title: Anabolic effects of IGF-1 signaling on the skeleton.
abstract: This review focuses on the anabolic effects of IGF-1 signaling on the skeleton, emphasizing the requirement for IGF-1 signaling in normal bone formation and remodeling. We first discuss the genomic context, splicing variants, and species conservation of the IGF-1 locus. The modulation of IGF-1 action by growth hormone (GH) is then reviewed while also discussing the current model which takes into account the GH-independent actions of IGF-1. Next, the skeletal phenotypes of IGF-1-deficient animals are described in both embryonic and postnatal stages of development, which include severe dwarfism and an undermineralized skeleton. We then highlight two mechanisms by which IGF-1 exerts its anabolic action on the skeleton. Firstly, the role of IGF-1 signaling in the modulation of anabolic effects of parathyroid hormone (PTH) on bone will be discussed, presenting in vitro and in vivo studies that establish this concept and the proposed underlying molecular mechanisms involving Indian hedgehog (Ihh) and the ephrins. Secondly, the crosstalk of IGF-1 signaling with mechanosensing pathways will be discussed, beginning with the observation that animals subjected to skeletal unloading by hindlimb elevation are unable to mitigate cessation of bone growth despite infusion with IGF-1 and the failure of IGF-1 to activate its receptor in bone marrow stromal cell cultures from unloaded bone. Disrupted crosstalk between IGF-1 signaling and the integrin mechanotransduction pathways is discussed as one of the potential mechanisms for this IGF-1 resistance. Next, emerging paradigms on bone-muscle crosstalk are examined, focusing on the potential role of IGF-1 signaling in modulating such interactions. Finally, we present a future outlook on IGF research.
authors: Endocrine Research Unit, Veterans Affairs Medical Center, Department of Medicine, University of California San Francisco, CA, USA.
authors: Candice G T
authors: CG
authors: Tahimic
authors: Yongmei
authors: Y
authors: Wang
authors: Daniel D
authors: DD
authors: Bikle
keywords: IGF-1; PTH; integrins; mechanotransduction; muscle-bone interactions; osteogenesis; skeletal unloading
references: Calcif Tissue Int. 1995 Nov;57(5):344-58
references: 8564797
references: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7324-9
references: 10377413
references: J Bone Miner Res. 2011 Dec;26(12):2948-58
references: 21932337
references: J Muscle Res Cell Motil. 1996 Aug;17(4):487-95
references: 8884603
references: Bone. 2003 Jun;32(6):669-80
references: 12810174
references: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13030-5
references: 9789035
references: J Biol Chem. 1999 Aug 13;274(33):23249-55
references: 10438499
references: J Physiol. 1999 Apr 15;516 ( Pt 2):583-92
references: 10087355
references: J Bone Miner Res. 1999 Jan;14(1):21-31
references: 9893062
references: Bone. 2013 Jan;52(1):133-44
references: 23032105
references: J Biol Chem. 2002 Nov 15;277(46):44005-12
references: 12215457
references: Endocrinology. 1995 Jan;136(1):124-31
references: 7828521
references: Nucleic Acids Res. 1986 Oct 24;14(20):7873-82
references: 3774549
references: Endocrinology. 2001 Oct;142(10):4349-56
references: 11564695
references: Nature. 1998 May 14;393(6681):125-6
references: 9603515
references: Arch Biochem Biophys. 2008 May 15;473(2):218-24
references: 18358824
references: J Endocrinol. 2007 Jan;192(1):131-40
references: 17210750
references: J Bone Miner Res. 2006 Apr;21(4):626-36
references: 16598383
references: Endocrinology. 1989 Sep;125(3):1484-91
references: 2759029
references: Am J Physiol Endocrinol Metab. 2000 Jun;278(6):E967-76
references: 10826997
references: J Bone Miner Res. 2002 Nov;17(11):1977-87
references: 12412805
references: Cell. 1993 Oct 8;75(1):73-82
references: 8402902
references: FASEB J. 1999 Nov;13(14):1985-90
references: 10544181
references: J Cell Physiol. 2007 Mar;210(3):609-15
references: 17133357
references: Am J Physiol Endocrinol Metab. 2011 Dec;301(6):E1191-7
references: 21878662
references: J Bone Miner Res. 1996 Jun;11(6):864-72
references: 8725185
references: J Bone Miner Res. 2004 Mar;19(3):436-46
references: 15040832
references: J Appl Physiol (1985). 1998 May;84(5):1716-22
references: 9572822
references: Comp Biochem Physiol B Biochem Mol Biol. 1998 Sep;121(1):35-41
references: 9972282
references: Cell Adh Migr. 2012 Mar-Apr;6(2):148-56
references: 22660185
references: Am J Physiol. 1995 Feb;268(2 Pt 1):E318-27
references: 7864109
references: Genes Dev. 1993 Dec;7(12B):2609-17
references: 8276243
references: Endocrinology. 1995 May;136(5):1939-44
references: 7720641
references: Curr Pharm Des. 2007;13(7):663-9
references: 17346182
references: Bone. 2013 Jun;54(2):182-90
references: 23085083
references: Leukemia. 2011 Aug;25(8):1370-4
references: 21566652
references: Mol Endocrinol. 2005 Jan;19(1):1-11
references: 15528274
references: J Bone Miner Res. 2011 Jul;26(7):1437-46
references: 21312270
references: Stem Cells Dev. 2013 Feb 15;22(4):622-30
references: 23020187
references: Development. 2002 Jun;129(12):2977-86
references: 12050144
references: J Anat. 1997 May;190 ( Pt 4):613-22
references: 9183683
references: Endocrinology. 1986 Mar;118(3):948-54
references: 3485043
references: Nature. 2003 May 15;423(6937):332-6
references: 12748651
references: Bone. 1994 Nov-Dec;15(6):717-23
references: 7873302
references: Horm Res. 2006;65 Suppl 2:2-10
references: 16707903
references: J Biol Chem. 2009 Sep 4;284(36):24106-14
references: 19578119
references: Appl Physiol Nutr Metab. 2006 Dec;31(6):791-7
references: 17213901
references: Endocrinology. 1995 Aug;136(8):3632-8
references: 7628403
references: J Bone Miner Res. 2002 Mar;17(3):493-501
references: 11874240
references: Genesis. 2000 Feb;26(2):145-6
references: 10686612
references: Nat Struct Biol. 2001 Dec;8(12):1058-63
references: 11694888
references: Endocr Rev. 2001 Feb;22(1):53-74
references: 11159816
references: J Biol Chem. 1986 Aug 5;261(22):10293-8
references: 2426261
references: J Endocrinol. 2004 Feb;180(2):247-55
references: 14765976
references: Nat Cell Biol. 2001 Nov;3(11):1009-13
references: 11715022
references: Ann N Y Acad Sci. 2006 Apr;1068:1-13
references: 16831900
references: J Bone Miner Res. 2000 Jun;15(6):1045-55
references: 10841173
references: Endocrinology. 1997 Dec;138(12):5202-9
references: 9389502
references: J Bone Miner Res. 1997 Jul;12(7):1068-74
references: 9200006
references: J Appl Physiol (1985). 2000 Oct;89(4):1365-79
references: 11007571
references: Am J Physiol Cell Physiol. 2002 Aug;283(2):C545-51
references: 12107064
references: Endocrinology. 2006 Oct;147(10):4753-61
references: 16857753
references: J Orthop Res. 2001 Jan;19(1):26-32
references: 11332617
references: Mol Endocrinol. 1990 Jun;4(6):899-904
references: 2233747
references: Nat Genet. 2001 Feb;27(2):195-200
references: 11175789
references: J Cell Sci. 2001 Apr;114(Pt 7):1417-25
references: 11257007
references: Nature. 2003 May 15;423(6937):316-8
references: 12748648
references: J Bone Miner Res. 2007 Sep;22(9):1329-37
references: 17539737
references: Age (Dordr). 2013 Apr;35(2):315-30
references: 22218782
references: Cell. 1993 Oct 8;75(1):59-72
references: 8402901
references: Development. 2000 Feb;127(3):543-8
references: 10631175
references: Growth Horm IGF Res. 2012 Oct;22(5):158-66
references: 22698731
references: J Bone Miner Res. 2006 Sep;21(9):1350-8
references: 16939393
references: Osteoarthritis Cartilage. 2009 Jan;17(1):100-6
references: 18595745
references: J Bone Miner Res. 2002 Sep;17(9):1570-8
references: 12211426
references: Bone. 1996 Jul;19(1):41-6
references: 8830986
references: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11217-22
references: 9736716
references: J Endocrinol. 1999 Mar;160(3):461-7
references: 10076192
references: N Engl J Med. 1996 Oct 31;335(18):1363-7
references: 8857020
references: Mol Endocrinol. 1995 Oct;9(10):1380-95
references: 8544846
references: Mamm Genome. 2009 Sep-Oct;20(9-10):654-63
references: 19513790
references: J Clin Invest. 1995 Aug;96(2):767-74
references: 7635970
references: Endocrinology. 1989 Jan;124(1):301-9
references: 2909370
references: Nat Cell Biol. 2012 Jun 10;14(7):659-65
references: 22684254
references: J Clin Invest. 1999 Aug;104(4):439-46
references: 10449436
references: Endocrinology. 2004 May;145(5):2478-86
references: 14749359
references: J Cell Sci. 2009 Jan 15;122(Pt 2):159-63
references: 19118207
references: J Biol Chem. 1987 Aug 25;262(24):11807-12
references: 3624235
references: Endocrinology. 2003 Mar;144(3):929-36
references: 12586770
references: Differentiation. 1985;29(3):195-8
references: 3908201
references: Endocrinology. 1997 Sep;138(9):3849-58
references: 9275074
references: Mol Cell Biochem. 2002 Jul;236(1-2):115-22
references: 12190109
references: Endocrinology. 1995 Feb;136(2):453-63
references: 7835276
references: Leukemia. 2013 Apr;27(4):773-9
references: 23135355
references: J Biol Chem. 1986 Apr 15;261(11):4828-32
references: 2937782
references: Endocrinology. 1988 Jan;122(1):254-60
references: 3335207
references: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):7088-92
references: 10359843
references: Science. 1996 Aug 2;273(5275):613-22
references: 8662546
references: Physiol Genomics. 2007 Aug 20;30(3):354-62
references: 17519362
references: Endocrinology. 2013 Jan;154(1):253-62
references: 23183171
references: J Clin Invest. 1989 Jan;83(1):60-5
references: 2910920
references: Bone. 1995 Mar;16(3):357-65
references: 7786639
references: Mol Reprod Dev. 1993 Aug;35(4):332-6; discussion 337-8
references: 8398110
references: Cell Metab. 2007 Jun;5(6):464-75
references: 17550781
references: Endocrinology. 2007 Dec;148(12):5706-15
references: 17717052
references: Clin Biochem. 2012 Aug;45(12):964-9
references: 22569597
references: Growth Factors. 2008 Oct;26(5):275-83
references: 18651287
references: Endocrinology. 2010 Mar;151(3):865-75
references: 20130113
references: Endocrinology. 2000 Jul;141(7):2674-82
references: 10875273
references: Endocrinology. 1984 Jun;114(6):2264-70
references: 6723581
references: J Bone Miner Res. 2001 Dec;16(12):2320-9
references: 11760848