Ascorbate synthesis pathway: dual role of ascorbate in bone homeostasis.
Using mouse gene knock-out models, we identify aldehyde reductase (EC 1.1.1.2, Akr1a4 (GR)) and aldose reductase (EC 1.1.1.21, Akr1b3 (AR)) as the enzymes responsible for conversion of D-glucuronate to L-gulonate, a key step in the ascorbate (ASC) synthesis pathway in mice. The gene knock-out (KO) mice show that the two enzymes, GR and AR, provide approximately 85 and approximately 15% of L-gulonate, respectively. GRKO/ARKO double knock-out mice are unable to synthesize ASC (>95% ASC deficit) and develop scurvy. The GRKO mice ( approximately 85% ASC deficit) develop and grow normally when fed regular mouse chow (ASC content = 0) but suffer severe osteopenia and spontaneous fractures with stresses that increase ASC requirements, such as pregnancy or castration. Castration greatly increases osteoclast numbers and activity in GRKO mice and promotes increased bone loss as compared with wild-type controls and additionally induces proliferation of immature dysplastic osteoblasts likely because of an ASC-sensitive block(s) in early differentiation. ASC and the antioxidants pycnogenol and resveratrol block osteoclast proliferation and bone loss, but only ASC feeding restores osteoblast differentiation and prevents their dysplastic proliferation. This is the first in vivo demonstration of two independent roles for ASC as an antioxidant suppressing osteoclast activity and number as well as a cofactor promoting osteoblast differentiation. Although humans have lost the ability to synthesize ASC, our mouse models suggest the mechanisms by which suboptimal ASC availability facilitates the development of osteoporosis, which has important implications for human osteoporosis.
Gabbay
Kenneth H
KH
Department of Pediatrics, Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030, USA. kgabbay@bcm.tmc.edu
Bohren
Kurt M
KM
Morello
Roy
R
Bertin
Terry
T
Liu
Jeff
J
Vogel
Peter
P
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism*; D049109:Cell Proliferation; D005419:Flavonoids / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism; D010936:Plant Extracts; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism
D000975:Antioxidants; D005419:Flavonoids; D010936:Plant Extracts; D013267:Stilbenes; C024070:pycnogenols; D001205:Ascorbic Acid; D000077185:Resveratrol
Mol Cell Biol. 2000 Aug;20(16):5840-6
10913167
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5723-8
16585534
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14109-14
14610273
J Bone Miner Res. 2002 Jan;17(1):101-10
11771655
FEBS J. 2007 Jan;274(1):1-22
17222174
J Bone Miner Res. 2005 Sep;20(9):1597-610
16059632
J Biol Chem. 1994 Sep 9;269(36):22500-6
8077198
J Biol Chem. 1989 Jun 5;264(16):9547-51
2498333
Calcif Tissue Int. 2005 Feb;76(2):79-89
15549637
Biochem Biophys Res Commun. 2001 Oct 19;288(1):275-9
11594785
J Biol Chem. 1992 Oct 25;267(30):21973-6
1400508
J Biol Chem. 2007 Jul 27;282(30):22052-61
17510056
Biosci Rep. 2004 Apr;24(2):75-100
15628664
Am J Epidemiol. 2001 Sep 1;154(5):427-33
11532784
J Biol Chem. 1991 Dec 15;266(35):24031-7
1748675
Bone. 2000 Nov;27(5):619-26
11062347
Am J Clin Nutr. 2005 Sep;82(3):581-8
16155271
Int J Clin Pharmacol Ther. 2002 Apr;40(4):158-68
11996210
Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1131-9
16352673
Arch Biochem Biophys. 1978 Apr 15;187(1):158-62
655719
J Virol. 1989 May;63(5):1924-8
2704070
Methods Enzymol. 1979;62:3-11
440112
N Engl J Med. 1973 Apr 19;288(16):831-6
4266466
J Clin Invest. 2007 Jun;117(6):1616-26
17549257
J Nutr. 2008 Oct;138(10):1931-8
18806103
Anal Biochem. 1998 Mar 15;257(2):107-11
9514779
J Bone Miner Res. 1987 Dec;2(6):595-610
3455637
Osteoporos Int. 2009 Nov;20(11):1853-61
19347239
J Clin Invest. 2003 Sep;112(6):915-23
12975476
Cell. 2006 Oct 20;127(2):291-304
17055431
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):686-91
18184809
Science. 1966 Jan 14;151(3707):209-10
5907911
Clin Chim Acta. 1973 Feb 12;43(3):305-10
4690902
Nutr Rev. 1992 Mar;50(3):65-70
1565288
Nature. 2006 Nov 16;444(7117):337-42
17086191
Science. 2001 Nov 9;294(5545):1337-40
11598268
J Biol Chem. 2008 Mar 28;283(13):8634-42
18222921
Cell. 2002 Jan 11;108(1):17-29
11792318
Endocrinology. 2005 Feb;146(2):728-35
15528306
J Bone Miner Res. 2001 Jan;16(1):135-40
11149477
Free Radic Biol Med. 1999 Sep;27(5-6):704-24
10490291
Biochem Biophys Res Commun. 2004 Sep 3;321(4):845-50
15358104
Curr Drug Targets. 2008 Jan;9(1):14-36
18220710