Vitamin a metabolism, action, and role in skeletal homeostasis

Endocrine Reviews

Volumn 34, Issue 6, 2013, Pages 766-797

  Herschel Conaway, H ^a   Henning, Petra ^b   Lerner, Ulf H ^b,c  

^a UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

^b UNIVERSITY OF GOTHENBURG   (Sweden)

^c UMEÅ UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

4 [2 (5,6,7,8 TETRAHYDRO 5,5,8,8 TETRAMETHYL 2 NAPHTHYL) 1 PROPENYL]BENZOIC ACID; 4 [2 (5,6,7,8 TETRAHYDRO 5,5,8,8 TETRAMETHYL 2 NAPHTHYL) 1 PROPENYL]BENZOIC ACID ETHYL ESTER; ALENDRONIC ACID; ALITRETINOIN; AROTINOID; BETA CAROTENE; BISPHOSPHONIC ACID DERIVATIVE; BONE MORPHOGENETIC PROTEIN 2; CD16 ANTIGEN; COLONY STIMULATING FACTOR 1; GR 104; ISOTRETINOIN; KILLER CELL ACTIVATING RECEPTOR ASSOCIATED PROTEIN; NRX 204647; OSTEOCLAST DIFFERENTIATION FACTOR; RETINOIC ACID; RETINOIC ACID RECEPTOR ALPHA; RETINOID; RETINOL; RETINOL ACETATE; RETINOL PALMITATE; RETINOL PALMITATE PLUS RETINOL ACETATE; UNCLASSIFIED DRUG; VITAMIN D;

ACNE; BONE MASS; BONE REMODELING; CELL DIFFERENTIATION; CELL FUNCTION; CELL GROWTH; CELL PROLIFERATION; DIET; DIETARY INTAKE; DRUG EFFECT; DRUG POTENTIATION; FRACTURE; FRAGILITY FRACTURE; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HOMEOSTASIS; HUMAN; HYPERCALCEMIA; KAPOSI SARCOMA; NEUROBLASTOMA; OSSIFICATION; OSTEOCLAST; OSTEOCLASTOGENESIS; OSTEOLYSIS; OSTEOPOROSIS; OVARY CARCINOMA; POSTMENOPAUSE; PRIORITY JOURNAL; PROMYELOCYTIC LEUKEMIA; RETINOL DEFICIENCY; REVIEW; SIGNAL TRANSDUCTION; SKELETON; STEM CELL; VISION; VITAMIN METABOLISM;

ANIMALS; BONE AND BONES; HOMEOSTASIS; HUMANS; LIVER; RECEPTORS, RETINOIC ACID; RETINOID X RECEPTORS; VISION, OCULAR; VITAMIN A; VITAMIN A DEFICIENCY;

EID: 84890840898     PISSN: 0163769X     EISSN: None     Source Type: Journal    
DOI: 10.1210/er.2012-1071     Document Type: Review

References (178)

1. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc. 1976;35:1332-1338
2. Palczewski K. Chemistry and biology of vision. J Biol Chem. 2012;287:1612-1619
3. von Lintig J. Metabolism of carotenoids and retinoids related to vision. J Biol Chem. 2012;287:1627-1634
4. Wolf G. The discovery of the visual function of vitamin A. J Nutr. 2001;131:1647-1650
5. Mellanby E. Skeletal changes affecting the nervous system produced in young dogs by diets deficient in vitamin A. J Physiol. 1941;99:467-486
6. Solon FS, Solon MS, Mehansho H, et al. Evaluation of the effect of vitamin A-fortified margarine on the vitamin A status of preschool Filipino children. Eur J Clin Nutr. 1996;50:720-723
7. Morriss-Kay GM, Sokolova N. Embryonic development and pattern formation. FASEB J. 1996;10:961-968
8. Cantorna MT, Nashold FE, Chun TY, Hayes CE. Vitamin Adown-regulation of IFN-synthesis in cloned mouse Th1lymphocytes depends on the CD28 costimulatory pathway. J Immunol. 1996;156:2674-2679
9. Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol. 2011;226:322-330
10. Eskild LW, Hansson V. Vitamin A functions in the reproductive organs. In: Blomhoff R, ed. Vitamin A in Health and Disease. Boca Raton, FL: CRC Press; 1994:531-559
11. Sommer A, West KP Jr. 1996 Vitamin A Deficiency: Health, Survival, and Vision. New York, NY: Oxford University Press; 1996
12. Harrison EH. Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. Biochim Biophys Acta. 2012;1821:70-77
13. D'Ambrosio DN, Clugston RD, Blaner WS. Vitamin A metabolism: an update. Nutrients. 2011;3:63-103
14. Blomhoff R, Wake K. Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J. 1991;5:271-277
15. Blaner WS, Obunike JC, Kurlandsky SB, et al. Lipoprotein lipase hydrolysis of retinyl ester. Possible implications for retinoid uptake by cells. J Biol Chem. 1994;269:16559-16565
16. Blomstrand R, Werner B. Studies on the intestinal absorption of radioactive β-carotene and vitamin A in man. Conversion of β-carotene into vitamin A. Scand J Clin Lab Invest. 1967;19:339-345
17. Harrison EH, Hussain MM. Mechanisms involved in the intestinal digestion and absorption of dietary vitamin A. J Nutr. 2001;131:1405-1408
18. Cooper AD. Hepatic uptake of chylomicron remnants. J Lipid Res. 1997;38:2173-2192
19. Soprano DR, Blaner WS. Plasma retinol-binding protein. In: Sporn MB, Roberts AB, Goodman DS, eds. The Retinoids, Biology, Chemistry and Medicine. New York, NY:Raven Press; 1994:257-282
20. Episkopou V, Maeda S, Nishiguchi S, et al. Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone. Proc Natl Acad Sci USA. 1993;90:2375-2379
21. van Bennekum AM, Wei S, Gamble MV, et al. Biochemical basis for depressed serum retinol levels in transthyretindeficient mice. J Biol Chem. 2001;276:1107-1113
22. Vogel S, Gamble MV. Retinoid uptake, metabolism and transport. In: Nau H, Blaner WS, eds. Handbook of Experimental Pharmacology, The Retinoids. New York, NY:Raven Press; 1999:31-96
23. Niemeier A, Niedzielska D, Secer R, et al. Uptake of postprandial lipoproteins into bone in vivo: impact on osteoblast function. Bone. 2008;43:230-237
24. Kawaguchi R, Yu J, Honda J, et al. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science. 2007;315:820-825
25. Kurlandsky SB, Gamble MV, Ramakrishnan R, Blaner WS. Plasma delivery of retinoic acid to tissues in the rat. J Biol Chem. 1995;270:17850-17857
26. Bastien J, Rochette-Egly C. Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene. 2004;328:1-16
27. Mic FA, Molotkov A, Benbrook DM, Duester G. Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis. Proc Natl Acad Sci USA. 2003;100:7135-7140
28. Kane MA, Folias AE, Pingitore A, et al. Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion. Proc Natl Acad Sci USA. 2010;107:21884-21889
29. Nagy L, Kao HY, Chakravarti D, et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell. 1997;89:373-380
30. Chen JD, Umesono K, EvansRM.SMRTisoforms mediate repression and anti-repression of nuclear receptor heterodimers. Proc Natl Acad Sci USA. 1996;93:7567-7571
31. Weston AD, Blumberg B, Underhill TM.Active repression by unliganded retinoid receptors in development: less is sometimes more. J Cell Biol. 2003;161:223-228
32. Weston AD, Chandraratna RA, Torchia J, Underhill TM. Requirement for RAR-mediated gene repression in skeletal progenitor differentiation. J Cell Biol. 2002;158:39-51
33. Williams JA, Kane M, Okabe T, et al. Endogenous retinoids in mammalian growth plate cartilage: analysis and roles in matrix homeostasis and turnover. J Biol Chem. 2010;285:36674-36681
34. Glass CK, Rosenfeld MG, Rose DW, et al. Mechanisms of transcriptional activation by retinoic acid receptors. Biochem Soc Trans. 1997;25:602-605
35. Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995;83:841-850
36. Bocher V, Pineda-Torra I, Fruchart JC, Staels B. PPARs: transcription factors controlling lipid and lipoprotein metabolism. Ann NY Acad Sci. 2002;967:7-18
37. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000;43:527-550
38. Berry DC, Noy N. Is PPARβ/- a retinoid receptor? PPAR Res. 2007;2007:73256
39. Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell. 2007;129:723-733
40. Wolf G. Retinoic acid as cause of cell proliferation or cell growth inhibition depending on activation of one of two different nuclear receptors. Nutr Rev. 2008;66:55-59
41. Stehlin-Gaon C, Willmann D, Zeyer D, et al. All-trans retinoic acid is a ligand for the orphan nuclear receptor RORβ. Nat Struct Biol. 2003;10:820-825
42. Jetten AM. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal. 2009;7:e003. 43. Roforth MM, Liu G, Khosla S, Monroe DG. Examination of nuclear receptor expression in osteoblasts reveals Rorβ as an important regulator of osteogenesis. J Bone Miner Res. 2012;27:891-901
43. Roforth MM, Liu G, Khosla S, Monroe DG. Examination of nuclear receptor expression in osteoblasts reveals Rorβ as an important regulator of osteogenesis. J Bone Miner Res. 2012;27:891-901
44. CanonE, Cosgaya JM, Scsucova S, Aranda A. Rapid effects of retinoic acid on CREB and ERK phosphorylation in neuronal cells. Mol Biol Cell. 2004;15:5583-5592
45. Aggarwal S, Kim SW, Cheon K, Tabassam FH, Yoon JH, Koo JS. Nonclassical action of retinoic acid on the activation of the cAMP response element-binding protein in normal human bronchial epithelial cells. Mol Biol Cell. 2006; 17:566-575
46. Chen N, Napoli JL. All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARα. FASEB J. 2008;22:236-245
47. Chen N, Onisko B, Napoli JL. The nuclear transcription factor RARα associates with neuronal RNA granules and suppresses translation. J Biol Chem. 2008;283:20841-20847
48. Poon MM, Chen L. Retinoic acid-gated sequence-specific translational control by RARα. Proc Natl Acad Sci USA.2008;105:20303-20308
49. Ziouzenkova O, Orasanu G, Sharlach M, et al. Retinaldehyde represses adipogenesis and diet-induced obesity. Nat Med. 2007;13:695-702
50. Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. J Neurobiol. 2006;66:606-630
51. Niederreither K, Dolle P. Retinoic acid in development: towards an integrated view. Nat Rev Genet. 2008;9:541-553
52. Humphrey JH, West KP Jr, Sommer A. Vitamin A deficiency and attributable mortality among under-5-yearolds. Bull World Health Organ. 1992;70:225-232
53. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid.N Engl J Med. 1979;300:329-333
54. Siddikuzzaman, Guruvayoorappan C, Berlin Grace VM. All trans retinoic acid and cancer. Immunopharmacol Immunotoxicol. 2011;33:241-249
55. Furr HC, Amedee-Manesme O, Clifford AJ, et al. Vitamin A concentrations in liver determined by isotope dilution assay with tetradeuterated vitamin A and by biopsy in generally healthy adult humans. Am J Clin Nutr. 1989;49:713-716
56. Ballew C, Bowman BA, Sowell AL, Gillespie C. Serum retinol distributions in residents of the United States: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2001;73:586-593
57. Gillespie C, Ballew C, Bowman BA, Donehoo R, Serdula MK. Intraindividual variation in serum retinol concentrations among participants in the third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2004;79:625-632
58. Underwood BA, Loerch JD, Lewis KC. Effects of dietary vitamin A deficiency, retinoic acid and protein quantity and quality on serially obtained plasma and liver levels of vitamin A in rats. J Nutr. 1979;109:796-806
59. Tanumihardjo SA. Assessing vitamin A status: past, present and future. J Nutr. 2004;134:290S-293S.
60. Tanumihardjo SA. Vitamin A: biomarkers of nutrition for development. Am J Clin Nutr. 2011;94:658S-665S.
61. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83:191-201
62. Croquet V, Pilette C, Lespine A, et al. Hepatic hyper-vitaminosis A: importance of retinyl ester level determination. Eur J Gastroenterol Hepatol. 2000;12:361-364
63. Krasinski SD, Russell RM, Otradovec CL, et al. Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinol-binding protein, retinyl esters, carotene, α-tocopherol, and cholesterol among elderly people and young adults: increased plasma retinyl esters among vitamin A-supplement users. Am J Clin Nutr. 1989;49:112-120
64. Ballew C, Bowman BA, Russell RM, Sowell AL, Gillespie C. Serum retinyl esters are not associated with biochemicalmarkers of liver dysfunction in adult participants in the third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Am J Clin Nutr. 2001;73: 934-940
65. Krasinski SD, Cohn JS, Schaefer EJ, Russell RM.Postprandial plasma retinyl ester response is greater in older subjects compared with younger subjects. Evidence for delayed plasma clearance of intestinal lipoproteins. J Clin Invest. 1990;85:883-892
66. Hollander D, Dadufalza V. Influence of aging on vitamin A transport into the lymphatic circulation. Exp Gerontol. 1990;25:61-65
67. Olson JA. Hypovitaminosis A: contemporary scientific issues.J Nutr. 1994;124:1461S-1466S.
68. Lascari AD. Carotenemia. A review. Clin Pediatr (Phila). 1981;20:25-29
69. Walker A, Zimmerman MR, Leakey RE.Apossible case of hypervitaminosis A in Homo erectus. Nature. 1982;296:248-250
70. Lips P. Hypervitaminosis A and fractures. N Engl J Med.2003;348:347-349
71. Kane EK. Arctic explorations in 1853, 1854, 1855. Vol 1.New York, NY: Arno Press and the New York Times; 1971
72. Bickel L Mawson's Will: The greatest polar survival story ever written. Hanover, NH: Steerforth Press; 2000
73. Lam HS, Chow CM, Poon WT, et al. Risk of vitamin A toxicity from candy-like chewable vitamin supplements for children. Pediatrics. 2006;118:820-824
74. Myhre AM, Carlsen MH, Bohn SK, Wold HL, Laake P, Blomhoff R. Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am J Clin Nutr. 2003;78:1152-1159
75. Kneissel M, Studer A, Cortesi R, Susa M.Retinoid-induced bone thinning is caused by subperiosteal osteoclast activity in adult rodents. Bone. 2005;36:202-214
76. Lind T, Lind PM, Jacobson A, et al. High dietary intake of retinol leads to bone marrow hypoxia and diaphyseal endosteal mineralization in rats. Bone. 2011;48:496-506
77. Johansson S, Lind PM, Hakansson H, Oxlund H, Orberg J, Melhus H. Subclinical hypervitaminosis A causes fragile bones in rats. Bone. 2002;31:685-689
78. Halkier-Sorensen L, Laurberg G, Andresen J. Bone changes in children on long-term treatment with etretinate. J Am Acad Dermatol. 1987;16:999-1006
79. Cuny JF, Schmutz JL, Terver MN, et al. Rheumatologiceffects of etretinate [in French]. Ann Dermatol Venereol.1989;116:95-102
80. Saltzman MD, King EC. Central physeal arrests as a manifestation of hypervitaminosis A. J Pediatr Orthop. 2007;27:351-353
81. Rothenberg AB, Berdon WE, Woodard JC, Cowles RA. Hypervitaminosis A-induced premature closure of epiphyses(physeal obliteration) in humans and calves (hyenadisease): a historical review of the human and veterinaryliterature. Pediatr Radiol. 2007;37:1264-1267
82. Jowsey J, Riggs BL. Bone changes in a patient with hypervitaminosis A. J Clin Endocrinol Metab. 1968;28:1833-1835
83. Miller JH, Hayon II. Bone scintigraphy in hypervitaminosis A. AJR Am J Roentgenol. 1985;144:767-768. 84. Frame B, Jackson CE, Reynolds WA, Umphrey JE. Hypercalcemia and skeletal effects in chronic hypervitaminosis A. Ann Intern Med. 1974;80:44-48
84. Frame B, Jackson CE, Reynolds WA, Umphrey JE. Hypercalcemia and skeletal effects in chronic hypervitaminosis A. Ann Intern Med
85. Baxi SC, Dailey GE III. Hypervitaminosis A. A cause of hypercalcemia. West J Med. 1982;137:429-431
86. Bhalla K, Ennis DM, Ennis ED. Hypercalcemia caused by iatrogenic hypervitaminosis A. J Am Diet Assoc. 2005;105:119-121
87. Vyas AK, White NH. Case of hypercalcemia secondary to hypervitaminosis A in a 6-year-old boy with autism. CaseRep Endocrinol. 2011;2011:424712
88. Bergman SM, O'Mailia J, Krane NK, Wallin JD. Vitamin-A-induced hypercalcemia: response to corticosteroids.Nephron. 1988;50:362-364
89. ConawayHH,Pirhayati A, Persson E, et al. Retinoids stimulate periosteal bone resorption by enhancing RANKL, a response inhibited by monomeric glucocorticoid receptor. J Biol Chem. 2011;286:31425-31436
90. Trumbo P, Yates AA, Schlicker S, Poos M. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. JAmDiet Assoc. 2001;101:294-301
91. Melhus H, Michaelsson K, Kindmark A, et al. Excessive dietary intake of vitaminAis associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med. 1998;129:770-778
92. Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med. 2003; 348:287-294
93. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women.JAMA. 2002;287:47-54
94. Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res. 2002;17:1349-1358
95. Opotowsky AR, Bilezikian JP. Serum vitamin A concentration and the risk of hip fracture among women 50 to 74 years old in the United States: a prospective analysis of theNHANES I follow-up study. Am J Med. 2004;117:169-174
96. Forsmo S, Fjeldbo SK, Langhammer A. Childhood cod liver oil consumption and bone mineral density in a population-based cohort of peri- and postmenopausal women: the Nord-Trondelag Health Study.AmJ Epidemiol. 2008;167:406-411
97. Lim LS, Harnack LJ, Lazovich D, Folsom AR. Vitamin A intake and the risk of hip fracture in postmenopausalwomen: the Iowa Women's Health Study. Osteoporos Int. 2004;15:552-559
98. Macdonald HM, New SA, Golden MH, Campbell MK,Reid DM. Nutritional associations with bone loss during the menopausal transition: evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids. Am J Clin Nutr. 2004;79:155-165
99. Penniston KL, Weng N, Binkley N, Tanumihardjo SA. Serum retinyl esters are not elevated in postmenopausal women with and without osteoporosis whose preformed vitamin A intakes are high. Am J Clin Nutr. 2006;84: 1350-1356
100. Wolf RL, Cauley JA, Pettinger M, et al. Lack of a relation between vitamin and mineral antioxidants and bone mineral density: results from the Women's Health Initiative. Am J Clin Nutr. 2005;82:581-588
101. Kaptoge S, Welch A, McTaggart A, et al. Effects of dietary nutrients and food groups on bone loss from the proximal femur in men and women in the 7th and 8th decades of age.Osteoporos Int. 2003;14:418-428
102. Sowers MF, Wallace RB. Retinol, supplemental vitamin A and bone status. J Clin Epidemiol. 1990;43:693-699
103. Kawahara TN, Krueger DC, Engelke JA, Harke JM, Binkley NC. Short-term vitamin A supplementation does not affect bone turnover in men. J Nutr. 2002;132:1169-1172
104. Rejnmark L, Vestergaard P, Charles P, et al. vitamin A intake on bone mineral density and fracture risk in perimenopausal women. Osteoporos Int. 2004;15:872-880
105. Ballew C, Galuska D, Gillespie C. High serum retinyl esters are not associated with reduced bone mineral density in the Third National Health and Nutrition Examination Survey, 1988-1994. J Bone Miner Res. 2001;16:2306-2312
106. Vestergaard P, Rejnmark L, Mosekilde L. High-dose treatment with vitamin A analogues and risk of fractures. Arch Dermatol. 2010;146:478-482
107. Barker ME, McCloskey E, Saha S, et al. Serum retinoids and β-carotene as predictors of hip and other fractures in elderly women. J Bone Miner Res. 2005;20:913-920
108. Maggio D, Barabani M, Pierandrei M, et al. Marked decrease in plasma antioxidants in aged osteoporoticwomen: results of a cross-sectional study. J Clin Endocrinol Metab. 2003;88:1523-1527
109. Maggio D, Polidori MC, Barabani M, et al. Low levels of carotenoids and retinol in involutional osteoporosis. Bone. 2006;38:244-248
110. Houtkooper LB, Ritenbaugh C, Aickin M, et al. Nutrients, body composition and exercise are related to change in bone mineral density in premenopausal women. J Nutr. 1995;125:1229-1237
111. Freudenheim JL, Johnson NE, Smith EL. Relationships between usual nutrient intake and bone-mineral content of women 35-65 years of age: longitudinal and cross-sectional analysis. Am J Clin Nutr. 1986;44:863-876
112. Ross AC, Taylor CL, Yaktine AL, Del Valle HB Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011
113. Glendenning P, Inderjeeth CA. Vitamin D: methods of 25 hydroxyvitamin D analysis, targeting at risk populations and selecting thresholds of treatment. Clin Biochem. 2012;45:901-906
114. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367:40-49
115. Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, Snetselaar LG, Chen Z. Vitamin A and retinol intakes and the risk of fractures among participants of the Women's Health Initiative Observational Study. Am J Clin Nutr. 2009;89:323-330
116. Mata-Granados JM, Cuenca-Acevedo R, Luque de Castro MD, Sosa M, Quesada-Gomez JM. Vitamin D deficiency and high serum levels of vitamin A increase the risk of osteoporosis evaluated by quantitative ultrasound measurements (QUS) in postmenopausal Spanish women. Clin Biochem. 2010;43:1064-1068
117. Mata-Granados JM, Cuenca-Acevedo JR, Luque de Castro MD, Holick MF, Quesada-Gomez JM. Vitamin D insufficiency together with high serum levels of vitamin A increases the risk for osteoporosis in postmenopausal women. Arch Osteoporos. 2013;8:124
118. Lips P. VitaminDstatus and nutrition in Europe and Asia. J Steroid Biochem Mol Biol. 2007;103:620-625
119. Langlois K, Greene-Finestone L, Little J, Hidiroglou N, Whiting S. Vitamin D status of Canadians as measured in the 2007 to 2009 Canadian Health Measures Survey. Health Rep. 2010;21:47-55
120. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31:48-54
121. Cho DY, Frey RA, Guffy MM, Leipold HW. Hypervitaminosis A in the dog. Am J Vet Res. 1975;36:1597-1603
122. Veltmann JR Jr, Jensen LS, Rowland GN. Excess dietary vitamin A in the growing chick: effect of fat source and vitamin D. Poult Sci. 1986;65:153-163
123. Clark I, Smith MR. Effects of hypervitaminosisAandDon skeletal metabolism. J Biol Chem. 1964;239:1266-1271
124. Aburto A, EdwardsHMJr, Britton WM. The influence of vitaminAon the utilization and amelioration of toxicity of cholecalciferol, 25-hydroxycholecalciferol, and 1,25 dihydroxycholecalciferol in young broiler chickens. Poult Sci.1998;77:585-593
125. Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001;16:1899-1905
126. Tata JR. Signalling through nuclear receptors. Nat Rev Mol Cell Biol. 2002;3:702-710
127. Carlberg C. Lipid soluble vitamins in gene regulation. Biofactors. 1999;10:91-97
128. Martin TJ, Seeman E. Bone remodelling: its local regulation and the emergence of bone fragility. Best Pract Res Clin Endocrinol Metab. 2008;22:701-722
129. Chambers TJ, Fuller K. How are osteoclasts induced to resorb bone? Ann NY Acad Sci. 2011;1240:1-6
130. Lerner UH. Osteoclast formation and resorption. Matrix Biol. 2000;19:107-120
131. Lorenzo J, Horowitz M, Choi Y. Osteoimmunology: interactions of the bone and immune system. Endocr Rev.2008;29:403-440
132. Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol. 2009;5:667-676
133. Nakashima T, Hayashi M, Fukunaga T, et al. Evidence for osteocyte regulation of bone homeostasis throughRANKL expression. Nat Med. 2011;17:1231-1234
134. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'BrienCA.Matrix-embedded cells control osteoclast formation. Nat Med. 2011;17:1235-1241
135. Rho J, Altmann CR, Socci ND, et al. Gene expression profiling of osteoclast differentiation by combined suppression subtractive hybridization (SSH) and cDNA microarray analysis. DNA Cell Biol. 2002;21:541-549
136. Nakashima T, Takayanagi H. New regulation mechanisms of osteoclast differentiation. Ann NY Acad Sci.2011;1240:E13-E18
137. Henriksen K, Bollerslev J, Everts V, Karsdal MA. Osteoclast activity and subtypes as a function of physiology and pathology-implications for future treatments of osteoporosis. Endocr Rev. 2011;32:31-63
138. Strauss MB, Maddock S. The relation of increased intraabdominal pressure to the liver lesions of eclampsia. Am J Pathol. 1934;10:821-825
139. Barnicot NA. Local action of calciferol and vitamin A on bone. Nature. 1948;162:848
140. Fell HB, Mellanby E. The effect of hypervitaminosis A on embryonic limb bones cultivated in vitro. J Physiol. 1952; 116:320-349
141. Raisz LG. Bone resorption in tissue culture. Factors influencing the response to parathyroid hormone. J Clin Invest. 1965;44:103-116
142. Poulain S, Evenou F, Carre MC, Corbel S, Vignaud JM, Martinet N. Vitamin A/retinoids signalling in the human lung. Lung Cancer. 2009;66:1-7
143. Zhou DC, Kim SH, Ding W, Schultz C, Warrell RP Jr, Gallagher RE. Frequent mutations in the ligand-binding domain ofPML-RARα after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo. Blood. 2002;99:1356-1363
144. Schmidt CK, Brouwer A, Nau H. Chromatographic analysis of endogenous retinoids in tissues and serum. Anal Biochem. 2003;315:36-48
145. Kane MA, Chen N, Sparks S, Napoli JL. Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS. Biochem J. 2005;388:363-369
146. DaviesMR,Ribeiro LR, Downey-JonesM,NeedhamMR, Oakley C, Wardale J. Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic joint. Arthritis Rheum. 2009;60:1722-1732
147. WrayAE, Okita N, RossAC.Cortical and trabecular bone, bone mineral density, and resistance to ex vivo fracture are not altered in response to life-long vitamin A supplementation in aging rats. J Nutr. 2011;141:660-666
148. Raisz LG, Simmons HA, Gworek SC, Eilon G. Studies on congenital osteopetrosis in microphthalmic mice using organ cultures: impairment of bone resorption in response to physiologic stimulators. J Exp Med. 1977;145:857-865
149. Delaisse JM, Eeckhout Y, Vaes G. Bone-resorbing agents affect the production and distribution of procollagenase as well as the activity of collagenase in bone tissue. Endocrinology. 1988;123:264-276
150. Togari A, Kondo M, Arai M, Matsumoto S. Effects of retinoic acid on bone formation and resorption in cultured mouse calvaria. Gen Pharmacol. 1991;22:287-292
151. Kindmark A, Melhus H, Ljunghall S, Ljunggren O. Inhibitory effects of 9-cis and all-trans retinoic acid on 1,25(OH)2 vitamin D3-induced bone resorption. Calcif Tissue Int. 1995;57:242-244
152. Conaway HH, Grigorie D, Lerner UH. Differential effects of glucocorticoids on bone resorption in neonatal mouse calvariae stimulated by peptide and steroid-like hormones. J Endocrinol. 1997;155:513-521
153. Hough S, Avioli LV, Muir H, et al. Effects of hypervitaminosis A on the bone and mineral metabolism of the rat. Endocrinology. 1988;122:2933-2939
154. Scheven BA, Hamilton NJ. Retinoic acid and 1,25-dihydroxyvitamin D3 stimulate osteoclast formation by different mechanisms. Bone. 1990;11:53-59
155. Conaway HH, Persson E, Halen M, et al. Retinoids inhibit differentiation of hematopoietic osteoclast progenitors. FASEB J. 2009;23:3526-3538
156. Thavarajah M, Evans DB, Kanis JA. 1,25(OH)2D3 induces differentiation of osteoclast-like cells from human bone marrow cultures. Biochem Biophys Res Commun. 1991;176:1189-1195
157. Hata K, Kukita T, Akamine A, Kukita A, Kurisu K. Trypsinized osteoclast-like multinucleated cells formed in rat bone marrow cultures efficiently form resorption lacunae on dentine. Bone. 1992;13:139-146
158. Wang X, Wu J, Shidoji Y, et al. Effects of geranylgeranoic acid in bone: induction of osteoblast differentiation and inhibition of osteoclast formation. J Bone Miner Res. 2002;17:91-100
159. Chiba M, Teitelbaum SL, Cao X, Ross FP. Retinoic acid stimulates expression of the functional osteoclast integrin α v β 3: transcriptional activation of the β 3 but not the α v gene. J Cell Biochem. 1996;62:467-475
160. Hu L, Lind T, Sundqvist A, Jacobson A, Melhus H. Retinoic acid increases proliferation of human osteoclast progenitors and inhibits RANKL-stimulated osteoclast differentiation by suppressing RANK. PLoS One. 2010;5: e13305
161. Saneshige S, Mano H, Tezuka K, et al. Retinoic acid directly stimulates osteoclastic bone resorption and gene expression of cathepsin K/OC-2. Biochem J. 1995;309:721- 724
162. Lakkakorpi PT, Vaananen HK. Kinetics of the osteoclast cytoskeleton during the resorption cycle in vitro. J BoneMiner Res. 1991;6:817-826
163. O'Neill RP, Jones SJ, Boyde A, Taylor ML, Arnett TR. Effect of retinoic acid on the resorptive activity of chick osteoclasts in vitro. Bone. 1992;13:23-27
164. Oreffo RO, Teti A, Triffitt JT, Francis MJ, Carano A, Zallone AZ. Effect of vitamin A on bone resorption: evidence for direct stimulation of isolated chicken osteoclasts by retinol and retinoic acid. J Bone Miner Res. 1988;3: 203-210
165. Bonewald LF, Oreffo RO, Lee CH, Park-Snyder S, Twardzik D, Mundy GR. Effects of retinol on activation of latent transforming growth factor-β by isolated osteoclasts. Endocrinology. 1997;138:657-666
166. Trechsel U, Stutzer A, Fleisch H. Hypercalcemia induced with an arotinoid in thyroparathyroidectomized rats.New model to study bone resorption in vivo. J Clin Invest. 1987; 80:1679-1686
167. Lind T, Hu L, Lind PM, et al. Microarray profiling of diaphyseal bone of rats suffering from hypervitaminosis A. Calcif Tissue Int. 2012;90:219-229
168. Kini AR, Peterson LA, Tallman MS, Lingen MW. Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid. Blood. 2001;97:3919-3924
169. Skillington J, Choy L, Derynck R. Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J Cell Biol. 2002; 159:135-146
170. Wan DC, Shi YY, Nacamuli RP, Quarto N, Lyons KM, Longaker MT. Osteogenic differentiation of mouse adipose-derived adult stromal cells requires retinoic acid and bone morphogenetic protein receptor type IB signaling. Proc Natl Acad Sci USA. 2006;103:12335-12340
171. ZhangW,Deng ZL, Chen L, et al. Retinoic acids potentiate BMP9-induced osteogenic differentiation of mesenchymal progenitor cells. PLoS One. 2010;5:e11917
172. Wang A, Ding X, Sheng S, Yao Z. Retinoic acid inhibits osteogenic differentiation of rat bone marrow stromal cells. Biochem Biophys Res Commun. 2008;375:435-439
173. Tanaka K, Tanaka S, Sakai A, Ninomiya T, Arai Y, Nakamura T. 2010 Deficiency of vitamin A delays bone healing process in association with reduced BMP2 expression after drill-hole injury in mice. Bone. 2010;47: 1006-1012
174. Cowan CM, Aalami OO, Shi YY, et al. Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover. Tissue Eng. 2005;11:645-658
175. Shimono K, Tung WE, Macolino C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-agonists. Nat Med. 2011;17:454-460
176. Kaplan FS, Shore EM. Derailing heterotopic ossification and RARing to go. Nat Med. 2011;17:420-421
177. Zasloff MA, Rocke DM, Crofford LJ, Hahn GV, Kaplan FS. Treatment of patients who have fibrodysplasia ossificans progressiva with isotretinoin. Clin Orthop Relat Res. 1998;121-129
178. Khosla S, Melton LJ III, Riggs BL. The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? J Bone Miner Res. 2011;26:441-451