title: Theobromine Upregulates Osteogenesis by Human Mesenchymal Stem Cells In Vitro and Accelerates Bone Development in Rats.
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-1day-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.
authors.affiliation: Institute for Regenerative Medicine, Texas A&M Health Science Center, Module C 5701 Airport Road, Temple, TX, 76502, USA.
authors.forename: Bret H
authors.initials: BH
authors.lastname: Clough
authors.affiliation: Department of Biology, University of Mary Hardin Baylor, 900 College Street, Belton, TX, 76513, USA.
authors.forename: Joni
authors.initials: J
authors.lastname: Ylostalo
authors.affiliation: Texas A&M Department of Comparative Medicine, College Station, TX, 77843, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Browder
authors.affiliation: Institute for Regenerative Medicine, Texas A&M Health Science Center, Module C 5701 Airport Road, Temple, TX, 76502, USA.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: McNeill
authors.affiliation: Institute for Regenerative Medicine, Texas A&M Health Science Center, Module C 5701 Airport Road, Temple, TX, 76502, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bartosh
authors.affiliation: Department of Comprehensive Dentistry, UT Health Science Center, San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA.
authors.forename: H Ralph
authors.initials: HR
authors.lastname: Rawls
authors.affiliation: Department of Physiology, 7th Floor Medical Education Building, LSU Health Sciences Center, New Orleans, LA, 70112, USA.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nakamoto
authors.affiliation: Institute for Regenerative Medicine, Texas A&M Health Science Center, Module C 5701 Airport Road, Temple, TX, 76502, USA. cgregory@medicine.tamhsc.edu.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Gregory
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D051381:Rats; D013805:Theobromine / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D013805:Theobromine
keywords: Anabolics; Nutrition; Preclinical studies; Stromal/stem cells; Theobromine