mRNA expression was decreased (4.6-fold). The changes in RANKL and OPG mRNA levels were rapid (as early as 1 h), dose dependent, and sustained over a 24-h period that was examined. Immunohistochemical evaluation of bone sections confirmed that OPG level was reduced in proximal tibial metaphysis upon PTH infusion. Circulating OPG protein level was also decreased by 32% when compared with the parathyroidectomized control. The expression of genes that mark the osteoblast phenotype was significantly decreased [osteoblast specific transcription factor (2.3-fold), osteocalcin (3-fold), bone sialoprotein (2.8-fold), and type I collagen (5-fold)]. These results suggest that the catabolic effect of PTH infusion in vivo in this well-established resorption model is associated with a reciprocal expression of OPG/RANKL and a co-ordinate decrease in the expression of bone formation-related genes. We propose that the rapid and sustained increase in RANKL and decrease in OPG initiate maintain and favor the cascade of events in the differentiation/recruitment and activation of osteoclasts.

This article has been cited by other articles:

				T. Kawano, N. Troiano, D. J. Adams, J. Jun Wu, B.-h. Sun, and K. Insogna The Anabolic Response to Parathyroid Hormone Is Augmented in Rac2 Knockout Mice Endocrinology, August 1, 2008; 149(8): 4009 - 4015. [Abstract] [Full Text] [PDF]

				S. U. Nigwekar, M. Wolf, R. H. Sterns, and J. K. Hix Calciphylaxis from Nonuremic Causes: A Systematic Review Clin. J. Am. Soc. Nephrol., July 1, 2008; 3(4): 1139 - 1143. [Abstract] [Full Text] [PDF]

				A. E. Kearns, S. Khosla, and P. J. Kostenuik Receptor Activator of Nuclear Factor {kappa}B Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease Endocr. Rev., April 1, 2008; 29(2): 155 - 192. [Abstract] [Full Text] [PDF]

				A. D Anastasilakis, D. G Goulis, S. A Polyzos, S. Gerou, V. Pavlidou, G. Koukoulis, and A. Avramidis Acute changes in serum osteoprotegerin and receptor activator for nuclear factor-{kappa}B ligand levels in women with established osteoporosis treated with teriparatide Eur. J. Endocrinol., March 1, 2008; 158(3): 411 - 415. [Abstract] [Full Text] [PDF]

				S. Lymperi, N. Horwood, S. Marley, M. Y. Gordon, A. P. Cope, and F. Dazzi Strontium can increase some osteoblasts without increasing hematopoietic stem cells Blood, February 1, 2008; 111(3): 1173 - 1181. [Abstract] [Full Text] [PDF]

				C. Galli, L. A. Zella, J. A. Fretz, Q. Fu, J. W. Pike, R. S. Weinstein, S. C. Manolagas, and C. A. O'Brien Targeted Deletion of a Distant Transcriptional Enhancer of the Receptor Activator of Nuclear Factor-{kappa}B Ligand Gene Reduces Bone Remodeling and Increases Bone Mass Endocrinology, January 1, 2008; 149(1): 146 - 153. [Abstract] [Full Text] [PDF]

				S. Ferrari Are Osteoclasts Necessary for PTH Anabolism? A Reappraisal from Osteoprotegerin Studies IBMS BoneKEy, October 1, 2007; 4(10): 278 - 281. [Full Text] [PDF]

				F. Joseph, B. Y. Chan, B. H. Durham, A. M. Ahmad, S. Vinjamuri, J. A. Gallagher, J. P. Vora, and W. D. Fraser The Circadian Rhythm of Osteoprotegerin and Its Association with Parathyroid Hormone Secretion J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3230 - 3238. [Abstract] [Full Text] [PDF]

				C. J. Xian Roles of Epidermal Growth Factor Family in the Regulation of Postnatal Somatic Growth Endocr. Rev., May 1, 2007; 28(3): 284 - 296. [Abstract] [Full Text] [PDF]

				Q. Fu, S. C. Manolagas, and C. A. O'Brien Parathyroid Hormone Controls Receptor Activator of NF-{kappa}B Ligand Gene Expression via a Distant Transcriptional Enhancer. Mol. Cell. Biol., September 1, 2006; 26(17): 6453 - 6468. [Abstract] [Full Text] [PDF]

				Y. Wang, T. Sakata, H. Z Elalieh, S. J Munson, A. Burghardt, S. Majumdar, B. P Halloran, and D. D Bikle Gender differences in the response of CD-1 mouse bone to parathyroid hormone: potential role of IGF-I. J. Endocrinol., May 1, 2006; 189(2): 279 - 287. [Abstract] [Full Text] [PDF]

				J. L. Fisher, R. J. Thomas-Mudge, J. Elliott, D. K. Hards, N. A. Sims, J. Slavin, T. J. Martin, and M. T. Gillespie Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically. Cancer Res., April 1, 2006; 66(7): 3620 - 3628. [Abstract] [Full Text] [PDF]

				L. M. Helvering, R. Liu, N. H. Kulkarni, T. Wei, P. Chen, S. Huang, F. Lawrence, D. L. Halladay, R. R. Miles, E. M. Ambrose, et al. Expression Profiling of Rat Femur Revealed Suppression of Bone Formation Genes by Treatment with Alendronate and Estrogen but Not Raloxifene Mol. Pharmacol., November 1, 2005; 68(5): 1225 - 1238. [Abstract] [Full Text] [PDF]

				C. A. O'Brien, R. L. Jilka, Q. Fu, S. Stewart, R. S. Weinstein, and S. C. Manolagas IL-6 is not required for parathyroid hormone stimulation of RANKL expression, osteoclast formation, and bone loss in mice Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E784 - E793. [Abstract] [Full Text] [PDF]

				S. Lossdorfer, W. Gotz, and A. Jager PTH(1-34) Affects Osteoprotegerin Production in Human PDL Cells in vitro J. Dent. Res., July 1, 2005; 84(7): 634 - 638. [Abstract] [Full Text] [PDF]

				S. L. Ferrari, D. D. Pierroz, V. Glatt, D. S. Goddard, E. N. Bianchi, F. T. Lin, D. Manen, and M. L. Bouxsein Bone Response to Intermittent Parathyroid Hormone Is Altered in Mice Null for {beta}-Arrestin2 Endocrinology, April 1, 2005; 146(4): 1854 - 1862. [Abstract] [Full Text] [PDF]

				E. Laspa, M. Bastepe, H. Juppner, and A. Tsatsoulis Phenotypic and Molecular Genetic Aspects of Pseudohypoparathyroidism Type Ib in a Greek Kindred: Evidence for Enhanced Uric Acid Excretion Due to Parathyroid Hormone Resistance J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5942 - 5947. [Abstract] [Full Text] [PDF]

				E. C. Buxton, W. Yao, and N. E. Lane Changes in Serum Receptor Activator of Nuclear Factor-{kappa}B Ligand, Osteoprotegerin, and Interleukin-6 Levels in Patients with Glucocorticoid-Induced Osteoporosis Treated with Human Parathyroid Hormone (1-34) J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3332 - 3336. [Abstract] [Full Text] [PDF]

				J. E. Onyia, R. J. S. Galvin, Y. L. Ma, D. L. Halladay, R. R. Miles, X. Yang, T. Fuson, R. L. Cain, Q. Q. Zeng, S. Chandrasekhar, et al. Novel and Selective Small Molecule Stimulators of Osteoprotegerin Expression Inhibit Bone Resorption J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 369 - 379. [Abstract] [Full Text]

				H.-I. Shin, P. Divieti, N. A. Sims, T. Kobayashi, D. Miao, A. C. Karaplis, R. Baron, R. Bringhurst, and H. M. Kronenberg gp130-Mediated Signaling Is Necessary for Normal Osteoblastic Function in Vivo and in Vitro Endocrinology, March 1, 2004; 145(3): 1376 - 1385. [Abstract] [Full Text] [PDF]

				K. A Cappuzzo and J. C Delafuente Teriparatide for Severe Osteoporosis Ann. Pharmacother., February 1, 2004; 38(2): 294 - 302. [Abstract] [Full Text] [PDF]

				N. A. McHugh, H. M. Vercesi, R. W. Egan, and J. A. Hey Receptor activator of NF-{kappa}B ligand arrests bone growth and promotes cortical bone resorption in growing rats J Appl Physiol, August 1, 2003; 95(2): 672 - 676. [Abstract] [Full Text] [PDF]

				V. Krishnan, T. L. Moore, Y. L. Ma, L. M. Helvering, C. A. Frolik, K. M. Valasek, P. Ducy, and A. G. Geiser Parathyroid Hormone Bone Anabolic Action Requires Cbfa1/Runx2-Dependent Signaling Mol. Endocrinol., March 1, 2003; 17(3): 423 - 435. [Abstract] [Full Text] [PDF]

				Q. Fu, R. L. Jilka, S. C. Manolagas, and C. A. O'Brien Parathyroid Hormone Stimulates Receptor Activator of NFkappa B Ligand and Inhibits Osteoprotegerin Expression via Protein Kinase A Activation of cAMP-response Element-binding Protein J. Biol. Chem., December 6, 2002; 277(50): 48868 - 48875. [Abstract] [Full Text] [PDF]

				M. R. Rubin and J. P. Bilezikian The Role of Parathyroid Hormone in the Pathogenesis of Glucocorticoid-Induced Osteoporosis: A Re-Examination of the Evidence J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4033 - 4041. [Full Text] [PDF]

				J. Rubin, C. L. Ackert-Bicknell, L. Zhu, X. Fan, T. C. Murphy, M. S. Nanes, R. Marcus, L. Holloway, W. G. Beamer, and C. J. Rosen IGF-I Regulates Osteoprotegerin (OPG) and Receptor Activator of Nuclear Factor-{kappa}B Ligand in Vitro and OPG in Vivo J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4273 - 4279. [Abstract] [Full Text] [PDF]

				M. Pazianas, M. Zaidi, S. Schmaldienst, E. Dittrich, B. Watschinger, and P. Pietschmann Two underlying diseases causing hypercalcaemia? Nephrol. Dial. Transplant., June 1, 2002; 17(6): 1141 - 1141. [Full Text] [PDF]