This Article Full Text Full Text (PDF) 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 Miyakoshi, N. Articles by Mohan, S. Search for Related Content PubMed PubMed Citation Articles by Miyakoshi, N. Articles by Mohan, S.

Evidence That Anabolic Effects of PTH on Bone Require IGF-I in Growing Mice

Musculoskeletal Disease Center (N.M., Y.K., T.A.L., D.J.B., S.M.), J.L. Pettis VA Medical Center, Loma Linda, California 92357; Departments of Medicine (D.J.B., S.M.), Biochemistry (T.A.L., S.M.), Physiology (S.M.), and Pediatrics (T.A.L.), Loma Linda University, Loma Linda, California 92350

Address all correspondence and requests for reprints to: Subburaman Mohan, Ph.D., Musculoskeletal Disease Center (151), JLP Veterans Affairs Medical Center, 11201 Benton Street, Loma Linda, California 92357. E-mail: mohans{at}lom.med.va.gov

Although it has been established that PTH exerts potent anabolic effects on bone in animals and humans, the mechanism of PTH action on bone remains controversial. Based on the previous findings that PTH treatment increased production of IGF-I in bone cells and that PTH effects on bone cells in vitro were blocked by IGF-I–blocking antibodies, we proposed that IGF-I action is required for the stimulatory effects of PTH on bone formation. To test this hypothesis, we evaluated the effects of PTH on bone formation parameters in growing mice lacking functional IGF-I genes. Five-week-old IGF-I(-/-) mice and wild-type littermates were given daily sc injections of 160 µg/kg body weight of PTH (1–34) or vehicle for 10 d. In wild-type animals, PTH caused a significant increase in serum osteocalcin levels (113%), serum alkaline phosphatase activity (48%), and alkaline phosphatase activity in femoral bone extracts (>80%), compared with the vehicle-treated control group. In contrast, in IGF-I(-/-) mice, there was no significant effect of PTH on any bone formation parameters. PTH treatment increased total bone mineral density, as evaluated by peripheral quantitative computer tomography, at the distal metaphysis of the femur by 40% in wild-type mice, but it had no effect on bone mineral density in mice lacking functional IGF-I genes. In vitro studies using osteoblasts derived from control and IGF-I(-/-) mice revealed that PTH treatment increased cell number in osteoblasts derived from IGF-I knockout mice in the presence of exogenously added IGF-I but not without IGF-I. These data to our knowledge provide the first direct evidence that the anabolic effects of PTH on bone formation in vivo require IGF-I action in growing mice.

This article has been cited by other articles:

				C. Ohlsson, S. Mohan, K. Sjogren, A. Tivesten, J. Isgaard, O. Isaksson, J.-O. Jansson, and J. Svensson The Role of Liver-Derived Insulin-Like Growth Factor-I Endocr. Rev., August 1, 2009; 30(5): 494 - 535. [Abstract] [Full Text] [PDF]

				K. E. Govoni, J. E. Wergedal, R. B. Chadwick, A. K. Srivastava, and S. Mohan Prepubertal OVX increases IGF-I expression and bone accretion in C57BL/6J mice Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1172 - E1180. [Abstract] [Full Text] [PDF]

				L. J. Raggatt, L. Qin, J. Tamasi, S. C. Jefcoat Jr., E. Shimizu, N. Selvamurugan, F. Y. Liew, L. Bevelock, J. H. M. Feyen, and N. C. Partridge Interleukin-18 Is Regulated by Parathyroid Hormone and Is Required for Its Bone Anabolic Actions J. Biol. Chem., March 14, 2008; 283(11): 6790 - 6798. [Abstract] [Full Text] [PDF]

				K. E. Govoni, J. E. Wergedal, L. Florin, P. Angel, D. J. Baylink, and S. Mohan Conditional Deletion of Insulin-Like Growth Factor-I in Collagen Type 1{alpha}2-Expressing Cells Results in Postnatal Lethality and a Dramatic Reduction in Bone Accretion Endocrinology, December 1, 2007; 148(12): 5706 - 5715. [Abstract] [Full Text] [PDF]

				X. Li, H. Liu, L. Qin, J. Tamasi, M. Bergenstock, S. Shapses, J. H. M. Feyen, D. A. Notterman, and N. C. Partridge Determination of Dual Effects of Parathyroid Hormone on Skeletal Gene Expression in Vivo by Microarray and Network Analysis J. Biol. Chem., November 9, 2007; 282(45): 33086 - 33097. [Abstract] [Full Text] [PDF]

				E. Canalis, A. Giustina, and J. P. Bilezikian Mechanisms of Anabolic Therapies for Osteoporosis N. Engl. J. Med., August 30, 2007; 357(9): 905 - 916. [Full Text] [PDF]

				K. E. Govoni, S. K. Lee, Y.-S. Chung, R. R. Behringer, J. E. Wergedal, D. J. Baylink, and S. Mohan Disruption of insulin-like growth factor-I expression in type II{alpha}I collagen-expressing cells reduces bone length and width in mice Physiol Genomics, August 20, 2007; 30(3): 354 - 362. [Abstract] [Full Text] [PDF]

				M. L. Adamo, X. Ma, C. L. Ackert-Bicknell, L. R. Donahue, W. G. Beamer, and C. J. Rosen Genetic Increase in Serum Insulin-Like Growth Factor-I (IGF-I) in C3H/HeJ Compared with C57BL/6J Mice Is Associated with Increased Transcription from the IGF-I Exon 2 Promoter Endocrinology, June 1, 2006; 147(6): 2944 - 2955. [Abstract] [Full Text] [PDF]

				S. Yakar, M. L Bouxsein, E. Canalis, H. Sun, V. Glatt, C. Gundberg, P. Cohen, D. Hwang, Y. Boisclair, D. LeRoith, et al. The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone. J. Endocrinol., May 1, 2006; 189(2): 289 - 299. [Abstract] [Full Text] [PDF]

				S Mohan and D J Baylink Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences J. Endocrinol., June 1, 2005; 185(3): 415 - 420. [Abstract] [Full Text] [PDF]

				M. Yamaguchi, N. Ogata, Y. Shinoda, T. Akune, S. Kamekura, Y. Terauchi, T. Kadowaki, K. Hoshi, U.-I. Chung, K. Nakamura, et al. Insulin Receptor Substrate-1 Is Required for Bone Anabolic Function of Parathyroid Hormone in Mice Endocrinology, June 1, 2005; 146(6): 2620 - 2628. [Abstract] [Full Text] [PDF]

				E. Maioli, V. Fortino, and A. Pacini Parathyroid Hormone-Related Protein in Preeclampsia: A Linkage Between Maternal and Fetal Failures Biol Reprod, December 1, 2004; 71(6): 1779 - 1784. [Abstract] [Full Text] [PDF]

				C. P. Sanchez and Y.-Z. He Growth Hormone Therapy in Calcium-Loaded Rats with Renal Failure Endocrinology, July 1, 2004; 145(7): 3375 - 3385. [Abstract] [Full Text] [PDF]

				T. Shimoaka, S. Kamekura, H. Chikuda, K. Hoshi, U.-i. Chung, T. Akune, Z. Maruyama, T. Komori, M. Matsumoto, W. Ogawa, et al. Impairment of Bone Healing by Insulin Receptor Substrate-1 Deficiency J. Biol. Chem., April 9, 2004; 279(15): 15314 - 15322. [Abstract] [Full Text] [PDF]

				Y. Kasukawa, D. J. Baylink, J. E. Wergedal, Y. Amaar, A. K. Srivastava, R. Guo, and S. Mohan Lack of Insulin-Like Growth Factor I Exaggerates the Effect of Calcium Deficiency on Bone Accretion in Mice Endocrinology, November 1, 2003; 144(11): 4682 - 4689. [Abstract] [Full Text] [PDF]

				A. Grey, Q. Chen, X. Xu, K. Callon, and J. Cornish Parallel Phosphatidylinositol-3 Kinase and p42/44 Mitogen-Activated Protein Kinase Signaling Pathways Subserve the Mitogenic and Antiapoptotic Actions of Insulin-Like Growth Factor I in Osteoblastic Cells Endocrinology, November 1, 2003; 144(11): 4886 - 4893. [Abstract] [Full Text] [PDF]

				S. Mohan, C. Richman, R. Guo, Y. Amaar, L. R. Donahue, J. Wergedal, and D. J. Baylink Insulin-Like Growth Factor Regulates Peak Bone Mineral Density in Mice by Both Growth Hormone-Dependent and -Independent Mechanisms Endocrinology, March 1, 2003; 144(3): 929 - 936. [Abstract] [Full Text] [PDF]

				B. Demiralp, H.-L. Chen, A. J. Koh, E. T. Keller, and L. K. McCauley Anabolic Actions of Parathyroid Hormone during Bone Growth Are Dependent on c-fos Endocrinology, October 1, 2002; 143(10): 4038 - 4047. [Abstract] [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]