Top

Published in:

01-01-2011

The Role of GH/IGF-I-Mediated Mechanisms in Sex Differences in Cortical Bone Size in Mice

Authors: Lisa E. Olson, Claes Ohlsson, Subburaman Mohan

Published in: Calcified Tissue International | Issue 1/2011

Abstract

Cortical bone dimensions are important determinants of bone strength. Gender differences in cortical bone size caused by greater periosteal expansion in males than in females during the pubertal growth spurt are well established both in humans and in experimental animal models. However, the mechanism by which gender influences cortical bone size is still a matter of investigation. The role of androgens and estrogen in pubertal bone growth has been examined in human disorders as well as animal models, such as gonadectomized or sex steroid receptor knockout mice. Based on the findings that growth hormone (GH) and insulin-like growth factor I (IGF-I) are major regulators of postnatal skeletal growth, we and others have predicted that sex hormones interact with the GH/IGF-I axis to regulate cortical bone size. However, studies conflict as to whether estrogen and androgens impact cortical bone size through the canonical pathway, through GH without IGF-I mediation, through IGF-I without GH stimulation, or independent of GH/IGF-I. We review recent data on the impact of sex steroids and components of the GH/IGF axis on sexual dimorphism in bone size. While the GH/IGF-I axis is a major player in regulating peak bone size, the relative contribution of GH/IGF-dependent mechanisms to sex differences in cortical bone size remains to be established.

Turner CH (2006) Bone strength: current concepts. Ann N Y Acad Sci 1068:429–446CrossRefPubMed

Bouxsein ML, Karasik D (2006) Bone geometry and skeletal fragility. Curr Osteoporos Rep 4:49–56CrossRefPubMed

Seeman E (2009) Bone modeling and remodeling. Crit Rev Eukaryot Gene Expr 19:219–233PubMed

Seeman E (2001) Clinical review 137. Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab 86:4576–4584CrossRefPubMed

Bachrach LK (2008) Skeletal development in childhood and adolescence. In: Rosen CJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research, Washington, DC, pp 74–79CrossRef

Christoforidis A, Maniadaki I, Stanhope R (2005) Growth hormone/insulin-like growth factor-1 axis during puberty. Pediatr Endocrinol Rev 3:5–10PubMed

Riggs BL, Khosla S, Melton LJ 3rd (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302CrossRefPubMed

Mauras N (2001) Growth hormone and sex steroids. Interactions in puberty. Endocrinol Metab Clin North Am 30:529–544CrossRefPubMed

Clark PA, Rogol AD (1996) Growth hormones and sex steroid interactions at puberty. Endocrinol Metab Clin North Am 25:665–681CrossRefPubMed

10.

Metzger DL, Kerrigan JR, Rogol AD (1994) Gonadal steroid hormone regulation of the somatotropic axis during puberty in humans: mechanisms of androgen and estrogen action. Trends Endocrinol Metab 5:290–296CrossRefPubMed

11.

Bautista CM, Mohan S, Baylink DJ (1990) Insulin-like growth factors I and II are present in the skeletal tissues of ten vertebrates. Metabolism 39:96–100CrossRefPubMed

12.

Zhang XZ, Kalu DN, Erbas B, Hopper JL, Seeman E (1999) The effects of gonadectomy on bone size, mass, and volumetric density in growing rats are gender-, site-, and growth hormone-specific. J Bone Miner Res 14:802–809CrossRefPubMed

13.

Bikle D, Majumdar S, Laib A, Powell-Braxton L, Rosen C, Beamer W, Nauman E, Leary C, Halloran B (2001) The skeletal structure of insulin-like growth factor I–deficient mice. J Bone Miner Res 16:2320–2329CrossRefPubMed

14.

Govoni KE, Wergedal JE, Florin L, Angel P, Baylink DJ, Mohan S (2007) Conditional deletion of insulin-like growth factor-I in collagen type 1alpha2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion. Endocrinology 148:5706–5715CrossRefPubMed

15.

Mohan S, Richman C, Guo R, Amaar Y, Donahue LR, Wergedal J, Baylink DJ (2003) Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormone-dependent and -independent mechanisms. Endocrinology 144:929–936CrossRefPubMed

16.

Ohlsson C, Mohan S, Sjogren K, Tivesten A, Isgaard J, Isaksson O, Jansson JO, Svensson J (2009) The role of liver-derived insulin-like growth factor-I. Endocr Rev 30:494–535CrossRefPubMed

17.

Govoni KE, Lee SK, Chung YS, Behringer RR, Wergedal JE, Baylink DJ, Mohan S (2007) Disruption of insulin-like growth factor-I expression in type IIalphaI collagen-expressing cells reduces bone length and width in mice. Physiol Genomics 30:354–362CrossRefPubMed

18.

Donahue LR, Beamer WG (1993) Growth hormone deficiency in “little” mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2, -1 or -4. J Endocrinol 136:91–104CrossRefPubMed

19.

Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59–72PubMed

20.

DeChiara TM, Efstratiadis A, Robertson EJ (1990) A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345:78–80CrossRefPubMed

21.

Mohan S, Govoni K, Wergedal J (2008) Is growth hormone/IGF-I mediated mechanism involved in regulating gender differences in bone size? In: Proceedings of the American society for bone and mineral research 30th annual meeting, September 12–16, 2008, Montreal, Canada

22.

Kim BT, Mosekilde L, Duan Y, Zhang XZ, Tornvig L, Thomsen JS, Seeman E (2003) The structural and hormonal basis of sex differences in peak appendicular bone strength in rats. J Bone Miner Res 18:150–155CrossRefPubMed

23.

Venken K, De Gendt K, Boonen S, Ophoff J, Bouillon R, Swinnen JV, Verhoeven G, Vanderschueren D (2006) Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. J Bone Miner Res 21:576–585CrossRefPubMed

24.

Callewaert F, Venken K, Kopchick JJ, Torcasio A, van Lenthe GH, Boonen S, Vanderschueren D (2010) Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time-specific actions of sex steroids and IGF-1: evidence from pubertal mouse models. J Bone Miner Res 25:617–626CrossRefPubMed

25.

Govoni KE, Wergedal JE, Chadwick RB, Srivastava AK, Mohan S (2008) Prepubertal OVX increases IGF-I expression and bone accretion in C57BL/6J mice. Am J Physiol Endocrinol Metab 295:E1172–E1180CrossRefPubMed

26.

Turner RT, Wakley GK, Hannon KS (1990) Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J Orthop Res 8:612–617CrossRefPubMed

27.

Frank GR (2003) Role of estrogen and androgen in pubertal skeletal physiology. Med Pediatr Oncol 41:217–221CrossRefPubMed

28.

Juul A (2001) The effects of oestrogens on linear bone growth. Hum Reprod Update 7:303–313CrossRefPubMed

29.

Meinhardt UJ, Ho KK (2006) Modulation of growth hormone action by sex steroids. Clin Endocrinol (Oxf) 65:413–422CrossRef

30.

Styne DM (2003) The regulation of pubertal growth. Horm Res 60:22–26CrossRefPubMed

31.

Cutler GB Jr (1997) The role of estrogen in bone growth and maturation during childhood and adolescence. J Steroid Biochem Mol Biol 61:141–144CrossRefPubMed

32.

Vanderschueren D, Venken K, Ophoff J, Bouillon R, Boonen S (2006) Clinical review. Sex steroids and the periosteum—reconsidering the roles of androgens and estrogens in periosteal expansion. J Clin Endocrinol Metab 91:378–382CrossRefPubMed

33.

Vanderschueren D, van Herck E, Nijs J, Ederveen AG, De Coster R, Bouillon R (1997) Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats. Endocrinology 138:2301–2307CrossRefPubMed

34.

Sjogren K, Lagerquist M, Moverare-Skrtic S, Andersson N, Windahl SH, Swanson C, Mohan S, Poutanen M, Ohlsson C (2009) Elevated aromatase expression in osteoblasts leads to increased bone mass without systemic adverse effects. J Bone Miner Res 24:1263–1270CrossRefPubMed

35.

Fritton JC, Emerton KB, Sun H, Kawashima Y, Mejia W, Wu Y, Rosen CJ, Panus D, Bouxsein M, Majeska RJ, Schaffler MB, Yakar S (2010) Growth hormone protects against ovariectomy-induced bone loss in states of low circulating insulin-like growth factor (IGF-1). J Bone Miner Res 25:235–246CrossRefPubMed

36.

Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL, Skinner RA, Hogue WR, Nicks KM, Pierson TM, Suva LJ, Gaddy D (2007) Inhibin A is an endocrine stimulator of bone mass and strength. Endocrinology 148:1654–1665CrossRefPubMed

37.

Belgorosky A, Baquedano MS, Guercio G, Rivarola MA (2008) Adrenarche: postnatal adrenal zonation and hormonal and metabolic regulation. Horm Res 70:257–267CrossRefPubMed

38.

Remer T, Boye KR, Hartmann M, Neu CM, Schoenau E, Manz F, Wudy SA (2003) Adrenarche and bone modeling and remodeling at the proximal radius: weak androgens make stronger cortical bone in healthy children. J Bone Miner Res 18:1539–1546CrossRefPubMed

39.

Cutler GB Jr, Loriaux DL (1980) Andrenarche and its relationship to the onset of puberty. Fed Proc 39:2384–2390PubMed

40.

Labrie F, Cusan L, Gomez JL, Martel C, Berube R, Belanger P, Belanger A, Vandenput L, Mellstrom D, Ohlsson C (2009) Comparable amounts of sex steroids are made outside the gonads in men and women: strong lesson for hormone therapy of prostate and breast cancer. J Steroid Biochem Mol Biol 113:52–56CrossRefPubMed

41.

Pignatelli D, Xiao F, Gouveia AM, Ferreira JG, Vinson GP (2006) Adrenarche in the rat. J Endocrinol 191:301–308CrossRefPubMed

42.

Johnsen IK, Slawik M, Shapiro I, Hartmann MF, Wudy SA, Looyenga BD, Hammer GD, Reincke M, Beuschlein F (2006) Gonadectomy in mice of the inbred strain CE/J induces proliferation of sub-capsular adrenal cells expressing gonadal marker genes. J Endocrinol 190:47–57CrossRefPubMed

43.

Grunt JA (1964) Effects of adrenalectomy and gonadectomy on growth and development in the rat. Endocrinology 75:446–451CrossRefPubMed

44.

Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K, Speed C, Jones M (2002) Aromatase—a brief overview. Annu Rev Physiol 64:93–127CrossRefPubMed

45.

Zhao H, Innes J, Brooks DC, Reierstad S, Yilmaz MB, Lin Z, Bulun SE (2009) A novel promoter controls Cyp19a1 gene expression in mouse adipose tissue. Reprod Biol Endocrinol 7:37CrossRefPubMed

46.

Lindberg MK, Alatalo SL, Halleen JM, Mohan S, Gustafsson JA, Ohlsson C (2001) Estrogen receptor specificity in the regulation of the skeleton in female mice. J Endocrinol 171:229–236CrossRefPubMed

47.

Vidal O, Lindberg MK, Hollberg K, Baylink DJ, Andersson G, Lubahn DB, Mohan S, Gustafsson JA, Ohlsson C (2000) Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. Proc Natl Acad Sci USA 97:5474–5479CrossRefPubMed

48.

Windahl SH, Vidal O, Andersson G, Gustafsson JA, Ohlsson C (1999) Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(−/−) mice. J Clin Invest 104:895–901CrossRefPubMed

49.

Vandenput L, Ederveen AG, Erben RG, Stahr K, Swinnen JV, Van Herck E, Verstuyf A, Boonen S, Bouillon R, Vanderschueren D (2001) Testosterone prevents orchidectomy-induced bone loss in estrogen receptor-alpha knockout mice. Biochem Biophys Res Commun 285:70–76CrossRefPubMed

50.

Callewaert F, Venken K, Ophoff J, De Gendt K, Torcasio A, van Lenthe GH, Van Oosterwyck H, Boonen S, Bouillon R, Verhoeven G, Vanderschueren D (2009) Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha. FASEB J 23:232–240CrossRefPubMed

51.

Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104:719–730PubMed

52.

Voide R, van Lenthe GH, Muller R (2008) Bone morphometry strongly predicts cortical bone stiffness and strength, but not toughness, in inbred mouse models of high and low bone mass. J Bone Miner Res 23:1194–1203CrossRefPubMed

53.

Volkman SK, Galecki AT, Burke DT, Paczas MR, Moalli MR, Miller RA, Goldstein SA (2003) Quantitative trait loci for femoral size and shape in a genetically heterogeneous mouse population. J Bone Miner Res 18:1497–1505CrossRefPubMed

54.

Veldhuis JD, Metzger DL, Martha PM Jr, Mauras N, Kerrigan JR, Keenan B, Rogol AD, Pincus SM (1997) Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement. J Clin Endocrinol Metab 82:3414–3420CrossRefPubMed

55.

Leung KC, Johannsson G, Leong GM, Ho KK (2004) Estrogen regulation of growth hormone action. Endocr Rev 25:693–721CrossRefPubMed

56.

Cohen P, Bright GM, Rogol AD, Kappelgaard AM, Rosenfeld RG (2002) Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. J Clin Endocrinol Metab 87:90–98CrossRefPubMed

57.

Span JP, Pieters GF, Sweep CG, Hermus AR, Smals AG (2000) Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: role of sex hormone replacement. J Clin Endocrinol Metab 85:1121–1125CrossRefPubMed

58.

Venken K, Schuit F, Van Lommel L, Tsukamoto K, Kopchick JJ, Coschigano K, Ohlsson C, Moverare S, Boonen S, Bouillon R, Vanderschueren D (2005) Growth without growth hormone receptor: estradiol is a major growth hormone–independent regulator of hepatic IGF-I synthesis. J Bone Miner Res 20:2138–2149CrossRefPubMed

59.

Mauras N, Rogol AD, Haymond MW, Veldhuis JD (1996) Sex steroids, growth hormone, insulin-like growth factor-1: neuroendocrine and metabolic regulation in puberty. Horm Res 45:74–80CrossRefPubMed

60.

Venken K, Moverare-Skrtic S, Kopchick JJ, Coschigano KT, Ohlsson C, Boonen S, Bouillon R, Vanderschueren D (2007) Impact of androgens, growth hormone, and IGF-I on bone and muscle in male mice during puberty. J Bone Miner Res 22:72–82CrossRefPubMed

61.

Salih DA, Mohan S, Kasukawa Y, Tripathi G, Lovett FA, Anderson NF, Carter EJ, Wergedal JE, Baylink DJ, Pell JM (2005) Insulin-like growth factor-binding protein-5 induces a gender-related decrease in bone mineral density in transgenic mice. Endocrinology 146:931–940CrossRefPubMed

62.

DeMambro VE, Clemmons DR, Horton LG, Bouxsein ML, Wood TL, Beamer WG, Canalis E, Rosen CJ (2008) Gender-specific changes in bone turnover and skeletal architecture in igfbp-2-null mice. Endocrinology 149:2051–2061CrossRefPubMed

63.

Courtland HW, DeMambro V, Maynard J, Sun H, Elis S, Rosen C, Yakar S (2010) Sex-specific regulation of body size and bone slenderness by the acid labile subunit. J Bone Miner Res 25:2059–2068CrossRefPubMed

64.

Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C (2004) Androgens and bone. Endocr Rev 25:389–425CrossRefPubMed

65.

Michael H, Harkonen PL, Vaananen HK, Hentunen TA (2005) Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. J Bone Miner Res 20:2224–2232CrossRefPubMed

66.

Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF (1996) Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 2:1132–1136CrossRefPubMed

67.

Wiren KM, Toombs AR, Zhang XW (2004) Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts. J Mol Endocrinol 32:209–226CrossRefPubMed

68.

Wiren KM, Zhang XW, Toombs AR, Kasparcova V, Gentile MA, Harada S, Jepsen KJ (2004) Targeted overexpression of androgen receptor in osteoblasts: unexpected complex bone phenotype in growing animals. Endocrinology 145:3507–3522CrossRefPubMed

69.

Gori F, Hofbauer LC, Conover CA, Khosla S (1999) Effects of androgens on the insulin-like growth factor system in an androgen-responsive human osteoblastic cell line. Endocrinology 140:5579–5586CrossRefPubMed

70.

Turner RT, Kidder LS, Zhang M, Harris SA, Westerlind KC, Maran A, Wronski TJ (1999) Estrogen has rapid tissue-specific effects on rat bone. J Appl Physiol 86:1950–1958PubMed

71.

Kearns AE, Khosla S, Kostenuik PJ (2008) Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 29:155–192CrossRefPubMed

72.

Wiren KM (2005) Androgens and bone growth: it’s location, location, location. Curr Opin Pharmacol 5:626–632CrossRefPubMed

73.

Jessop HL, Sjoberg M, Cheng MZ, Zaman G, Wheeler-Jones CP, Lanyon LE (2001) Mechanical strain and estrogen activate estrogen receptor alpha in bone cells. J Bone Miner Res 16:1045–1055CrossRefPubMed

74.

Aguirre JI, Plotkin LI, Gortazar AR, Millan MM, O’Brien CA, Manolagas SC, Bellido T (2007) A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction. J Biol Chem 282:25501–25508CrossRefPubMed

75.

Saxon LK, Robling AG, Castillo AB, Mohan S, Turner CH (2007) The skeletal responsiveness to mechanical loading is enhanced in mice with a null mutation in estrogen receptor-beta. Am J Physiol Endocrinol Metab 293:E484–E491CrossRefPubMed

76.

Lee KC, Jessop H, Suswillo R, Zaman G, Lanyon LE (2004) The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-alpha and -beta. J Endocrinol 182:193–201CrossRefPubMed

77.

Damien E, Price JS, Lanyon LE (2000) Mechanical strain stimulates osteoblast proliferation through the estrogen receptor in males as well as females. J Bone Miner Res 15:2169–2177CrossRefPubMed

78.

Cheng MZ, Rawlinson SC, Pitsillides AA, Zaman G, Mohan S, Baylink DJ, Lanyon LE (2002) Human osteoblasts’ proliferative responses to strain and 17beta-estradiol are mediated by the estrogen receptor and the receptor for insulin-like growth factor I. J Bone Miner Res 17:593–602CrossRefPubMed

79.

Zofkova I (2008) Hormonal aspects of the muscle-bone unit. Physiol Res 57(Suppl 1):S159–S169PubMed

80.

Ophoff J, Van Proeyen K, Callewaert F, De Gendt K, De Bock K, Vanden Bosch A, Verhoeven G, Hespel P, Vanderschueren D (2009) Androgen signaling in myocytes contributes to the maintenance of muscle mass and fiber type regulation but not to muscle strength or fatigue. Endocrinology 150:3558–3566CrossRefPubMed

Title: The Role of GH/IGF-I-Mediated Mechanisms in Sex Differences in Cortical Bone Size in Mice
Authors: Lisa E. Olson
Claes Ohlsson
Subburaman Mohan
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Calcified Tissue International / Issue 1/2011
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-010-9436-2

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The Role of GH/IGF-I-Mediated Mechanisms in Sex Differences in Cortical Bone Size in Mice

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2011

Osteoclasts Lacking Rac2 Have Defective Chemotaxis and Resorptive Activity

Imatinib Mesylate Does Not Increase Bone Volume In Vivo

Jaw and Long Bone Marrows Have a Different Osteoclastogenic Potential

Effects of Nicotine Administration and Nicotine Cessation on Bone Histomorphometry and Bone Biomarkers in Sprague–Dawley Male Rats

Improvement of Femoral Bone Quality After Low-Magnitude, High-Frequency Mechanical Stimulation in the Ovariectomized Rat as an Osteopenia Model

Continuous Treatment with a Low-Dose β-Agonist Reduces Bone Mass by Increasing Bone Resorption Without Suppressing Bone Formation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page