Skip to main content
Top
Published in: Calcified Tissue International 3/2017

01-03-2017 | Original Research

Theobromine Upregulates Osteogenesis by Human Mesenchymal Stem Cells In Vitro and Accelerates Bone Development in Rats

Authors: Bret H. Clough, Joni Ylostalo, Elizabeth Browder, Eoin P. McNeill, Thomas J. Bartosh, H. Ralph Rawls, Tetsuo Nakamoto, Carl A. Gregory

Published in: Calcified Tissue International | Issue 3/2017

Login to get access

Abstract

Theobromine (THB) is one of the major xanthine-like alkaloids found in cacao plant and a variety of other foodstuffs such as tea leaves, guarana and cola nuts. Historically, THB and its derivatives have been utilized to treat cardiac and circulatory disorders, drug-induced nephrotoxicity, proteinuria and as an immune-modulator. Our previous work demonstrated that THB has the capacity to improve the formation of hydroxyl-apatite during tooth development, suggesting that it may also enhance skeletal development. With its excellent safety profile and resistance to pharmacokinetic elimination, we reasoned that it might be an excellent natural osteoanabolic supplement during pregnancy, lactation and early postnatal growth. To determine whether THB had an effect on human osteoprogenitors, we subjected primary human bone marrow mesenchymal stem cells (hMSCs) to osteogenic assays after exposure to THB in vitro and observed that THB exposure increased the rate of osteogenesis and mineralization by hMSCs. Moreover, THB exposure resulted in a list of upregulated mRNA transcripts that best matched an osteogenic tissue expression signature as compared to other tissue expression signatures archived in several databases. To determine whether oral administration of THB resulted in improved skeletal growth, we provided pregnant rats with chow supplemented with THB during pregnancy and lactation. After weaning, offspring received THB continuously until postnatal day 50 (approximately 10 mg kg−1 day−1). Administration of THB resulted in neonates with larger bones, and 50-day-old offspring accumulated greater body mass, longer and thicker femora and superior tibial trabecular parameters. The accelerated growth did not adversely affect the strength and resilience of the bones. These results indicate that THB increases the osteogenic potential of bone marrow osteoprogenitors, and dietary supplementation of a safe dose of THB to expectant mothers and during the postnatal period could accelerate skeletal development in their offspring.
Appendix
Available only for authorised users
Literature
1.
go back to reference Smit HJ (2011) Theobromine and the pharmacology of cocoa. Handb Exp Pharmacol 200:201–234CrossRef Smit HJ (2011) Theobromine and the pharmacology of cocoa. Handb Exp Pharmacol 200:201–234CrossRef
2.
go back to reference Stavric B (1988) Methylxanthines: toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines. Food Chem Toxicol 26:725–733CrossRefPubMed Stavric B (1988) Methylxanthines: toxicity to humans. 3. Theobromine, paraxanthine and the combined effects of methylxanthines. Food Chem Toxicol 26:725–733CrossRefPubMed
3.
go back to reference Champion S, Lapidus N, Cherié G, Spagnoli V, Oliary J, Solal AC (2014) Pentoxifylline in heart failure: a meta-analysis of clinical trials. Cardiovasc Ther 32:159–162CrossRefPubMed Champion S, Lapidus N, Cherié G, Spagnoli V, Oliary J, Solal AC (2014) Pentoxifylline in heart failure: a meta-analysis of clinical trials. Cardiovasc Ther 32:159–162CrossRefPubMed
4.
go back to reference Kaur J, Sodhi GS (1992) Diuretic activity of organomercury (II) complexes of theophylline and theobromine. J Inorg Biochem 48:305–310CrossRefPubMed Kaur J, Sodhi GS (1992) Diuretic activity of organomercury (II) complexes of theophylline and theobromine. J Inorg Biochem 48:305–310CrossRefPubMed
5.
go back to reference Skudicky D, Bergemann A, Sliwa K, Candy G, Sareli P (2001) Beneficial effects of pentoxifylline in patients with idiopathic dilated cardiomyopathy treated with angiotensin-converting enzyme inhibitors and carvedilol: results of a randomized study. Circulation 103:1083–1088CrossRefPubMed Skudicky D, Bergemann A, Sliwa K, Candy G, Sareli P (2001) Beneficial effects of pentoxifylline in patients with idiopathic dilated cardiomyopathy treated with angiotensin-converting enzyme inhibitors and carvedilol: results of a randomized study. Circulation 103:1083–1088CrossRefPubMed
6.
go back to reference Sliwa K, Skudicky D, Candy G, Bergemann A, Hopley M, Sareli P (2002) The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy. Eur J Heart Fail 4:305–309CrossRefPubMed Sliwa K, Skudicky D, Candy G, Bergemann A, Hopley M, Sareli P (2002) The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy. Eur J Heart Fail 4:305–309CrossRefPubMed
7.
go back to reference Nasiri-Toosi Z, Dashti-Khavidaki S, Khalili H, Lessan-Pezeshki M (2013) A review of the potential protective effects of pentoxifylline against drug-induced nephrotoxicity. Eur J Clin Pharmacol 69:1057–1073CrossRefPubMed Nasiri-Toosi Z, Dashti-Khavidaki S, Khalili H, Lessan-Pezeshki M (2013) A review of the potential protective effects of pentoxifylline against drug-induced nephrotoxicity. Eur J Clin Pharmacol 69:1057–1073CrossRefPubMed
8.
go back to reference Badri S, Dashti-Khavidaki S, Lessan-Pezeshki M, Abdollahi M (2011) A review of the potential benefits of pentoxifylline in diabetic and non-diabetic proteinuria. J Pharm Pharm Sci 14:128–137CrossRefPubMed Badri S, Dashti-Khavidaki S, Lessan-Pezeshki M, Abdollahi M (2011) A review of the potential benefits of pentoxifylline in diabetic and non-diabetic proteinuria. J Pharm Pharm Sci 14:128–137CrossRefPubMed
10.
go back to reference Noel C, Copin MC, Hazzan M, Labalette M, Susen S, Lelievre G, Dessaint JP (2000) Immunomodulatory effect of pentoxifylline during human allograft rejection: involvement of tumor necrosis factor-alpha and adhesion molecules. Transplantation 69:1102–1107CrossRefPubMed Noel C, Copin MC, Hazzan M, Labalette M, Susen S, Lelievre G, Dessaint JP (2000) Immunomodulatory effect of pentoxifylline during human allograft rejection: involvement of tumor necrosis factor-alpha and adhesion molecules. Transplantation 69:1102–1107CrossRefPubMed
11.
go back to reference Costantini TW, Deree J, Peterson CY, Putnam JG, Woon T, Loomis WH, Bansal V, Coimbra R (2010) Pentoxifylline modulates p47phox activation and downregulates neutrophil oxidative burst through PKA-dependent and -independent mechanisms. Immunopharmacol Immunotoxicol 32:82–91CrossRefPubMed Costantini TW, Deree J, Peterson CY, Putnam JG, Woon T, Loomis WH, Bansal V, Coimbra R (2010) Pentoxifylline modulates p47phox activation and downregulates neutrophil oxidative burst through PKA-dependent and -independent mechanisms. Immunopharmacol Immunotoxicol 32:82–91CrossRefPubMed
12.
go back to reference Rieneck K, Diamant M, Haahr PM, Schönharting M, Bendtzen K (1993) In vitro immunomodulatory effects of pentoxifylline. Immunol Lett 37:131–138CrossRefPubMed Rieneck K, Diamant M, Haahr PM, Schönharting M, Bendtzen K (1993) In vitro immunomodulatory effects of pentoxifylline. Immunol Lett 37:131–138CrossRefPubMed
13.
go back to reference Zoumas BL, Kreiser WR, Martin RA (1980) Theobromine and caffeine content in chocolate products. J Food Sci 45:314CrossRef Zoumas BL, Kreiser WR, Martin RA (1980) Theobromine and caffeine content in chocolate products. J Food Sci 45:314CrossRef
14.
go back to reference Craig WJ, Nguyen TT (1984) Caffeine and theobromine levels in cocoa and cocoa products. J Food Sci 49:302CrossRef Craig WJ, Nguyen TT (1984) Caffeine and theobromine levels in cocoa and cocoa products. J Food Sci 49:302CrossRef
15.
go back to reference Tarka SM Jr, Zoumas BL, Gans JH (1979) Short-term effects of graded levels of theobromine in laboratory rodents. Toxicol Appl Pharmacol 49:127–149CrossRefPubMed Tarka SM Jr, Zoumas BL, Gans JH (1979) Short-term effects of graded levels of theobromine in laboratory rodents. Toxicol Appl Pharmacol 49:127–149CrossRefPubMed
16.
go back to reference Nakamoto T, Simmons WB, Falster AU (1999) Products of apatite-forming-systems. US Patent US5919426A Nakamoto T, Simmons WB, Falster AU (1999) Products of apatite-forming-systems. US Patent US5919426A
17.
go back to reference Nakamoto T, Simmons WB, Falster AU (2001) Apatite-forming-systems: Methods and products. US Patent US 6183711 Nakamoto T, Simmons WB, Falster AU (2001) Apatite-forming-systems: Methods and products. US Patent US 6183711
18.
go back to reference Nakamoto T, Falster AU, Simmons WB (2016) Theobromine: a safe and effective alternative for fluoride in dentifrices. J Caffeine Res 6(1):1–9CrossRef Nakamoto T, Falster AU, Simmons WB (2016) Theobromine: a safe and effective alternative for fluoride in dentifrices. J Caffeine Res 6(1):1–9CrossRef
19.
go back to reference Amaechi BT, Porteous N, Ramalingam K, Mensinkai PK, Ccahuana Vasquez RA, Sadeghpour A, Nakamoto T (2013) Remineralization of artificial enamel lesions by theobromine. Caries Res 47:399–405CrossRefPubMed Amaechi BT, Porteous N, Ramalingam K, Mensinkai PK, Ccahuana Vasquez RA, Sadeghpour A, Nakamoto T (2013) Remineralization of artificial enamel lesions by theobromine. Caries Res 47:399–405CrossRefPubMed
20.
go back to reference Namgung R, Tsang RC (2000) Factors affecting newborn bone mineral content: in utero effects on newborn bone mineralization. Proc Nutr Soc 59:55–63CrossRefPubMed Namgung R, Tsang RC (2000) Factors affecting newborn bone mineral content: in utero effects on newborn bone mineralization. Proc Nutr Soc 59:55–63CrossRefPubMed
21.
go back to reference Habbick BF, Blakley PM, Houston CS, Snyder RE, Senthilselvan A, Nanson JL (1998) Bone age and growth in fetal alcohol syndrome. Alcohol Clin Exp Res 22:1312–1316CrossRefPubMed Habbick BF, Blakley PM, Houston CS, Snyder RE, Senthilselvan A, Nanson JL (1998) Bone age and growth in fetal alcohol syndrome. Alcohol Clin Exp Res 22:1312–1316CrossRefPubMed
22.
go back to reference Godfrey K, Walker-Bone K, Robinson S, Taylor P, Shore S, Wheeler T, Cooper C (2001) Neonatal bone mass: influence of parental birthweight, maternal smoking, body composition, and activity during pregnancy. J Bone Miner Res 16:1694–1703CrossRefPubMed Godfrey K, Walker-Bone K, Robinson S, Taylor P, Shore S, Wheeler T, Cooper C (2001) Neonatal bone mass: influence of parental birthweight, maternal smoking, body composition, and activity during pregnancy. J Bone Miner Res 16:1694–1703CrossRefPubMed
23.
go back to reference Curtis EM, Moon RJ, Dennison EM, Harvey NC (2014) Prenatal calcium and vitamin D intake, and bone mass in later life. Curr Osteoporos Rep 12:194–204CrossRefPubMed Curtis EM, Moon RJ, Dennison EM, Harvey NC (2014) Prenatal calcium and vitamin D intake, and bone mass in later life. Curr Osteoporos Rep 12:194–204CrossRefPubMed
24.
go back to reference Sanz-Salvador L, Garcia-Perez MA, Tarin JJ, Cano A (2015) Bone metabolic changes during pregnancy: a period of vulnerability to osteoporosis and fracture. Eur J Endocrinol 172:R53–R65CrossRefPubMed Sanz-Salvador L, Garcia-Perez MA, Tarin JJ, Cano A (2015) Bone metabolic changes during pregnancy: a period of vulnerability to osteoporosis and fracture. Eur J Endocrinol 172:R53–R65CrossRefPubMed
25.
go back to reference Gerin M, Jambon G, Fouque-Aubert A, Raybaud C, Cochat P, Claris O, Bacchetta J (2016) Neonatal transient hypophosphatemic hypercalciuric rickets in dizygous twins: a role for maternal alendronate therapy before pregnancy or antireflux medications? Arch Pediatr 23:957–962CrossRefPubMed Gerin M, Jambon G, Fouque-Aubert A, Raybaud C, Cochat P, Claris O, Bacchetta J (2016) Neonatal transient hypophosphatemic hypercalciuric rickets in dizygous twins: a role for maternal alendronate therapy before pregnancy or antireflux medications? Arch Pediatr 23:957–962CrossRefPubMed
26.
go back to reference French AE, Kaplan N, Lishner M, Koren G (2003) Taking bisphosphonates during pregnancy. Can Fam Physician 49:1281–1282PubMedPubMedCentral French AE, Kaplan N, Lishner M, Koren G (2003) Taking bisphosphonates during pregnancy. Can Fam Physician 49:1281–1282PubMedPubMedCentral
27.
go back to reference Rosenkranz HS, Ennever FK (1987) Evaluation of the genotoxicity of theobromine and caffeine. Food Chem Toxicol 25:247–251CrossRefPubMed Rosenkranz HS, Ennever FK (1987) Evaluation of the genotoxicity of theobromine and caffeine. Food Chem Toxicol 25:247–251CrossRefPubMed
28.
go back to reference Shively CA, White DM, Blauch JL, Tarka SM Jr (1984) Dominant lethal testing of theobromine in rats. Toxicol Lett 20:325–329CrossRefPubMed Shively CA, White DM, Blauch JL, Tarka SM Jr (1984) Dominant lethal testing of theobromine in rats. Toxicol Lett 20:325–329CrossRefPubMed
29.
go back to reference Drouillard DD, Vesell ES, Dvorchik BH (1978) Studies on theobromine disposition in normal subjects. Alterations induced by dietary abstention from or exposure to methylxanthines. Clin Pharmacol Ther 23:296–302CrossRefPubMed Drouillard DD, Vesell ES, Dvorchik BH (1978) Studies on theobromine disposition in normal subjects. Alterations induced by dietary abstention from or exposure to methylxanthines. Clin Pharmacol Ther 23:296–302CrossRefPubMed
30.
go back to reference Shively CA, Tarka SM Jr, Arnaud MJ, Dvorchik BH, Passananti GT, Vesell ES (1985) High levels of methylxanthines in chocolate do not alter theobromine disposition. Clin Pharmacol Ther 37:415–424CrossRefPubMed Shively CA, Tarka SM Jr, Arnaud MJ, Dvorchik BH, Passananti GT, Vesell ES (1985) High levels of methylxanthines in chocolate do not alter theobromine disposition. Clin Pharmacol Ther 37:415–424CrossRefPubMed
31.
go back to reference Gregory CA, Prockop DJ (2007) Fundementals of culture and characterization of mesenchymal stem/progenitor cells from bone marrow stroma. In: Freshney RI, Stacey GN, Auerbach JM (eds) Culture of human stem cells. Wiley-Liss, Hoboken, p 208 Gregory CA, Prockop DJ (2007) Fundementals of culture and characterization of mesenchymal stem/progenitor cells from bone marrow stroma. In: Freshney RI, Stacey GN, Auerbach JM (eds) Culture of human stem cells. Wiley-Liss, Hoboken, p 208
32.
go back to reference Zeitouni S, Krause U, Clough BH, Halderman H, Falster A, Blalock DT, Chaput CD, Sampson HW, Gregory CA (2012) Human mesenchymal stem cell-derived matrices for enhanced osteoregeneration. Sci Transl Med 4:132ra155CrossRef Zeitouni S, Krause U, Clough BH, Halderman H, Falster A, Blalock DT, Chaput CD, Sampson HW, Gregory CA (2012) Human mesenchymal stem cell-derived matrices for enhanced osteoregeneration. Sci Transl Med 4:132ra155CrossRef
33.
go back to reference Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4:P3CrossRefPubMed Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4:P3CrossRefPubMed
34.
go back to reference Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317CrossRefPubMed Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317CrossRefPubMed
35.
go back to reference Krause U, Seckinger A, Gregory CA (2011) Assays of osteogenic differentiation by cultured human mesenchymal stem cells. Methods Mol Biol 698:215–230CrossRefPubMed Krause U, Seckinger A, Gregory CA (2011) Assays of osteogenic differentiation by cultured human mesenchymal stem cells. Methods Mol Biol 698:215–230CrossRefPubMed
36.
go back to reference Johnsson MS, Nancollas GH (1992) The role of brushite and octacalcium phosphate in apatite formation. Crit Rev Oral Biol Med 3:61–82CrossRefPubMed Johnsson MS, Nancollas GH (1992) The role of brushite and octacalcium phosphate in apatite formation. Crit Rev Oral Biol Med 3:61–82CrossRefPubMed
37.
go back to reference Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PV, Komm BS, Javed A, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2005) Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem 280:33132–33140CrossRefPubMed Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PV, Komm BS, Javed A, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2005) Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem 280:33132–33140CrossRefPubMed
38.
go back to reference Dong YF, Soung DY, Schwarz EM, O’Keefe RJ, Drissi H (2006) Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J Cell Physiol 208:77–86CrossRefPubMed Dong YF, Soung DY, Schwarz EM, O’Keefe RJ, Drissi H (2006) Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J Cell Physiol 208:77–86CrossRefPubMed
39.
go back to reference Zhang R, Oyajobi BO, Harris SE, Chen D, Tsao C, Deng HW, Zhao M (2013) Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone 52:145–156CrossRefPubMed Zhang R, Oyajobi BO, Harris SE, Chen D, Tsao C, Deng HW, Zhao M (2013) Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone 52:145–156CrossRefPubMed
40.
go back to reference Kugimiya F, Kawaguchi H, Ohba S, Kawamura N, Hirata M, Chikuda H, Azuma Y, Woodgett JR, Nakamura K, Chung UI (2007) GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS ONE 2:e837CrossRefPubMedPubMedCentral Kugimiya F, Kawaguchi H, Ohba S, Kawamura N, Hirata M, Chikuda H, Azuma Y, Woodgett JR, Nakamura K, Chung UI (2007) GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS ONE 2:e837CrossRefPubMedPubMedCentral
41.
go back to reference Wang Z, Zhang JN, Hu XF, Chen XL, Wang XR, Zhao TT, Peng MJ, Zou P (2010) Effects of pentoxifylline on Wnt/beta-catenin signaling in mice chronically exposed to cigarette smoke. Chin Med J 123:2688–2694PubMed Wang Z, Zhang JN, Hu XF, Chen XL, Wang XR, Zhao TT, Peng MJ, Zou P (2010) Effects of pentoxifylline on Wnt/beta-catenin signaling in mice chronically exposed to cigarette smoke. Chin Med J 123:2688–2694PubMed
42.
go back to reference Jang YJ, Koo HJ, Sohn EH, Kang SC, Rhee DK, Pyo S (2015) Theobromine inhibits differentiation of 3T3-L1 cells during the early stage of adipogenesis via AMPK and MAPK signaling pathways. Food Funct 6:2365–2374CrossRefPubMed Jang YJ, Koo HJ, Sohn EH, Kang SC, Rhee DK, Pyo S (2015) Theobromine inhibits differentiation of 3T3-L1 cells during the early stage of adipogenesis via AMPK and MAPK signaling pathways. Food Funct 6:2365–2374CrossRefPubMed
43.
go back to reference Krause U, Harris S, Green A, Ylostalo J, Zeitouni S, Lee N, Gregory CA (2010) Pharmaceutical modulation of canonical Wnt signaling in multipotent stromal cells for improved osteoinductive therapy. Proc Natl Acad Sci USA 107:4147–4152CrossRefPubMedPubMedCentral Krause U, Harris S, Green A, Ylostalo J, Zeitouni S, Lee N, Gregory CA (2010) Pharmaceutical modulation of canonical Wnt signaling in multipotent stromal cells for improved osteoinductive therapy. Proc Natl Acad Sci USA 107:4147–4152CrossRefPubMedPubMedCentral
44.
go back to reference Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD, MacDougald OA (2002) Regulation of Wnt signaling during adipogenesis. J Biol Chem 277:30998–31004CrossRefPubMed Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD, MacDougald OA (2002) Regulation of Wnt signaling during adipogenesis. J Biol Chem 277:30998–31004CrossRefPubMed
45.
go back to reference Farmer SR (2005) Regulation of PPARgamma activity during adipogenesis. Int J Obes (Lond) 29(Suppl 1):S13–S16CrossRef Farmer SR (2005) Regulation of PPARgamma activity during adipogenesis. Int J Obes (Lond) 29(Suppl 1):S13–S16CrossRef
46.
go back to reference Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J, Farmer SR (2003) Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis. Biochem J 376:607–613CrossRefPubMedPubMedCentral Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J, Farmer SR (2003) Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis. Biochem J 376:607–613CrossRefPubMedPubMedCentral
47.
go back to reference Xu C, Wang J, Zhu T, Shen Y, Tang X, Fang L, Xu Y (2016) Cross-talking between PPAR and WNT signaling and its regulation in mesenchymal stem cell differentiation. Curr Stem Cell Res Ther 11(3):247–254CrossRefPubMed Xu C, Wang J, Zhu T, Shen Y, Tang X, Fang L, Xu Y (2016) Cross-talking between PPAR and WNT signaling and its regulation in mesenchymal stem cell differentiation. Curr Stem Cell Res Ther 11(3):247–254CrossRefPubMed
48.
go back to reference Takada I, Kouzmenko AP, Kato S (2009) Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol 5:442–447CrossRefPubMed Takada I, Kouzmenko AP, Kato S (2009) Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol 5:442–447CrossRefPubMed
49.
go back to reference Tarka SM Jr, Applebaum RS, Borzelleca JF (1986) Evaluation of the perinatal, postnatal and teratogenic effects of cocoa powder and theobromine in Sprague-Dawley/CD rats. Food Chem Toxicol 24:375–382CrossRefPubMed Tarka SM Jr, Applebaum RS, Borzelleca JF (1986) Evaluation of the perinatal, postnatal and teratogenic effects of cocoa powder and theobromine in Sprague-Dawley/CD rats. Food Chem Toxicol 24:375–382CrossRefPubMed
50.
go back to reference Inoue H, Kobayashi-Hattori K, Horiuchi Y, Oishi Y, Arai S, Takita T (2006) Regulation of the body fat percentage in developmental-stage rats by methylxanthine derivatives in a high-fat diet. Biosci Biotechnol Biochem 70:1134–1139CrossRefPubMed Inoue H, Kobayashi-Hattori K, Horiuchi Y, Oishi Y, Arai S, Takita T (2006) Regulation of the body fat percentage in developmental-stage rats by methylxanthine derivatives in a high-fat diet. Biosci Biotechnol Biochem 70:1134–1139CrossRefPubMed
51.
go back to reference Parfitt AM (1994) The two faces of growth: benefits and risks to bone integrity. Osteoporos Int 4:382–398CrossRefPubMed Parfitt AM (1994) The two faces of growth: benefits and risks to bone integrity. Osteoporos Int 4:382–398CrossRefPubMed
52.
go back to reference Heaney RP, Weaver CM (2005) Newer perspectives on calcium nutrition and bone quality. J Am Coll Nutr 24:574S–581SCrossRefPubMed Heaney RP, Weaver CM (2005) Newer perspectives on calcium nutrition and bone quality. J Am Coll Nutr 24:574S–581SCrossRefPubMed
53.
go back to reference Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602CrossRefPubMedPubMedCentral Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602CrossRefPubMedPubMedCentral
54.
go back to reference Seminara S, Rapisardi G, La Cauza F, Mattei P, Donzelli G (2000) Catch-up growth in short-at-birth NICU graduates. Horm Res 53:139–143PubMed Seminara S, Rapisardi G, La Cauza F, Mattei P, Donzelli G (2000) Catch-up growth in short-at-birth NICU graduates. Horm Res 53:139–143PubMed
55.
go back to reference van der Steen M, Hokken-Koelega AC (2016) Growth and metabolism in children born small for gestational age. Endocrinol Metab Clin North Am 45:283–294CrossRefPubMed van der Steen M, Hokken-Koelega AC (2016) Growth and metabolism in children born small for gestational age. Endocrinol Metab Clin North Am 45:283–294CrossRefPubMed
Metadata
Title
Theobromine Upregulates Osteogenesis by Human Mesenchymal Stem Cells In Vitro and Accelerates Bone Development in Rats
Authors
Bret H. Clough
Joni Ylostalo
Elizabeth Browder
Eoin P. McNeill
Thomas J. Bartosh
H. Ralph Rawls
Tetsuo Nakamoto
Carl A. Gregory
Publication date
01-03-2017
Publisher
Springer US
Published in
Calcified Tissue International / Issue 3/2017
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-016-0215-6

Other articles of this Issue 3/2017

Calcified Tissue International 3/2017 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.